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FAMILIAL SPINAL CORD SYNDROMES (SPG)
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General principles Protein types Metabolic testing Familial Spastic Paraplegia + Ataxia CNS Dystonia Mitochondrial Motor neuron ALS Primary Lateral Sclerosis Ocular PNS: Motor; PN Systemic Disorders Spasticity: Other syndromes Cerebral palsy Spastic quadriplegic (CPSQ) Leukodystrophies Spastic Ataxias (SPAX) Spine disorders, Familial Spinal cord  From: Wikipedia Adolph Strümpell
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SPG: General Principles 11
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- Protein types
- Endoplasmic reticulum
- Mitochondrial
- Chaperone activity
- Lipid & Ganglioside metabolism
- Axon guidance & Synapse
- Golgi
- Myelination
- Transport proteins
- SPG3A: Atlastin; Dynamin, Vesicle recycling
- SPG4: Spastin; Microtubule cytoskeleton
- SPG10: KIF5A; Anterograde Transport
- SPG11: Spatacsin; Cargo trafficking
- SPG20: Spartin; Late endosomal components
- SPG22: SLC16A2; Iodothyronine transport
- SPG30: ATSV (KIF1A); Synaptic vesicle transport
- SPG 53: VPS37a; Endosomal sorting
- SPG58: KIF1C; Axon transport, Anterograde
- SPG59: USP8
- SPG60: WDR48
- SPG 88: KPNA3; Nuclear-Cytoplasmic transport
- ALS2 & IAHSP: Alsin; ? Vesicle transport
- BICD2: Axon transport
- Nucleotide metabolism, Purine
- Other
- SPG 44: GJA12; Gap junctions
- SPG 48: KIAA0415
- SPG 49: TECPR2; Autophagy
- SPG 61: ARL6IP1; Endoplasmic reticulum
- SPG 70: MARS; ARS, Cytoplasmic
- SPG 71: ZFR
- SPG 77: FARS2; ARS, Mitochondrial
- SPG 87: TMEM63C; Hyperosmolarity-activated channel
- ALDH18A1; Amino acid biosynthesis
- LYST: Membrane fusion & fission
- TPP1: Lysosomal exopeptidase
- SINO: KIDINS220; Axon & Dendrite development
Familial Spastic Paraplegia (Strumpell; FSP): Dominant
- SPG3A (FSP1)
19
● Atlastin (ATL1; SPG3A); Chromosome 14q22.1; Dominant or de novo
- Epidemiology: Common cause of dominant, early onset FSP
- Genetics
- ATL1 Gene mutations
- > 500 described
- Most families have private mutations
- Missense (90%)
- Arg217Asp; Arg239Cys (Exon 7); His258Arg (Exon 8); Ser259Tyr (Exon 8); R495W (Exon 12)
- Early onset: Thr156Ile (Exon 4)
- Frameshift: 1688insA (Exon 12)
- Common locations: Exons 7, 8, 12, 13
- Complex SPG phenotype: de novo mutations; Middle domain & Linker regions
- Allelic with: Hereditary Sensory Neuropathy ID
- ATL3 mutations: Hereditary sensory neuropathy with pedal bone destruction
- ATL1 Gene mutations
- Atlastin protein
- Homology
- Dynamin family of large GTPases: Dynamins play role in
- Synaptic vesicles: Recycling
- Mitochondria: Maintenance & Distribution
- Guanylate binding protein 1 (GBP1)
- Dynamin family of large GTPases: Dynamins play role in
- Expression: Predominantly in CNS
- Enriched in cerebral cortex: Especially lamina V
- Subcellular: Golgi apparatus; Oligomeric integral membrane protein
- Mediates formation of tubular ER network
- Interacts with: ARL6IP1
- Homology
- Clinical
- Onset
- Age: Early
- Range: 1 year to 7th decade
- Mean in 1st or 2nd decade
- Anticipation & variation within families
- Spasticity
- Age: Early
- Spastic paraparesis
- Legs
- Motor dysfunction
- Atrophy: Distal legs
- Bladder dysfunction: Some patients
- Tendon reflexes: Increased in legs > Arms
- Sensory loss
- Mild
- Vibration sense
- Course
- Progression: Static or Very slow
- Few with loss of walking: ? Related to contractures
- CNS other: Occasional patients
- Neurodevelopmental delay
- Bulbar symptoms
- Upper limb spasticity
- Ataxia
- Seizures
- MRI: Hyperintensities
- Mutations: Middle domain & Linker regions
- Onset
- Comparison to SPG4
- Onset: Earlier
- Course: More benign
- Laboratory
- Electrodiagnostic: Sensory-motor axonal neuropathy (R495W mutation)
- Pathology: Predominant loss of large myelinated axons
- SPG3A variant syndrome: Hereditary Sensory Neuropathy I
(HSN 1D)
81
- Genetics
- Atlastin mutations: Asn355Lys; Glu66Gln; c.976 delG [p.Val326TrpfsX8]
- Inheritance: Dominant
- Clinical
- Variable within families
- Some patients with spastic paraparesis & no neuropathy
- Onset
- Age: Early adult
- Trophic changes: Skin & Nail
- Childhood spasticity: In one patient
- Sensory loss
- Severe
- Distal
- Weakness
- Distal
- Legs
- Acromutilation
- Osteomyelitis
- Amputations: Toe & Foot
- Pain
- Lancinating
- Some patients
- Tendon reflexes
- Knee: Increased or Normal
- Ankles: Increased or Reduced
- Variable within families
- Laboratory
- Nerve conduction testing: Axonal loss in most but not all
- Nerve biopsy: Axon loss
- Genetics
- SPG4 (FSP2)
● Spastin (SPAST);
Chromosome 2p22.3; Dominant
- Epidemiology
- Most common dominant FSP: 28% to 50% of families
- Prominent variation of severity, even within families
- Similar clinical phenotype with missense & truncation mutations
- Male ≥ Female
- ? Anticipation in some families: Probably related to very variable phenotype
- Genetics
- Mutations
- > 250 different pathogenic mutations identified 9
- Patterns
- Types: Deletions; Insertions; Base substitutions
- Functional types: Missense; Nonsense; Splice-site; Deletion & Insertion
- Locations
- Many exons & splice sites
- Missense commonly in functional AAA domain
- Some truncation mutations
- Clustering in some domains
- AAA (ATPases associated with diverse cellular activities)
- MIT (microtubule interacting and trafficking)
- MTBD (microtubule-binding domain)
- N-terminal region (228-269 residues)
- Commonly private: Specific mutation unique to most individual kindreds
- Missense: May have earlier onset
- Exon 10-12 duplication
- Brazilian family
- Males: Earlier age of onset; More severely affected
- Females: 50% unaffected
- Large exon deletions
- Onset age: Earlier
- Clinical syndrome: Similar
- Frequency: Common
- Technical: May not be detected by gene sequencing
- Large deletion involving SPAST & neighboring DPY30
gene
- Spastic paraplegia: Early childhood onset
- Other systems: Cognitive & bladdder involvement
- Females: Miscarriages
- Compound heterozygote
47
- Mutations: 2 Missense; P361L & S44L
- More severe disease
- Infantile onset
- Parents: Asymptomatic or Paraparesis
- Homozygous mutations: S44L
- Adult onset
- Paraparesis
- Disease mechanisms
- Loss of function vs Dominant negative
- Some leaky mutations at splice sites: May explain clinical variability
- Deletions: Earlier onset but similar phenotype vs missense mutations
- No correlation between mutation site & disease severity
- Gly563Ala polymorphism in HSP60: May cause earlier onset of SPG4
- Mutations
- Protein
- ATPase family:
ATPases Associated
with diverse cellular Activities (AAA)
- Share 230 amino acid domain with ATPase function
- Subfamily-7: Meiotic group
- Expression: Early & ubiquitously in fetal and adult tissues
- Subcellular Location: Perinuclear; Punctate
- Structure
- 2 Leucine-zipper domains & 1 Coiled-coil dimerization motif
- Homology with 26S proteasome subunits
- Interacts with: RTN2
- Functions
22
- Associates with microtubule cytoskeleton
- Binding via N-terminal region
- Regulation by ATPase activity of AAA domain
- Promotes microtubule disassembly: Action similar to microtubule-severing protein, katanin
- ? Involved in
- Fine regulation of microtubule cytoskeleton
- Assembly or function of nuclear protein complexes
- Chaperone activity: Also see SPG7 & SPG13
- Axon transport
- Mutant protein
- Disappearance of aster
- Formation of thick perinuclear microtubule bundles
- Altered ability to regulate interaction with tubules
- Constitutive binding to microtubules
- Aggregation of microtubules in long axons of pyramidal neurons
- ? Disrupts ATPase activity of the AAA cassette
- Forms aggregates: Normal protein does not form aggregates
- Associates with microtubule cytoskeleton
- ATPase family:
ATPases Associated
with diverse cellular Activities (AAA)
- Clinical
- Onset
- Typical
- Range: 0 to 74 years; Variable within & between families
- Signs: Leg stiffness (86%); Gait unsteadiness (19%)
- Penetrance (+ Examination)
- 20 years: 60%
- 40 years: 85%
- Asymptomatic patients (Non-penetrance): 6% at age 70
- Sub-clinical manifestations: ~ 20% of patients with + exam are unaware of symptoms
- Spasticity (100%)
- Scissoring gait
- Extensor plantar responses (88%)
- Tone increased
- Muscle spasms & leg cramps
- Legs (94%) > Arms (22%)
- Weakness: Legs; 70%
- Sensory: Vibration reduced in legs (30% to 50%)
- Tendon reflexes: Increased at knee and ankle
- Neurogenic bladder: Common (34%), not universal
- Cognitive impairment: 40%
- Subcortical
- Frequency: Higher with increasing age
- Not related to severity of paraplegia
- Late: Back pain (50%)
- Progression: Faster in older onset patients
- Adult onset
- Slowly progressive spastic paraparesis with bladder dysfunction
- Functional deficit: Mild in most; Severe in < 20%
- "Congenital" onset: May be non-progressive
- Adult onset
- Onset
- Lab
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- MRI: Normal
- Nerve conduction studies: Normal
- Central motor conduction times: Normal
- Pathology
- Spinal cord: Predominant loss of large myelinated axons
- Cortex
- Neuronal loss
- Hippocampus: Tau reactive neurofibrillary tangles
- Limbic & Neocortex: Tau reactive balloon cells
- Substantia nigra: Lewy bodies
- Epidemiology
- SPG6 (FSP3)
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● Nonimprinted in Prader-Willi/Angelman syndrome (NIPA1)
; Chromosome 15q11.2; Dominant or de novo
- Epidemiology: > 100 patients
- Genetics
- Mutations
- Missense
- Thr45Arg
- Gly106Arg (316G>A & 316G>C): Hot spot; Complex phenotypes common
- c.159C>G, c.298GC>A, c.731AC>G, c.748AC>C): Pure phenotype common
- Mechanism: Probably dominant negative
- Missense
- Prader-Willi region
- Gene probably commonly deleted in Prader-Willi & Angelman syndromes
- Other Prader-Willi gene: MAGEL2 (Lethal congenital contractures)
- Sporadic ALS: Copy number variation
- Mutations
- NIPA1 protein
- Location: Probably membrane; ? Transporter or Receptor
- 9 predicted membrane spanning regions
- Constitutively expressed in all tissues: Enriched in nervous system
- Clinical
- Onset: Mean 22 years; Range 2 to 35 years
- No anticipation
- Spastic paraparesis
- Relatively severe
- Pure syndrome: 80%
- Tendon reflexes: Brisk in Arms & Legs
- Extensor plantar responses
- Bladder dysfunction (10%)
- Weakness & Atrophy: Distal in legs
- Sensory loss: Vibratory in legs; Frequent; Mild
- Pes Cavus: Common
- CNS: Epilepsies, generalized, in some patients ± treatment responsive
- Polyneuropathy: 6%
- Course
- Progression: Relatively rapid paraparesis
- May need wheelchair in 30's to 50's
- SPG8
61
● KIAA0196 (Strumpellin)
; Chromosome 8q24.13; Dominant
- Epidemiology: 6 families - North American, British, Brazilian, Canadian
- KIAA0196 gene mutations
- Missense: Val626Phe (Hotspot); Leu619Phe; N471D
- Impair protein function
- Increased copy number associated with prostate cancer
- Strumpellin protein: Coded by KIAA0196 gene
- α-helical protein
- Contains spectrin repeat domain
- Expression: Ubiquitous
- Knockout: Impaired motor neuron outgrowth in spinal cord
- Clinical
- General
- Pure spastic paraplegia
- Intrafamilial phenotypic heterogeneity: Present
- Onset age: 22 to 60 years
- Pyramidal signs
- Spasticity
- Hyperreflexia
- Extensor plantar responses
- Gait disorder
- Relatively severe: 60% use wheelchair by age 40
- Spasticity
- Weakness: Hip flexion; Ankle dorsiflexion
- Gait: Spastic diplegia
- Sensory loss: Vibratory in feet
- Bladder disorders (50%): Urgency; Incontinence
- Pes cavus
- Occasional: Dysmetria (Finger-Nose)
- General
- Muscle biopsy: Normal
- SPG10
6
● Kinesin Heavy Chain 5A (KIF5A); Chromosome 12q13.3; Dominant
- Epidemiology: 3% of European AD HSP families
- Genetics
- Mutations
- Types
- Missense: R162W; Asn256Ser; Arg280Cys; Tyr276Cys; Ala361Val
- Other: In-frame deletion; Splice site
- Locations
- Often in kinesin motor or neck domain of kinesin
- Hot spots: R204, N256, R280
- Types
- Allelic disorders
- CMT2 syndrome
- ALS
- ? LHON, Dominant, Paraneoplastic
- Myoclonus, intractable, neonatal (NEIMY)
- Mutations
- KIF5A protein
- KIF5
- 3 heavy chain isoforms
- KIF5A: Neuron specific
- KIF5B: Ubiquitous
- KIF5C: Neuron specific
- Form: Dimers; Complex with kinesin light chains
- Anterograde axon transport
- Transport many cargos by binding to adaptor proteins
- 3 heavy chain isoforms
- Mediates transport of
- RNA & RNA-binding protein granules
- VAPB
- Mitochondria
- Mutation effects
- Prevents stimulation of the motor ATPase by microtubule-binding
- Impairs axonal transport
- Reduces gross cargo flux: Leads to deficient supply of synapse
- KIF5
- Kinesin disorders
123:
Anterograde axon transport machinery
- Kinesin 1
- Kinesin 3
- KIF1A (ATSV): SPG30; HSMN with ulcero-mutilation (HSAN 2C)
- KIF1C: SPAX2/SPG58
- KIF14
: MKS12
; MCPH20
- KIF 16A (STARD9)
: Microcephaly & Blindness
- Kinesin 4
- Kinesin 5
- KIF11
:
Microcephaly with or without chorioretinopathy, lymphedema or mental retardation (MCLMR)
- KIF11
- Kinesin 7
- KIF10 (CENPE)
: Primary microcephaly 13 (MCPH13)
- KIF10 (CENPE)
- Kinesin 9
- KIF6
: Intellectual disability
- KIF6
- Kinesin 12
- KIF15
: Microcephally & Thrombocytopenia
- KIF15
- Kinesin 13
- KIF2A
: Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3)
- KIF2A
- KIF1Bβ: ?? CMT 2A; Multiple sclerosis predisposition
- KIF1B: ?? CMT2A1
- KIF26B: Ponto-Cerebellar Atrophy with SMA
- KLC2: SPOAN
- Kinesin-binding protein (KIFBP; KIF1BP/KBP
)
- Goldberg–Shprintzen syndrome (GOSHS)
- Goldberg–Shprintzen syndrome (GOSHS)
- Paclitaxel toxicity
- Clinical
- Onset
- Age
- Mean 10 to 23 years
- Range: Infancy to 55 years
- Varies within families
- Gait disorder
- Age
- Pure spastic paraparesis: Some patients
- Spastic paraparesis
- Hyperreflexia: Lower limbs
- Extensor plantar responses
- Disability (Wheelchair): 23%
- Cerebellar signs in arms: 23%
- Foot deformity: 92%
- Bladder dysfunction: 62%
- Sensory loss: Vibration 31%
- Amyotrophy: Rare
- Progression
- Moderate
- Variable severity: From asymptomatic to wheelchair at 40 years
- Most patients continue to ambulate independently
- Spastic paraparesis
- Complex phenotypes: May include
- Peripheral neuropathy
- Sensory-Motor
- Axon Loss
- Upper limb amyotrophy: Severe; Silver syndrome-like
- Mental impairment
- Parkinsonism: Tremor; Bradykinesia; Rigidity
- Deafness
- Retinitis pigmentosa
- Varicose veins
- Dupuytren’s disease
- Frequency: 10% of complicated forms of SPG
- Peripheral neuropathy
- Onset
- Laboratory
- Electrophysiology
- Subclinical sensory-motor neuropathy in all patients
- Electrophysiology
- KIF5A Variant syndrome: CMT2 ± Pyramidal signs
98
- Epidemiology: 3 patients
- KIF5A mutations: D232N; R280C; R280H; Leu558Pro
- Clinical
- Onset age: 8 to 42 years
- Polyneuropathy
- Weakness
- Distal > Proximal
- Legs > Arms
- Symmetric
- Muscle wasting: Distal
- Sensory loss
- Pin & Vibration
- Weakness
- Pyramidal syndrome (67%)
- Spasticity
- Gait disorder
- Tendon reflexes: Increased
- Course: Progressive to Cane or Wheelchair
- Skeletal: Pes cavus
- Laboratory
- Nerve pathology
- Axon loss
- Axon regeneration
- NCV: Axonal neuropathy
- SNAP & CMAP amplitudes: Reduced or absent, Legs > Arms
- Velocities: 40 to 52 M/s
- Nerve pathology
- Also see: CMT + Upper motor neuron
- KIF5A Variant syndrome: ALS 25
118
- Epidemiology: 0.5% of FALS; 9 families
- Genetics
- Mutations
- Location: C-terminal
- Often splice site: Also frameshift & missense (Arg1007)
- Splicing of exon 27: Commonly affected
- Mutation effects
143
- ? More penetrance with: Loss of function
- Common
- Exon 27: Skipping
- Tail domain altered
- Defective autoinhibition: Gain-of-function 135
- Cytoplasmic inclusions
- Neuromuscular junctions: Abnormal
- RBM24: More cytoplasmic location
- Inheritance: Dominant or Sporadic
- Mutations
- Clinical
- Onset age
- Adult
- Range: 29 to 56 years
- Younger than typical ALS
- Weakness
- Asymmetric
- Arms & Legs
- Bulbar
- Upper motor neuron
- Emotional lability
- Course
- Progressive: Slower than typical ALS
- Death in 3 to > 10 years
- Onset age
8
● Reticulon 2 (RTN2)
;
Chromosome 19q13.32; Dominant
- Epidemiology: USA, Welsh, German & Italian families
- Genetics
- Mutations: Deletion; Frameshift & Truncation
- Disease mechanism: Haploinsufficiency
- Some heterozygous mutations present without disease
- Allelic disorder
- Reticulon 2 protein
- Clinical
- Onset
- Age: Mean 7 to 14 years; Range 5 to 39 years
- Spinal
- Spasticity: Legs > Arms
- Reflexes
- Tendon: Legs increased
- Plantar: Extensor
- Sensory loss: Vibration (11% to 80%)
- Bladder dysfunction: 33%
- Progression: Slow
- Functional deficit
- Mild in some
- Many require wheelchair within 4 years of onset
- Other
- Cerebellar signs: 12%
- Systemic disorders: None
- Foot deformity: 22%
- Onset
- Laboratory
- Nerve conduction & EMG: Normal
- MRI: Spinal cord usually normal
- SSEP: Delayed
- RTN2 variant: HMNR11, Distal motor neuropathy + Lower limb spasticity, Recessive
145
- Epidemiology: 7 families; 14 patients
- Genetics
- Inheritance: Recessive; Homozygous
- Mutations: Loss of function; Most stop
- Clinical
- Onset age: 1 to 6 years
- Weakness
- Distal
- Arms & Legs
- Finger extensors
- Lower limbs
- Spasticity
- Tendon reflexes: Increased
- Sensation: Normal
- Course
- Slow progression
- Remain ambulatory
- Laboratory
- NCV: Motor neuropathy
7● Heat-shock 60-kD protein 1 (HSPD1; HSP60)
; Chromosome 2q33.1; Dominant
- Epidemiology: 2 families; Unusual cause of FSP
- Genetics
- Mutations: Missense (Val72Ileu); Deletion (Exons 4 to 17)
- Multiple pseudogenes in addition to functional gene
- Gly563Ala polymorphism: May cause earlier onset of FSP with spastin mutations (SPG4)
- Allelic with: Hypomyelination & Leukodystrophy syndrome
- HSPD1 protein
- Chaperonin: Involved in folding & assembly of proteins
- Location
- Most protein: Mitochondrial matrix
- 20% Extramitochondrial
- Mutant protein: Inactive
- Other FSP with chaperone protein mutations: SPG4; SPG7
- Spasticity & Hyperreflexia
- Lower (67%) & Upper limbs (67%)
- Extensor plantar responses (56%)
- Sensory loss: Vibration (77%)
- Bladder dysfunction (14%)
- Functional deficit: Severe in 40% to 50%
- Systemic disorders: None
7
- Nosology
- Pelizaeus-Merzbacher–Like Disease (PMLD)
- Hypomyelinating leukodystrophy 4 (HLD4)
- Epidemiology: Israeli Bedouin kindred, 23 children
- Genetics
- Clinical
- Intra-familial variation
- Onset: Early
- Hypotonia: Poor head control; titubation
- Eye: Nystagmus, rotary; Strabismus
- Psychomotor developmental delay & regression
- Spasticity: More prominent with survival > 2 years
- Head circumference: Decreased growth rate
- Seizures: 60%
- Feeding problems: Malnutrition & Growth failure
- Course
- Exacerbation during fever
- Progression: Rapid (Death < 2 years to slow
- Death: 1st two decades; Aspiration pneumonia; Sudden death
- Laboratory
- MRI: Hypomyelinating leukodystrophy: No normal myelination
- Urinary ethylmalonic acid: High on 60%
- Plasma lactate: High during acute illness
- CSF lactate: Normal
- Muscle biopsy
- Electron microscopy: Abnormal 25%
- Cytochrome c oxidase activity: Mildly reduced 25%
- Other hypomyelination & leukodystrophy syndromes
- Encephalomyopathy: COX6B1
- Pelizaeus-Merzbacher: PLP
- PMLD: GJA12
- Cockayne syndromes
- Hypomyelination, Atrophy of basal ganglia & cerebellum
- Hypomyelination & Congenital cataract syndrome (HCC): DRCTNNB1A
- Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL): DARS2
- Vanishing white matter
26
● Chromosome 9q33-q34; Dominant
- Genetic: Similar locus to ALS4; HMN + Upper motor neuron signs
- Epidemiology: Italian family
- Onset
- Age: Mean 47 years; Range 36 to 55 years
- Clinical: Spastic gait disorder; Bladder dysfunction
- Some patients unaware of signs
- Clinical
- Spastic paraparesis
- Spasticity: Legs
- Hyperreflexia: Legs 100%; Arms 20%
- Extensor plantar responses (90%)
- Bladder dysfunction (100%)
- Sensory loss: Reduced vibration in 40%
- Functional deficit: Mild in most; Wheelchair in 10%
- Skeletal: Scoliosis (20%)
- Systemic disorders: None
- Spastic paraparesis
- Laboratory
- Motor evoked potentials: Slowed central motor conduction velocity in legs
● Chromosome 1p31.1-p21.1; Dominant
- Epidemiology: Scottish family
- Onset
- Age: 2nd & 3rd decade; ? Anticipation
- Clinical: Gait disorder
- Clinical
- Spastic paraparesis
- Spasticity: Legs
- Hyperreflexia: Legs 100%; Arms 10%
- Extensor plantar responses (100%)
- Bladder dysfunction (30%)
- Sensory loss: Reduced vibration in 15%
- Functional deficit: Major gait disorder or wheelchair in 60%
- Paraesophageal hernia: Persistent vomiting (80%)
- Hearing loss: Sensorineural
- Spastic paraparesis
- Laboratory
- Hyperbilirubinemia
- NCV & EMG: Normal
- Motor evoked potentials: Reduced from lower limbs
- CNS imaging: Normal
57
● Receptor expression–enhancing protein 1 gene (REEP1)
; Chromosome 2p11.2; Dominant
- Epidemiology
- > 40 families, most European
- Frequency
- 2% to 6% of Dominant spastic paraparesis
- 8% of Pure SPG
- Genetics
- Mutation types: Varied
- Most common: Frameshift; Small insertions, Deletions or Splice site causing premature termination
- Specific examples
- 1 base pair deletion: c.507delC; c.526delG (Gly176fs)
- Splice-site mutation: c.182-2ArG,
- Missense: P19R; Ala20Glu
- UTR changes: c.606.43GrT; c.606.50GrA
- Alter sequence in binding site for microRNA (miRNA) gene miR-140
- Nonsense: Arg113X
- General disease mechanisms
- Haploinsufficiency
- Loss of protein function
- Allelic disorders
- Mutation types: Varied
- REEP1 protein
- Location
- Tubular portion of peripheral endoplasmic reticulum (ER)
- ER-Mitochondria interface
- Expression: Ubiquitous; Neuronal & Non-neuronal tissues
- Functions
- Rab-mediated vesicle transport
- Facilitates ER-mitochondria interactions
- ? Involved in chaperone-like activities
- Location
- Clinical
- Common phenotype: Pure spastic paraplegia
- Onset age
- Bimodal
- 1st & 2nd decade (> 3 years): 71%
- 31 to 91 years
- Inter- & Intrafamilial variation
- Penetrance: Incomplete
- Bimodal
- Weakness: Proximal legs; Hands (Mild)
- Upper motor neuron signs
- Spasticity: Legs; Gain
- Plantar response: Extensor
- Ankle clonus: 50%
- Sensation: Normal
- Scoliosis: Mild; 30% of families
- Peripheral neuropathy: Some patients
121
- Axon loss
- Compression
- Carpal tunnel: Common
- Multifocal in a few
- Autonomic: Some with adrenergic dysfunction
- Some patients have
- Amyotrophy: Silver syndrome
- Bulbar palsy: More severe disease
- Mitochondrial dysfunction
- Cerebellar ataxia
- Dementia
- Laboratory
- Nerve conduction: Normal velocity
- MRI: Normal spinal cord & Cranial
- REEP1 Variant syndrome: Hereditary Motor Neuropathy 5B (HMND12; HMN 5B)
86
● Receptor expression–enhancing protein 1 gene (REEP1); Chromosome 2p11.2; Dominant
- Epidemiology: 1 Austrian family
- Genetics
- Inheritance: Dominant
- REEP1 mutation
- Splice-site: c.304-2A>G
- In-frame deletes exon 5
- Encodes internally shortened protein
- Allelic with: SPG31
- REEP1 protein: Expressed in lower motor neurons
- Clinical
- Onset age: 2nd decade
- Weakness & Muscle atrophy: Intrinsic hands; Distal legs, mild
- Tendon reflexes: Absent at ankles
- Upper motor neuron features: None
- Pes cavus
- Gait: Mild steppage in some patients
- Nerve conduction studies
- CMAP amplitudes: Reduced in arms & legs
- Motor conduction velocities: Normal or mildly reduced
- SNAP amplitudes: Normal
- REEP1 Variant syndrome: Distal spinal muscular atrophy-6, Autosomal recessive (DSMA6)
- Nosology: Axonal neuropathy & Diaphragm palsy, Congenital 104
- Epidemiology: 3 families
- Genetics
- Inheritance: Recessive
- Mutation: Homozygous; Splice donor (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912)
- Clinical
- Onset age: Congenital
- Hypotonia
- Weakness
- Distal ± Proximal
- Legs > Arms
- Respiratory: Diaphragm palsy
- Skeletal
- Arthrogryposis, Distal
- Palate: High arched
- Tendon reflexes: Increased; Reduced at ankles
- Course: Static or Slow progression
- Laboratory
- NCV: CMAP ± SNAP amplitudes reduced or absent; Velocities normal
- Muscle histology: Fiber type grouping; IM nerves with loss of neurofilaments
- Nerve pathology: Axon loss
- Brain MRI: Normal
- Heterozygous parents: Normal or Mild skeletal changes
- Differential diagnosis: SMARD
58
● ? ZFYVE27
; Chromosome 10q24.2; Dominant
- Epidemiology: German family
- Genetics
- Mutation associatd with disease is Variant of Unknown Significance (VUS)
- Missense
- G191V (G105V of isoform-c)
- ZFYVE27 protein
- Interacts with spastin
- FYVE-finger family
- Expressed in punctate vesicles
- Overlapping expression with endosomal & endoplasmic reticulum markers
- Mutant protein
- Aberrant intracellular pattern in its tubular structure
- Interaction with spastin severely affected
- Clinical: Pure spastic paraparesis syndrome
- Onset
- Age: Adult
- Pes equinus: Many years before symptoms
- Gait disorder
- Spastic paraparesis
- Spasticity
- Tendon reflexes: Brisk or Normal in legs
- Progression: Slow over decade; Eventual inability to walk
- Sensation: Normal
- Onset
31
● Chromosome 12q23-q24; Dominant
- Epidemiology: German family
- Onset: Mean 24-30 years; Range 14 to 33 years
- Clinical
- Spastic paraparesis
- Legs > Arms
- Weakness: Legs
- Plantar responses: Extensor
- Tendon reflexes: Brisk
- Sensory loss: Pan-modal; Legs
- Bladder: Urinary urgency
- Amyotrophy: Moderate to severe
- Polyneuropathy: Motor & Sensory
- Progression: May develop walking aid or wheelchair dependency after 1 to 2 decades
- Spastic paraparesis
- Laboratory
- Brain MRI: Normal
- Central motor conduction time: Prolonged
- Motor & Sensory NCV: Abnormal in legs
- NCV: Mildly slow
- Motor DL: Prolonged
- SNAP amplitude: Reduced
● Chromosome 8p21.1-q13.3; Dominant
- Epidemiology: French family
- Genetics
- Possible incomplete penetrance
- ? Phenotype modifier at: 10q22.3-23.31: Polymorphism could lead to more severe phenotype
- Locus near SPG5
- Onset age: 8 to 60 years; Mean 32 years
- Clinical: "Uncomplicated"
- Spastic paraparesis
- Legs > Arms
- Gait disorder: Spastic
- Tendon reflexes
- Brisk in Legs ± Arms (60%)
- Ankle clonus: Some patients
- Plantar response: Extensor
- Bladder dysfunction (38%)
- Sensation: Vibration reduced at ankles (38%)
- Course
- Slowly progressive
- No requirement for walking aids
- Proximal weakness: Legs (Psoas)
- Spastic paraparesis
- Laboratory
- MRI: Normal
- EMG: Normal
- Evoked potentials: Normal
69● Chromosome 4p16-p15; Dominant
- Epidemiology: Italian family
- Onset
- Age: Mean 17 years
- Gait disorder: Spastic
- Clinical
- Spastic paraparesis
- Legs & Arms
- Gait disorder: Spastic
- Tendon reflexes: Brisk in Legs
- Plantar response: Extensor
- Sensation: Normal or Reduced at ankles
- Pes cavus
- Course
- Progressive
- Walking aids or Wheelchair
- Weakness
- Hands: Thenar & 1st dorsal Interosseus; Uni- or Bilateral
- Foot: Extensors, Some patients
- Spastic paraparesis
- Laboratory
- CMAP amplitudes: Variably reduced, Median > Ulnar
- EMG: Chronic denervation, Distal
- Evoked potentials: Normal
- Also see: SPG17 (Silver syndrome)
65
● Chromosome 11p14.1-p11.2; Dominant
- Epidemiology: Chinese family
- Genetics: Linkage with low LOD score (2.36)
- Onset age: 2nd decade; Mean 17 years
- Clinical
- Spastic paraparesis
- Legs > Arms
- Gait disorder: Spastic
- Tendon reflexes: Brisk
- Urinary urgency
- Sensation: Normal
- Course: Slowly progressive
- Weakness
- Legs: Proximal
- Arms: Small hand muscles
- Spastic paraparesis
71● Solute carrier family 33 (Acetyl-CoA Transporter), Member 1 (SLC33A1)
; Chromosome 3q25.31; Dominant
- Epidemiology: One Chinese family
- Genetics
- Mutation
- Missense: Ser113Arg
- Mechanism: ? Haploinsufficiency
- Allelic disorders
- CCHLND, Recessive
- Chromosomal duplications of 3q25.31 locus: Autism; Seizures
- Mouse SLC33A1 overexpression: Progeria phenotype
- Mutation
- SLC33A1 protein
- Cytoplasmic: Endoplasmic reticulum
- Copper chaperone
- Acetyl-CoA transporter
- Transports acetyl-CoA from cytosol into ER lumen
- Necessary for O-acetylation of gangliosides
- Acetyl group in Nε-lysine acetylation
- May play role in axon growth
- Clinical: Spastic paraparesis
- Onset Age: 4 to 40 years; Rare incomplete penetrance
- Distribution: Legs
- Tendon reflexes: Increased in legs
- Extensor plantar response: Common
- Disability: Most patients remain walking
- Pes cavus: Some patients
- Laboratory
- MRI: Normal
- EMG: Normal
- Muscle biopsy: Normal
- SLC33A1 variant: Congenital Cataracts, Hearing loss & Neurodegeneration (CCHLND)
- Nosology: Huppke-Brendel syndrome (HBS)
- Epidemiology: 5 families
- Genetics
- Inheritance: Recessive
- Mutations: Missense; Splice; Stop
- Clinical
- Onset age: Infancy
- Cataracts: Congenital
- Psychomotor development: Delayed; Hypotonia, severe
- Eyes: Gaze fixation instability; Rotary nystagmus
- Hearing loss
- Seizures
- Course: Progressive
- Laboratory
- Brain MRI: Cerebral & Cerebellar atrophy; Hypomyelination
- Muscle: Mitochondria abnormal; Cytochrome c oxidase activity reduced
- Copper & Ceruloplasmin: Low in serum
- Neutropenia
● Chromosome 21q22.3; Dominant
- Epidemiology: 1 American family, 8 patients
- Genetics
- Inheritance: Dominant
- Clinical
- Onset
- Age: Mean 45 years; Range 35 to 56 years
- Leg stiffness
- Spasticity
- Legs > Arms
- Tendon reflexes: Brisk in Legs > Arms
- Plantar response: Extensor in 40%
- Gait disorder
- Sensory loss
- Proprioception & Vibration
- With disease progression
- Progression: Slow
- Onset
- Electrodiagnostic
- Axon loss: Sensory & Motor
● Receptor expression-enhancing protein 2 (REEP2)
; Chromosome 5q31.2; Dominant or Recessive
- Epidemiology: French & Portuguese families
- Genetics
- Dominant mutation: Val36Glu
- Recessive mutations: M1T; Phe72Tyr & Splice site (c.105+3G>T)
- Allelic disorders
- SPG72A
: Dominant
- SPG72B
: Recessive
- SPG72A
- REEP2 protein
- Clinical: Pure SPG phenotype
- Dominant family (SPG72A)
- Onset
- Age: Mean 3.7 years
- Stiff legs
- Spasticity
- Gait disorder
- Mild stiffness at rest
- Plantar response: Extensor
- Tendon reflexes: Increased in legs
- Progression: Slow over decades
- Sphincter disturbance (50%)
- Pes cavus 30%
- Postural tremor (20%)
- Sensory loss (20%): Decreased vibration sense at ankles
- Onset
- Recessive family (SPG72B)
- Onset age: 2 years
- Spasticity
- Gait
- Rest
- Plantar response: Extensor
- Tendon reflexes: Increased in legs
- Sensation: Normal
- Course: Progressive to cane use at 8 to 25 years
- Dominant family (SPG72A)
● Carnitine palmitoyltransferase IC (CPT1C)
; Chromosome 19q13.33; Dominant
- Epidemiology: Italian family
- Genetics
- Mutation: Missense; Arg37Cys
- CPT1C protein
- Endoplasmic reticulum
- No enzymatic activity in fatty acid oxidation
- Clinical
- Onset age: Mean 36 years; Range 19 to 48 years
- Spastic paraparesis
- Legs: Gait disorder
- Tendon reflexes: Increased
- Plantar response: Extensor
- Urinary dysfunction: Some patients
- Course: Slow progression
- Weakness: Proximal
- Sensory: Vibration loss in feet
- Foot deformities: Some patients
- Laboratory
- NCV: Normal
- Brain imaging: Normal
- Sensory evoked potentials: Delayed
136● Ubiquitin-Associated Protein (UBAP1)
; Chromosome 9p13.3; Dominant or de novo
- Epidemiology: > 90 patients; 1.2% of Dominant HSP
- Genetics
- Mutations
- Truncation: Stop, Out-of-frame duplications
- Locations
- After N-terminal UMA domain (Mediates association with ESCRT-I complex)
- Before C-terminal SOUBA domain (Interaction with ubiquitinated proteins)
- Hotspot: Exon 4
- Mechanism: Dominant negative
- Mutations
- UBAP1 protein
- Subunit of endosomal sorting complex: Required for transport-1 (ESCRT-I)
- Regulator of vesicular trafficking processes
- Proteasomal degradation of ubiquitinated cell-surface proteins
- EGFR (Epidermal growth factor receptor)
- BST2 (Bone marrow stromal cell antigen)
- EGFR (Epidermal growth factor receptor)
- Clinical
- Onset
- Age: Median 8 years; Range 4 to 26 years
- Spastic gait
- Spasticity
- Legs
- Tendon reflexes: Increased
- Gait disorder
- Urinary urgency (37%)
- Course: Progressive; Wheelchair in many
- Some patients
- Cerebellar: Ataxia; Saccadic EOM; Limbs
- Cognitive impairment: Mild
- Sensation: Normal
- Onset
- Laboratory
- Brain imaging: Normal
● KCNA2
; Chromosome 1p13.3; Dominant
- Epidemiology: 2 families (Norwegian/French-Canadian; German), 5 patients
- Genetics
- Mutation: Missense; Arg294His
- Allelic disorders
- Ataxia
- Developmental and epileptic encephalopathy 32 (DEE32)
- KCNA2 protein
- Clinical
- Onset age: 1 to 30 years
- Development: Motor or Global delay in some patients
- Intellectual disability: Mild to Moderate
- Spasticity: Legs > Arms; Gait disorder
- Ataxia: Limb & Gait (1 family)
- Bladder disorder: 1 patient
- Polyneuropathy: 1 older patient
- Course: Progressive
- Laboratory
- Brain MRI: Non-diagnostic
- EEG: Epileptiform discharges (50%)
- KCNA2 variant syndrome: Ataxia + Epilepsy
- Epidemiology: 2 families, 2 patients
- Genetics
- Mutations: Arg294His; Arg297Gln
- Inheritance: Dominant
- Clinical
- Onset age: 15 months to Childhood
- Ataxia: Limb & Trunk
- Epilepsy: Febrile seizures; Myoclonus
- Tremor: Hands
- Intellectual disability
- Treatment: Acetazolamide
- Laboratory
- EEG: Spike-Wave
- Brain MRI: Normal
● Chromosome 2q24-2q31; Dominant
- Epidemiology: Central Ohio, US Family
- Genetics: Highly penetrant
- Clinical
- Onset
- Age: 1 to 51 years; Most often in 1st decade
- Dystonia: Childhood
- Spasticity: Adults
- Spasticity
- Legs > Arms
- Gait
- Tendon reflexes: Increased; Clonus
- Dystonia
- Location: Arms, Legs & Generalized
- Present in most, but not all, patients
- Normal: Cognition, Cerebellar & Bladder function
- Course: Progressive
- Onset
- Laboratory
- CNS MRI: Normal
- Nerve conduction studies: Normal
- Dystonia treatment: Deep pallidal stimulation
- Alzheimer's disease ± Spasticity
37
● Presenilin 1 (PSEN1); Chromosome 14q24.3; Dominant
- Genetics
- Mutation: Deletion of exon 9
- Allelic disorders
- Epidemiology: Finnish, British & Australian families
- Onset age: 4th & 5th decade
- Clinical
- Spastic paraparesis: May precede dementia
- Dementia: Rapidly progressive; May be delayed when preceded by paraparesis
- Progression: Death in < 10 years
- Pathology
- Plaques: Non-neuritic; ‘Cotton wool’
- Large, round & eosinophilic
- Immunoreactive for A-β
- No congophilic dense core or plaque-related neuritic pathology
- Neurofibrillary tangles
- Amyloid angiopathy: Throughout cerebral cortex
- Plaques: Non-neuritic; ‘Cotton wool’
- Genetics
- SOX10
- Adult-onset Leukodystrophy (ADLD)
- Multiple exostoses and spastic tetraparesis
: 1 family
Familial Spastic Paraplegia (RFSP): Recessive
Spastic Paraplegia: Non-syndromic or Complex
- SPG5A
● CYP7B1; Chromosome 8q12.3; Recessive
39
- Epidemiology: Tunisian, American, Australian & British families
- Genetics
- Mutations: Homozygous; Missense or Nonsense; > 17 identified
- Allelic with: Congenital bile acid synthesis defect
- CYP7B1 protein
- Cytochrome P450 enzyme
- Hydroxylates
- Endogenous substrates
- Carbons 6 & 7 of B ring of oxysterols & steroids
- Expression: Liver, Lung, Kidney, Brain & Reproductive tract
- Function
- Role in metabolism of brain cholesterol
- Conversion of 27-OH-cholesterol to 3β, 7α-diOH-5-cholestinoic acid
- Clinical features: Pure HSP with sensory loss
- Onset age: 1 to 40 years; Median 13 years
- Spasticity: Lower limbs; Gait disorder
- Weakness: Legs
- Sensory loss
- Distribution: Legs
- Modalities: Joint Position; Vibration
- Tendon reflexes: Increased in arms & legs
- Plantar responses: Extensor
- Bladder dysfunction: 66%
- Associated signs: ? 2 families with mild cerebellar features late in course
- Course: Progressive
- Loss of walking independently: Median disease duration 23 years
- Wheelchair dependent: Median 33 years
- Laboratory
- Cortical evoked responses: Abnormal
- Muscle biopsy
- Few SDH-positive muscle fibers
- Normal mitochondrial enzyme analysis
- CYP7B1 substrates: Oxysterols; High in serum & CSF
- 25-OHC, 27-OHC & ratio to total cholesterol
- 27-hydroxycholesterol: Serum levels correlate with disease severity & duration
- Atorvastatin + Chenodeoxycholic acid: Improve metabolic abnormalities
- SPG5B
● Recessive- Epidemiology: Tunisian family
- Genetics
- Clinical: Pure spastic pararplegia
- SPG7 or SPG5C
54
● Paraplegin (SPG7 gene; CMAP); Chromosome 16q24.3; Recessive or Dominant (Few mutations)
- Epidemiology
- Frequency: ~1.5% to 6% of SPG families
- European, Moroccan & Turkish families
- May present as sporadic HSP: Predominant spasticity in legs
- Genetics
- Mutation Types
- Frameshift: Insertion or Deletion
- Missense: A10S; Ala510Val (Common); A572V; G577S; F676L
- Inheritance
- Recessive: Usual
- Dominant (Probable): 9 base pair deletion in exon 11; Missense mutations
- Clinical correlations
- Null mutations: Associated with ataxia
- Optic atrophy: Arg470Gln (Homozygous); Asp411Ala (Heterozygous)
- Allelic disorders
- Ataxia, Spasticity + PEO, Adult onset
- Optic atrophy, Non-syndromic, Dominant: Asp411Ala
- SPG7
- Mutation Types
- Protein
5
- Cell localization: Mitochondria
- Inner mitochondrial membrane
- Hetero-oligomer with ATPase family gene 3-like 2 (AFG3L2): Forms m-AAA protease
- Tissue localization: Numerous; Higher in adult than fetal brain
- Structure: Homologous to yeast mitochondrial ATPases (metalloprotease)
- Function: Mitochondrial AAA-metalloprotease
- Substrate: OPA1
- Mutations: Frameshift
- Cell localization: Mitochondria
- Clinical: Pure spastic paraparesis, or Complicated syndromes (69%)
- Onset
- Age: 2nd to 5th decade
- Presenting feature: Gait change
- Clinical features
- Complex phenotype: More with younger onset age
- Upper motor neuron signs
- Tone: Increased; Legs > Arms
- Gait: Spastic
- Tendon reflexes in arms & legs: Increased
- Plantar response: Extensor
- Strength
- Relatively preserved compared to spasticity: May be normal
- Reduced
- Lower ± Upper extremities
- Proximal > Distal
- ? Distal predominance in some
- Sensation: Vibration sense reduced
- Bladder dysfunction (50%)
- Skeletal (40%): Scoliosis; Pes cavus
- CNS
- Eye
- Ptosis
- Movement
- Vertical gaze palsy
- External ophthalmoplegia
- Optic neuropathy
- Frequency: 40% to 100%
- Imaging: May be abnormal in asymptomatic patients
- May be only sign with dominant Asp411Ala mutation
- Cerebellar (57%)
- Limb ataxia
- Dysarthria
- Nystagmus
- Cervical dystonia
- Intellectual disability
- Eye
- Severe cases: Dysarthria; Dysphagia
- Progression
- Slow over decades
- May eventually need walking aids
- Onset
- Laboratory
- Serum CK: May be elevated
- Muscle pathology
- Histology (More severe involvement): COX- fibers; Some ragged red
- Mitochondrial oxidative enzyme activities in muscle or fibroblasts: Variable
- Complex I & II/III: Often Reduced
- Complex IV: Normal or reduced
- MRI: Cerebellar or cortical atrophy; Spinal cord normal
- EMG & NCV: Normal
- SPG7 variant syndrome: Ataxia + Spasticity & PEO, Adult onset
100
- Genetics
- Inheritance: Recessive
- Mutations: One mutation always Ala510Val
- Paraplegin protein
- Clinical
- Onset age: 1st to 5th decade; Mean 36 years
- Ataxia
- Gait & Trunk: Onset
- Limbs & Dysarthria: With disease progression
- Ocular
- Eye: PEO
- Cerebellar: Slow saccades; Nystagmus
- Pyramidal: With disease progression
- Spasticity: Legs
- Tendon reflexes: Brisk
- Plantar response: Extensor
- Course: Progression over years
- Laboratory
- Brain MRI: Cerebellar atrophy
- Muscle
- COX- muscle fibers
- Coenzyme Q10: Low in 1 patient
- Carriers: Some reported with
- Cerebellum: Signs or Atrophy
- Peripheral neuropathy
- Mouse model: Paraplegin knock-out
- Abnormal mitochondria in nerve terminals
- Distal axonopathy
- Spinal cord & PNS
- Axons: Swelling and degeneration
From: R Bucelli
SPG7 variant
Atrophy of Cerebellar hemispheres +
Medial & Lateral Rectus muscles - Genetics
- Epidemiology
- SPG 11
:
Spastic paraplegia with Thin corpus callosum (ARHSP-TCC)
4
● Spatacsin (ALS5; SPG11; KIAA1840; FLJ21439)
; Chromosome 15q21.1; Recessive
- Epidemiology
- Relatively common: Especially for complex SPG
- North America, Europe, Japan, Turkey
- Genetics
- Mutations: Nonsense, Deletion & Insertion
- Mechanism: Loss of function
- Allelic disorders
- Juvenile ALS, Recessive (ALS5)
- PLS, Juvenile onset
- Parkinsonism, levodopa responsive, juvenile onset
- HMSN, Axonal, Recessive (CMT 2X)
- SPG11
- Spatacsin protein
- Cytosolic & perinuclear distribution: Diffuse & reticular
- Possibly membrane associated
- Adult: Distributed throughout brain
- Neuron location: Axons & Dendrites
- Subcellular: Cytoskeletal & synaptic vesicles; Synaptosomes
- Axon maintenance: Cargo trafficking
- Clinical
- Onset
- Age: Usually before 20 years; Range 1 to 50 years
- Spasticity: Legs
- Mental slowing
- Parkinsonism: Occasional patient; Tremor & Akinesia
- Upper motor neuron signs
- Spasticity: Legs
- Hyperreflexia: Knees; Ankles may be increased or reduced
- Upgoing toes
- Dysarthria: Pseudo-bulbar
- Asymmetry: Mild
- Bladder function: Normal or Abnormal
- Lower motor neuron
- Weakness: Legs
- Wasting: Distal
- Sensory
- Early: Commonly normal
- Later in course: Neuropathy
- Pin, Temperature or Vibration sense reduced
- Neuropathic pain
- Ataxia: Mild
- CNS: Other
- Mental retardation: 25%; Progressive disorder
- Extrapyramidal: Parkinsonism, Juvenile, Levodopa responsive
- Other occasional features
- Eye
- Optic atrophy: May be more prominent on temporal side
- Retinitis pigmentosa
- Cataract
- Movement: Strabismus or Reduced convergence
- Clinodactyly
- Eye
- Course
- Progressive: Gait disorder & disability
- Wheelchair in 3rd decade
- Onset
- Laboratory
- Imaging: White matter lesions
- Corpus callosum
- Agenesis of, or thin, in 25%
- More abnormality: Increasing age; Rostral
- Periventricular
- Cortical atrophy: Frontal
- Corpus callosum
- NCV: Motor neuropathy
- Motor axon loss: Reduced CMAP amplitudes
- SNAPs: Normal
- EMG: Denervation in limbs
- Motor evoked potentials: Central conduction slow
- Imaging: White matter lesions
From: R Bucelli
SPG11: Thin Corpus Callosum
From: R Bucelli
SPG11: Ears of the Lynx sign
(T2 signal projecting from anterior lateral ventricles)- SPG11 variant syndrome: HMSN, Axonal, Recessive (ARCMT2X; CMT 2X)
106
- Epidemiology
- 12 families: 29 individuals
- Italy, Brazil, Canada, England, Iran, Japan
- Genetics
- Mutations: 15 different; Most truncating; Arg945Gly; Some same as for SPG11
- Mutation locations: Entire gene
- Inheritance: Recessive
- Allelic disorders
- Clinical
- Onset age: 4 to 35 years; Mean 11 years
- Weakness
- Distal
- Legs > Arms
- Asymmetric (40%)
- Gait disorder
- Proximal (14%)
- Wasting (Muscle): Legs & Hands
- Spasticity: Some patients
- Sensory loss (85%)
- Legs
- Modalities: Pin; Light touch; Proprioception
- Fasciculations (30%): Legs
- Skeletal
- Pes cavus
- Ankle contractures
- Scoliosis
- Tremor (34%)
- Bladder (31%) or Sexual (24%) dysfunction
- Cognitive impairment (10%)
- Course: Slow progression
- Laboratory
- NCV
- Axon loss: Small CMAP & SNAP amplitudes
- Velocities: Median > 38 m/s
- EMG: Denervation in hands & distal legs
- Nerve biopsy: Loss of Myelinated & Unmyelinated axons; Intra-axon aggregates
- Brain MRI: Thin corpus callosum in some patients
- Serum CK: Normal
- NCV
- Epidemiology
- Epidemiology
- SPG 14
10
● Chromosome 3q27-q28; Recessive- Epidemiology: Italian family
- Onset: Mean 30 years
- Clinical
- Spastic paraplegia
- Spasticity: Leg & gait
- Plantar response: Extensor
- Tendon reflexes: Increased in Legs
- Neuropsychological impairment
- Mental retardation: Mild
- Visual agnosia
- Memory disorder: Short & Long term
- Motor neuropathy
- Distal
- Mild
- NCV: Mild slowing in legs
- Skeletal: Pes cavus
- Progression: Slow over decades
- Spastic paraplegia
- SPG 15
16
● Spastizin (ZFYVE26; KIAA0321)
; Chromosome 14q24.1; Recessive
- Nosology: Kjellin syndrome
- Genetics
- Mutations
- Homozygous
- Truncating: Nonsense; Frameshift deletions; Complex rearrangements
- Mutation effects
- Degradation of mutant RNA or protein
- Loss of C-terminal putative leucine zipper domain & usually FYVE domain
- Mutations
- Spastizin protein
- Onset
- Age: 5 to 23 years
- Gait disorder
- Clinical
- Spasticity & Pyramidal features
- Tetraparesis
- Clonus
- Extensor plantar responses
- Increased tone
- Tendon reflexes: Increased
- Dysarthria
- Fecal & Urinary incontinence: Late in course
- Lower motor neuron
- Weakness: Distal arms & hands; Neck flexion
- Amyotrophy: Distal
- Cerebellar (32%): Mild upper limb ataxia; Some patients
- Cognitive (73%)
- Mental retardation
- Progressive intellectual deterioration in 2nd decade
- Other CNS features in few patients
- Psychosis
- Epilepsy
- Dystonia
- Hearing loss
- Visual acuity decreased
- Pigmented maculopathy
- Mildly reduced visual acuity
- Present at onset or few years later
- Slow progression
- Progression
- Often moderate to severe disability
- Wheelchair in 3 to 21 years
- Spasticity & Pyramidal features
- Laboratory
- MRI: Atrophy of cerebral hemispheres, corpus callosum, brainstem
- NCV: Axonal neuropathy (67%)
- Muscle biopsy: Denervation
- CSF: Normal
- SPG 18B
● Endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2; SPFH2); Chromosome 8p11.23; Recessive
- Epidemiology: 7 families
- ERLIN2 genetics
- Mutations
83: Recessive
- Types: Deletion; Null; Insertion, Out of frame
- Allelic disorders
- SPG18A, Dominant: Spastic paraparesis, Pure
- PLS, Juvenile onset
- Intellectual disability, Motor dysfunction & Joint contractures (IDMDC)
- ALS variant: Onset late in SPG course
- Mutations
83: Recessive
- ERLIN2 protein
- ERAD pathway
- Family: SPFH domain-containing lipid raft-associated proteins
- Location: Lipid rafts of Endoplasmic reticulum (ER)
- Associates with: Activated Inositol 1,4,5-trisphosphate (IP3) receptors
- May act as substrate recognition factor
- Endoplasmic reticulum–associated degradation pathway of IP3Rs
- Homologous protein: ERLIN1 (SPG62)
- Clinical
- Onset age: 2 to 6 years
- Gait disorder: Spastic
- Spasticity: Legs > Arms
- Weakness: Legs, some patients
- Reflexes: Tendon brisk; Plantar extensor
- Skeletal: Joint contractures; Scoliosis
- CNS: Varies among patients
- Mental retardation: 2 families
- Language disorders
- Epilepsy: 2 families
- Squint
- Course
- Spastic paraparesis: Progressive
- May evolve to: Rapidly progressive ALS-like syndrome
126
- Genetics
- Mutations: V168M & A309V (Dominant); D300V(Recessive); N125S (Sporadic)
- Clinical
- Onset
- Ages: 45 to 66 years
- Disease course before ALS: 20 to 45 years
- Site: Arms or Bulbar
- Other weakness: Respiratory
- Course: Death in 1 to 4 years
- Onset
- Genetics
- Laboratory
- EMG & Muscle biopsy: Normal
- CNS imaging: Often normal; Agenesis or hypoplasia of corpus callosum in 1 family
- ERLIN2 Variant syndrome: Primary Lateral Sclerosis, Juvenile onset
88
- Epidemiology: Saudi family
- ERLIN2 Genetics
- Mutation: Splice acceptor site; c.499-1G>T; Intron 7 of long gene isoform
- Inheritance: Recessive
- Clinical
- Onset
- Age: 8 months
- Difficulty crawling
- Muscle spasms
- Motor functions
- Walking: Delayed
- Progressive loss: After 2 years
- Wheelchair dependent: 11 to 12 years
- Bedridden: 15 years
- Other motor
- Weakness: Distal > Proximal
- Spasticity
- Tongue: Slow movement; No fasciculations
- Tone: Increased
- Tendon reflexes: Increased
- Plantar response: Extensor
- Speech: Progressively lost after 2 years
- Skeletal
- Spine: Kyphosis; Scoliosis
- Palate: High arched
- Upper jaw: Narrow
- Small limbs
- Eye movements: Saccadic pursuit
- Onset
- Laboratory
- Brain MRI: Normal
- NCV & EMG: Normal
- ERLIN2 variant syndrome: SPG18A, Dominant
- Epidemiology: 3 families, 13 patients
- Genetics
- Dominant mutations: SPFH domain
- Mutations: D69V, V71A, S129T, A151V, V168M, A309V
- Clinical: Spastic paraparesis, Pure
- Onset age: 9 to 46 yeaars
- Spastic paraplegia
- Spasticity: Legs
- Gait disorder
- Tendon reflexes: Brisk in legs
- Vibration loss (25%): Legs
- Bladder dysfunction: Few patients
- Course: Slow progression
- No seizures or cognitive Δ
- Laboratory
- Brain MRI: Normal
- NCV: Normal
- SPG, infantile onset (IAHSP)
29
● Alsin (ALS2); Chromosome 2q33.1; Recessive
- Epidemiology: Families in Algeria, Italy & France
- Genetics
- Mutations
- Type: Deletions & Splice site
- Frequency: Found in 4 of 10 families
- Allelic with
- Mutations
- Clinical
- Birth: Normal
- Onset: Infantile
- Spasticity
- Paraplegia: Onset at time of initial walking
- Upper limbs: Onset at 7 to 10 years
- Wheelchair necessary: < 10 years
- Progression to tetraplegia during 2nd decade
- Cranial nerves
- Onset 2nd decade
- Anarthria
- Dysphagia
- Eye movements: Slow
- Survival: Some patients into 3rd & 4th decade
- Cognitive functions: Normal
- Laboratory
- NCV & EMG: Normal
- Muscle biopsy: Normal
- Motor-evoked potentials (MEP): Early loss of corticospinal responses, in contrast with
- Somatosensory-evoked potentials: SSEP: Abnormal only in the later stages
- MRI
- Atrophy: Sylvian, Brainstem & Spinal cord
- Hyperlucencies in T2-weighted images: Along the pyramidal tract in oldest patient
- SPG24: Pure spastic paraplegia
33
● Chromosome 13q14; Recessive- Epidemiology: Saudi Arabian family
- Onset
- 1 year: Standing difficulty
- Gait disorder: Toe walking
- Clinical
- Spasticity: Legs > Arms; Scissor gait
- Tendon reflexes: Brisk in arms & legs
- Speech: Usually normal; May be dysarthric
- Weakness: Mild
- Bladder: Normal
- Sensation: Normal
- Laboratory
- MRI: Normal brain & spine
- SPG 26
50
● β-1,4-N-Acetylgalactosaminyltransferase 1 (B4GALNT1); Chromosome 12q13.3; Recessive
- Epidemiology: > 10 families
- B4GALNT1 genetics
- Mutations: Loss of function; Missense (Arg300Cys; Asp433Ala), Frameshift, Nonsense
- Allelic disorders
- AR-CMT2 + CNS
- Glutaric acidemia, Type 2
: c.263dupG mutation
- Neoplasms: Overexpression promotes progression & metastasis
- B4GALNT1 protein
- Function
- Ganglioside biosynthesis
- Adds GalNAc to carbohydrate moieties
- GA3 → GA2 ganglioside
- GM3 → GM2 ganglioside
- GD3 → GD2 ganglioside
- GT3 → GT2 ganglioside
- Reverse reaction: Performed by β-hexosaminidase
- Other Ganglioside & Glycolipid disorders
- Synthetic
- Infantile epileptic encephalopathy
:
ST3GAL5
- SPG26: B4GALNT1
- Infantile epileptic encephalopathy
- Glycolipid Degradation
- Gaucher disease
: GBA
- Fabry disease
: GLA
- Metachromatic leukodystrophy: ARSA
; Saposin
- Krabbe: GALC
- Tay-Sachs: HEXA
- Tay-Sachs AB variant/GM2 gangliosidosis
: GM2A
- Sandhoff disease
: HEXB
- GM1 gangliosidosis
: GLB1
- Gaucher disease
- Antibodies
- Synthetic
- Function
- Clinical
- Onset ages: 2 to 19 years
- Spastic paraparesis
- Legs: Spastic, moderate to severe
- Arm spasticity (33%)
- Dysarthria, pseudobulbar, mild (47%)
- Tendon reflexes: Brisk in legs; May be reduced late in disease course
- Plantar response: Upgoing in 60%
- Gait disorder: Spastic
- Bladder dysfunction
- Progression: Slow over decades; Most walk independently
- Strength: Leg weakness
- Amyotrophy: Distal Arms & Legs (60%), Late in disease course
- Vibration sense: Reduced at ankles in 50%
- Intellectual
- Impairment: IQ 50 to 70
- Emotional lability
- Cerebellar (55%): Saccadic dysfunction; Nystagmus; Dysmetria
- Pyramidal (44%)
- Skeletal: Pes cavus (50%); Socliosis (67%)
- Tongue: Tremor
- Other occasional
- Dyskinetic facial movements
- Dystonia
- Cataracts
- Strabismus (22%)
- Psychiatric (22%)
- Delayed puberty
- Laboratory
- NCV: Axonal sensory or motor neuropathy (60%)
- EEG: Normal
- MRI: Corpus callosum thick; Cortical atrophy; WM change; May be normal
- Testosterone: Reduced (67%)
- B4GALNT1 variant disorder: AR-CMT2 + Intellectual disability
129
- Epidemiology: 1 Korean patient
- Genetics
- Inheritance: Recessive
- Mutations: c.128dupC; c.451G>A
- Clinical
- Onset: 20 years
- Weakness: Distal legs
- Sensory loss: Large fiber
- Tendon reflexes: Absent at knees & ankles
- Cognitive impairment: Mild to Moderate
- Laboratory
- NCV: SNAP amplitudes reduced
- EMG: Denervation in distal legs
- Brain MRI: Normal
- SPG27: Pure spastic paraplegia
● Chromosome 10q22.1-q24.1; Recessive- Epidemiology: French-Canadian family
- Genetics: Overlap with locus for Dominant SPG9
- Clinical
- Onset age: 25 to 45 years
- Spastic paraparesis
- Legs
- Bladder involvement
- Tongue: Slow movements; Dysarthria
- Progression: Slow; Most walk independently
- Vibration sense: Reduced in feet
- Strength: Normal
- Laboratory
- NCV: Normal
- EMG: Normal; No denervation in legs
- SSEP: Reduced amplitudes
- SPG28: Pure spastic paraplegia
51
● Phospholipase DDHD1
;
Chromosome 14q22.1; Recessive
- Epidemiology: Moroccan, Turkish & French families
- Genetics
- Mutations: Missense; Splice; Stop
- Allelic syndrome: Retinopathy & Neurodegeneration with Brain Iron Accumulation (NBIA)
- DDHD1 protein
- Localization: Cytosol; Microsomes; Mitochondria
- Phospholipase A1, PA preferring
- Tissue expression: Ubiquitous
- ? Maintenance of organelle membranes & intracellular trafficking
- Clinical
- Onset age: Infancy to 15 years
- Spastic paraparesis
- Legs
- Progression: Assisted gait in 5th decade
- Tendon reflexes: Increased in Legs & arms
- Sensory loss
- Vibration: Reduced in distal legs
- Pin: reduced in legs
- Strength: Mild leg weakness
- Eye: Saccadic pursuit
- Laboratory
- Nerve: Axon loss
- Muscle: Mitochondrial changes in some patients
107
- mtDNA deletions
- SPG32: Paraplegia with Mental retardation & Brainstem malformation
63
● Chromosome 14q12-q21; Recessive- Epidemiology: 1 Portuguese family
- Onset age: 6 to 8 years
- Clinical
- Pyramidal signs
- Gait disorder: Walking with cane
- Tendon reflexes: Brisk in legs
- Plantar response: Extensor
- Bladder: Normal
- Skeletal: Pes cavus
- Mental retardation: Mild; IQ 50 to 60
- Polyneuropathy: 1 patient
- Ataxia: None
- Progression: Very slow
- Pyramidal signs
- MRI
- Cerebellar & Cortical atrophy
- Pontine dysraphism
- SPG35
68
● Fatty acid 2-hydroxylase (FA2H); Chromosome 16q23.1; Recessive
- Epidemiology: Omani and Pakistani families
- Genetics
- Mutations: Missense & Nonsense; Arg235Cys, p.Arg53_Ile58del
- Some patients: Uniparental chromosome 16 disomy
- Allelic disorder: Leukodystrophy with Spasticity & Dystonia
- FA2H protein
- Membrane bound
- Catalyzes 2-hydroxylation of galactosylceramide & sulfatide
- First step in incorporation of α-hydroxylated GalCer into myelin
- CNS location: Oligodendrocytes
- Required for long-term maintenance of myelin
- Mutations cause
- Reduced FA2H enzyme activity
- Abnormal hydroxylation of myelin galactocerebroside lipid components
- Clinical: NBIA syndrome
- Onset
- Age: 4 to 11 years
- Clinical: Gait disorder, spastic & Foot drop
- Pyramidal signs
- Gait disorder: Progression to wheelchair
- Spasticity: Legs > Arms
- Tendon reflexes: Brisk in legs
- Plantar response: Extensor
- Dysarthria: Mild
- Bladder: Urinary frequency
- Weakness: Legs
- Other CNS
- Cognition: Mental retardation (2 patients); Poor school performance
- Seizures: 2 patients
- Dystonia
- Sensation: Normal
- Course: Progressive
- Onset
- Laboratory
- MRI: Unremarkable or Leukodystrophy
- Bilateral & symmetric T2 hyperintensity in cerebral white matter
- Atrophy: Cerebellum, Brainstem, Cervical spinal cord
- Nerve conduction studies: Motor & Sensory normal
- Muscle biopsy: Denervation & Reinnervation
- MRI: Unremarkable or Leukodystrophy
- Spastic paraplegia with Leukodystrophy & Dystonia
72
● Fatty Acid 2-Hydroxylase (FA2H); Chromosome 16q23.1; Recessive
- Epidemiology: Consanguinous Arab-Muslim families; 9 patients
- Genetics:
- Mutations
- Intronic: Homozygous, c.786+1G/A
- Missense: Homozygous, D35Y
- Allelic disorder: SPG 35
- Mutations
- FA2H protein
- Membrane bound
- Catalyzes 2-hydroxylation of galactosylceramide & sulfatide
- Clinical: NBIA syndrome
- Onset
- Age: Childhood; 4 to 6 years
- Gait disorder
- Spasticity: Legs
- Dystonia: Trunk, Limbs & Face; Dysarthria
- Cerebellum: Dysmetria; Dysdiadochokinesis
- Cognitive dysfunction: Some patients
- Seizures: Mild; Some patients
- Progression: Rapid or Slow; Some lose ambulation in teens
- Onset
- Laboratory
- VEPs: Delayed
- EMG & NCV: Normal
- Brain MRI: Leukodystrophy
- Early: Abnormal periventricular white matter
- Tract involvement: Posterior limbs of internal capsules; Corticospinal
- Thinning of corpus callosum & pons
- SPG43
75
● c19orf12; Chromosome 19q12; Recessive
- Epidemiology: 1 Mali (Bambra) family
- Genetics
- Mutation: Ala63Pro
- Allelic disorder: NBIA4 (MPAN)
- c19orf12 protein
- Clinical
- Onset age: 7 to 12 years
- Pyramidal signs
- Gait disorder: Spastic
- Tendon reflexes: Brisk at knees; Reduced or increased at ankles
- Plantar response: Extensor
- Bulbar: Dysarthria in 1 patient
- Bladder: Normal
- Motor neuronopathy: Weakness & Wasting
- Hands & Feet
- Proximal leg weakness
- Contractures: Knees & Ankles
- Cognition: Normal
- Ataxia: None
- Progression: Slow; Ambulation present
- Same mutation may produce
270
- Optic atrophy
- Motor neuronopathy
- No spasticity
- SPG45: Spastic Paraplegia with early onset (SPG65)
74,
97
● 5'-Nucleotidase, cytosolic II (NT5C2);
Chromosome 10q24.32; Recessive
- Epidemiology: 10 patients
- Genetics
- Mutations
- Splice: c.175+1G>A; c.988-1G>T
- Frameshift: c.1225delA
- Stop: c.G86A (R29X); c.A445T (R149X)
- Mutations
- NT5C2 protein function
- Preferentially hydrolyzes IMP
- Purine & Pyrimidine nucleotide metabolism
- Clinical: Uncomplicated or Complicated SPG
- Onset age: Infancy to 18 months
- Upper motor neuron
- Spasticity: Mild; Legs > Arms
- Tendon reflexes: Increased
- Gait: Unsteady
- Strength: Normal
- Intellectual disability
- Ocular: Optic atrophy; Myopia; Some patients
- Skeletal: Some patients
- Contractures: Toes, Knees
- Hyperextension: Knees
- Pes equinovarus
- Laboratory
- MRI: Corpus callosum thin
- SPG46: Spastic Paraplegia with Mental impairment & Thin Corpus callosum
76
● β-Glucosidase 2 (Non-lysosomal glucosylceramidase; GBA2); Chromosome 9p13.3; Recessive
- Epidemiology: Tunisian & Italian families
- Genetics
- Mutations: Trp173*, Arg234*, Arg630Trp, c.1471_1474dupGGCA; Arg879Gln; Arg399* (Recurrent)
- Allelic with: Spastic Ataxia
- GBA2 protein
- Clinical
- Onset ages: 2 to 10 years
- Spastic paraplegia
- Legs > Arms
- Spasticity
- Tendon reflexes: Brisk
- Plantar reflexes: Extensor
- Bladder dysfunction (50%)
- CNS
- Mental retardation
- Cerebellar signs: Mild
- Pseudobulbar dysarthria
- Strength: Normal
- Skeletal: Pes cavus, Scoliosis
- Cataracts: Congenital
- Polyneuropathy (27%): Axon loss
- Disease progression: Slow
- Hypogonadism
- Laboratory
- EMG & NCV: Normal
- MRI
- Thin corpus callosum
- Cerebellar & Cerebral atrophy
- Variant syndrome: Spastic Ataxia
92
● β-Glucosidase 2 (Non-lysosomal glucosylceramidase; GBA2); Chromosome 9p13.3; Recessive
- Epidemiology: Tunisian & Cypriot families
- Genetics
- Mutations: Nonsense & Missense; Tyr121*, Arg340*, Arg873His
- Allelic with: SPG 46
- GBA1 mutations cause Gaucher disease
- GBA2 protein
- Cell membrane
- Catalyzes conversion of glucosylceramide to free glucose & ceramide
- Involved in sphingomyelin generation
- Clinical
- Onset
- Age: Childhood to Teens; 3 to 15 years
- Gait ataxia
- Ataxia
- Gait: Wide based
- Dysarthria
- Truncal
- Eyes: Saccadic pursuit; Nystagmus
- Upper motor neuron features
- Legs > Arms
- Tendon reflexes: Brisk in legs
- Spasticity: Legs > Arms
- Plantar response: Extensor
- Bladder dysfunction
- Peripheral nerve: Position sense loss in some patients
- Skeletal (50%): Pes cavus; Scoliosis
- Hearing loss
- Disease course: Slow progression; Wheelchair after 2 to 3 decades
- Other, occasional
- Ophthalmoparesis (Jerky pursuit & Slow saccades)
- Intellectual disability (Mild)
- Sphincter disorders
- Head tremor
- Onset
- Laboratory
- NCV: Axonal neuropathy; Sensory ± Motor
- EMG: Denervation
- MRI: Head & Spine normal or Cerebellar atrophy
- SPG47: Spastic Paraplegia with Thin Corpus callosum
84,
130
● Adaptor-related protein complex 4, Beta-1 subunit (AP4B1)
Chromosome 1p13.2; Recessive
- Epidemiology: Multiple families
- Genetics
- Mutations: Stop
- Allelic with: CPSQ5
- AP4B1 protein
- Clinical
- Onset age: Infancy
- Spastic paraparesis
- Gait: Spastic; Loss of ambulation
- Tendon reflexes: Brisk
- Plantar reflexes: Extensor
- Course: Slowly progressive
- Mental retardation: Delayed psychomotor development
- Seizures
- Head: Face dysmorphism; Microcephaly
- Laboratory
- Brain MRI
- Corpus callosum thin
- Periventricular white matter abnormalities
- Ventriculomegaly: Asymmetric
- Brain MRI
- SPG48: Spastic Paraplegia
77
● Adaptor-related protein complex 5, Zeta-1 subunit (AP5Z1; KIAA0415)
;
Chromosome 7p22.1; Recessive
- Epidemiology: 5 families
- Genetics: Mutations
- Complex indel in exon 2: c.[80_83del4;79_84ins22]
- Insertion is imperfect quadruplication of CTGTAA(A)
- Generates frameshift & stop codon following amino-acid 29 (p.R27LfsX3)
- Other: Stop & Missense
- AP5Z1 protein
- Clinical
- Onset ages: 13 to 60 years
- Spastic paraparesis
- Gait disorder
- Urinary incontinence
- Polyneuropathy: Sensory-Motor
- CNS: Ataxia; Dystonia; Parkinsonism
- Progression: Slow
- Laboratory
- Brain MRI: Periventricular white matter hyperintensities
- Spine MRI: Cord hyperintensities in 1 patient
- Retina: Depigmented zones
- Skin fibroblasts: Autofluorescent & lamellar lysosomal storage material
- SPG49: Spastic Paraplegia, Complex, with Thin Corpus Callosum
90
● Tectonin beta-propeller repeat containing 2 (TECPR2)
;
Chromosome 14q32.31; Recessive
- Nosology: HUGO designates SPG49 as being due to CYPUI mutations (SPG56)
- Epidemiology: Jewish Bukharian families
- Genetics
- Mutation: 1 bp frameshift; Leads to premature stop; c.3416delT
- Allelic disorder: Dysautonomia with Intellectual disability (HSAN9)
- TECPR2 protein
- Autophagy: Positive regulator
- Interacts with six human Atg8 homologs, including LC3
- Clinical
- Onset
- Age: < 2 years
- Hypotonia
- Developmental delay
- Spastic paraparesis
- Gait: Spastic, Rigid, Ataxic
- Speech: Dysarthric
- Intellectual disability: Severe
- Face: Hypomimic
- Respiratory disorders
- Central hypoventilation, episodic
- Wake apnea: With disease progression
- Dysmetria: Arms
- Tendon reflexes: Absent
- Seizures: Occasional patient
- Gastroesophageal reflux: Recurrent pulmonary infections
- Skeletal: Dysmorphic features
- Short stature, mild
- Brachycephalic microcephaly,
- Face: Round; Low anterior hairline, Dental crowding
- Neck: Short broad
- Chubby appearance
- Onset
- Laboratory
- Metabolic testing: Normal
- MRI
- Corpus callosum: Thin
- Atrophy: Cerebral & Cerebellar (Vermis)
- Muscle biopsy: Normal
- EMG & Nerve conduction: Normal
- EEG: Diffuse slowing
- TECPR2 variant syndrome: Dysautonomia with Intellectual disability (HSAN9; HSAN IX)
105
- Epidemiology
- > 10 families
- Pathogenic carrier frequencies
- General 1:1221
- Ashkenazi-Jewish 1:155
- South Asian 1:7654
- Genetics
- Mutations
- Types: Stop or Missense
- Missense: N& Cterminal regions containing β-propeller repeats
- Ashkenazi-Jewish founder mutation: c.1319delT
- Inheritance: Recessive
- Mutations
- Clinical
- Onset age: Congenital or 1st year
- CNS
- Intellectual disability
- Delayed global psychomotor development
- Speech delay
- Hyperactivity (30%)
- Walking: Very delayed
- Sleep disorder: Apnea, central
- Ataxia: Gait
- Vision impairment (40%)
- Intellectual disability
- Hypotonia
- Dysarthria
- Autonomic
- GI: Vomiting; GE reflux; Dysphagia
- Cough
- Blood pressure: Instability
- Other: Temperature instability; Hyperhidrosis
- Respiratory
- Apnea, central; Hypoventilation; Infections
- Common cause of morbidity
- Polyneuropathy
- Sensory loss: Pain (25%); Ataxia in some
- Tendon reflexes: Reduced in legs
- Skeletal
- High arched palate
- Pectus carinatum
- Short stature & neck
- Face: Dysmorphism
- Plantar response: Extensor
- Laboratory
- Sympathetic skin response: Autonomic neuropathy
- EMG: Normal
- NCV: Normal
- EEG: Normal in most
- Nerve biopsy: Normal
- Brain MRI: Cerebral & Vermian atrophy; Corpus callosum thin (50%)
- Epidemiology
- SPG53: Spastic Paraplegia with Mental Impairment
● Vacuolar protein sorting 37, yeast, homolog of, A (VPS37A; HCRP1);
Chromosome 8p22; Recessive
- Epidemiology: 2 Arab Moslem families, 9 patients
- Mutation: Lys382Asn; Missense; Homozygous
- VPS37A protein
- Location: LAMP1-positive endosomes
- Subunit of the endosomal sorting complex
- Required for transport I (ESCRT-I) complex
- May play a role in ubiquitination
- Clinical
- Onset age: Early childhood; 7 to 36 months
- Delay
- Developmental: Cognitive & Speech
- Motor: Difficulty standing & walking
- Spasticity
- Legs > Arms
- Tendon reflexes: Increased
- Clonus
- Vibration sense: Reduced in some
- Skeletal
- Kyphosis
- Pectus carinatum
- Hyperflexibility: Small joints
- Hypertrichosis (30%)
- Laboratory
- Brain MRI: Usually normal; Occasional white or gray matter changes
- Normal: EMG, Muscle biopsy & EEG
- SPG54: Spastic Paraplegia with Thin Corpus Callosum
89
● Phospholipase DDHD2
;
Chromosome 8p11.23; Recessive
- Epidemiology: > 20 families
- Mutations
- > 35 described
- Location: DDHD domain & other
- Often private
- Stop, Frameshift. or Missense
- Allelic disorder: Spastic-Ataxia, Adult onset
- Phospholipase DDHD2 protein
- Intracellular phospholipase A1 (iPLA1)
- Localization: cis-Golgi; ER -Golgi intermediate compartment
- Hydrolyzes preferentially phosphatidic acid & phosphatidylethanolamine.
- May be involved maintenance of endoplasmic reticulum or Golgi
- Synaptic function: Active zones; Facilitates membrane & vesicle fusion
- Organelle biogenesis
- Membrane trafficking
- Clinical
- Onset age: < 2 years
- Spastic paraplegia
- Legs & Arms
- Gait: Spastic
- Tendon reflexes: Brisk
- Urinary or fecal incontinence (33%)
- Sensation: Normal
- Intellectual disability
- Eye: Strabismus; Optic nerve hypoplasia
- Contractures: Foot
- Laboratory
- MRI
- Thin corpus callosum
- Periventricular white-matter hyperintensities
- Syrinx (50%)
- Mitochondrial function: Normal
- MRS: Lipid accumulation in thalami & basal ganglia
- MRI
- DDHD2 variant: Spastic ataxia syndrome
140
- Epidemiology: 7 families; 1% to 2% of AR SP
- Genetics
- Inheritance: Recessive
- Mutations: Missense or Stop; R112Q, D660H
- Clinical
- Onset age: 3rd to 6th decade
- Spasticity
- Tendon Reflexes: Increased
- Sensory loss: large fiber modalities
- Cognitive Δ: Some patients
- Ataxia (50%)
- Sensory neuropathy
- Laboratory
- Lipid droplets & triglycerides in brain & spinal cord
- SPG56: Spastic Paraplegia with Thin Corpus Callosum
91
● Cytochrome P450, Family 2, Subfamily U, Polypeptide 1 (CYP2U1);
Chromosome 4q25; Recessive
- Nosology: Called SPG49 by HUGO
- Epidemiology: 16 patients
- Mutations: Missense or Deletion; Homozygous or Heterozygous; Asp316Val
- CYP2U1 protein
- Location: Endoplasmic reticulum & Mitochondrial
- ω- and ω-1 fatty-acid (C16–C22) hydroxylation
- Catalyzes hydroxylation of arachidonic acid & related long-chain fatty acids
- Eicosapentaenoic (EPA) & Docosahexaenoic (DHA) acids
- Metabolites: 19- and 20-hydroxyeicosatetraenoic (HETE) acids
- Clinical
- Onset
- Age: Birth to 8 years
- Gait disorder
- Spastic paraplegia
- Spastic gait
- Tendon reflexes: Increased in Legs > Arms
- Dysarthria: Mild in few patients
- Course: Slow progression
- Dystonia (25%)
- Cognitive delay (20%): May be progressive
- Eye: Pigmentary degenerative maculopathy
- Onset
- Laboratory
- MRI
- May be Normal
- White matter: Lesions & Corpus callosum thin
- Calcifications: Globus pallidus
- NCV: Axonal neuropathy
- Sub-clinical
- Motor-Sensory
- Legs > Arms
- MRI
- SPG59: Spastic Paraplegia
97
● Ubiquitin-specific protease 8 (USP8);
Chromosome 15q21.2; Recessive
- Epidemiology: 1 family, 3 patients
- Genetics: Q310K; Missense mutation
- Clinical
- Onset age: 20 months
- Spasticity
- Gait, Scissors: Walk with support
- Tendon reflexes: Increased in legs
- Progression: Slow
- Sphincter: Normal
- Sensation: Normal
- Cognition: Normal or Borderline
- Laboratory
- EMG/NCV: Normal
- Brain MRI: Normal
- SPG60: Spastic Paraplegia
97
● WD repeat domain 48 (WDR48);
Chromosome 3p22.2; Recessive
- Epidemiology: 1 patient
- Genetics
- Mutation: del628E
- WDR48 protein function
- Regulator of deubiquitination
- Clinical: Complicated SPG
- Onset age: 1 year
- Motor: Gait difficulty
- UMN: Increased tone; Knee DTRs increased
- Neuropathy: Ankle DTRs reduced
- Other: Nystagmus; Mild learning disability
- Laboratory
- NCV: Polyneuropathy
- SPG61: Spastic Paraplegia
97
● ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1);
Chromosome 16p12.3; Recessive
- Epidemiology: 10 patients; 6 families
- Genetics
- Mutations: Stop > Missense
- ARL6IP1 protein function
- Clinical: Complicated SPG
- Onset age: Prenatal to 14 months
- Development
- Hypotonia: Axial
- Motor delay
- Respiratory insufficiency
- Regression in some
- Pyramidal (UMN): Spasticity
- Scissor gait
- Knee DTRs brisk
- Gait: Unsteady or Non-ambulatory
- Tendon reflexes
- Ankles: Absent
- Other: Brisk
- Plantar response: Extensor
- Polyneuropathy
- Sensory loss
- Acromutilation: Asymptomatic bone fractures
- Cognition: Normal
- Course: Death in childhood in some
- Laboratory
- NCV: Motor & Sensory axon loss, Legs > Arms
- Muscle: Denervation
- Brain MRI: Subcortical atrophy; Leukoencephalopathy; Corpus callosum agenesis
- SPG62: Spastic Paraplegia
97
● ER lipid raft associated 1 (ERLIN1);
Chromosome 10q24.31; Recessive
- Epidemiology: > 20 patients
- Genetics
- Mutations
- Stop: c.C763T; p. R255X
- Missense: c.G149T ;p.G50V
- Frameshift: c.862_868delACCAGG; p.del203-204YQ
- Allelic disorder
- Mutations
- ERLIN1 protein function
- ER-associated degradation
- Lipid rasft protein
- Subcellular: Endoplasmic reticulum; Nuclear envelope
- Homologous protein: ERLIN2 (SPG18)
- ER disorders
- Clinical
- Onset age: 17 months to 13 years
- UMN
- Spasticity: Legs > Arms
- Gait: Unsteady; spastic
- DTRs: Increased in most
- Plantar reflex: Extensor
- Ataxia (50%)
- Amyotrophy (50%)
- Skeletal
- Contractures: Knees (20%)
- Scoliosis
- Intelligence: Borderline or Normal
- Laboratory
- EMG/NCV: Normal
- Brain MRI: Normal
- ERLIN1 variant syndrome: ALS, Early onset, Slow progression
119
- Epidemiology: Turkish family
- Genetics
- Inheritance: Recessive
- Mutation: Homozygous; Missense; Val94Ala
- Clinical
- Onset age: 2nd decade
- Spasticity
- Gait: Onset in teens
- Bulbar: Onset in 5th decade
- Plantar response: Extensor
- Tendon reflexes: Brisk
- Lower motor neuron: Hand atrophy
- Course: Slow progression over decades
- Laboratory
- EMG: Denervation in tongue, arms & legs
- SPG63: Spastic Paraplegia + Thin corpus callosum
97
● Adenosine monophosphate deaminase 2 (AMPD2);
Chromosome 1p13; Recessive
- Epidemiology: 2 patients
- Genetics
- Mutation: c.318delT; p.C107Afs365X; Frameshift
- Allelic with: Pontocerebellar hypoplasia 9 (PCH9)
- AMPD2 protein function
- Deaminates AMP to IMP in purine nucleotide metabolism
- Maintenance of cellular guanine nucleotide pools
- Regulates feedback inhibition of adenosine derivatives on de novo purine synthesis
- Expression: Widespread; Type I & Smooth muscle; Nerve
- Also see: AMPD1
- Clinical: Complicated
- Onset age: 1 to 2 years
- UMN
- Delayed walking
- Gait: Scissors
- Tone: Increased
- DTRs: Increased
- Plantar response: Extensor
- Cognition: Normal
- Sensation: Normal or Reduced
- Laboratory
- MRI: Periventricular WM changes; Corpus callosum thin
- AMPD2 Variant syndrome: Pontocerebellar hypoplasia 9 (PCH9)
- AMPD2 Genetics
- Inheritance: Recessive
- Mutations
- Null alleles or Missense: Some have residual activty
- D552fs; E778D; Y349X; R674H; D793Y
- Allelic with: SPG63
- AMPD2 protein
- Clinical
- Microcephaly
- Hypotonia
- Spasticity
- Limbs
- Tendon reflexes: Increased
- Contractures: Progressive
- Seizures: Some patients
- Face: Dysmorphic features
- Course
- Laboratory
- MRI
- Cerebellum & Pons: Size reduced ≥ 50%
- Posterior fossa: Mega cisterna magna; Flat ventral pons (Fluid-filled)
- Atrophy: Cerebral cortex
- Corpus callosum: Hypoplasia or Aplasia
- EEG: Epileptic activity
- NCV: Neuropathy, Axonal
- MRI
- AMPD2 Genetics
- SPG64: Spastic Paraplegia
97
● Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1);
Chromosome 10q24.1; Recessive
- Epidemiology: 2 families, 4 patients
- Genetics
- Mutations
- Missense: c.G649A; p.G217R
- Stop: c.G719T; p.E181X
- Mutations
- ENTPD1 protein function
- Hydrolyzes ATP & other nucleotides
- Regulates purinergic transmission
- Clinical: Complicated SPG
- Onset age: 1 to 4 years
- UMN: Spasticity; Abnormal gait; Plantar reflex extensor
- CNS, other
- Intelligence: Moderate disability or Borderline
- Aggressive behavior
- Amyotrophy (75%)
- DTRs: Varied
- Puberty: Delayed
- Some patients
- Microcephaly
- Cataract, congenital
- Pes equinovarus
- Laboratory
- Brain MRI: White matter changes, mild
- SPG66: Spastic Paraplegia
97
● Arylsulfatase family, member I (ARSI);
Chromosome 5q32; Recessive
- Epidemiology: 1 patient
- Genetics
- Mutation: c.1641insA; p.C548Mfs559X; Frameshift
- ARSI protein function
- Hydrolyze sulfate esters
- Hormone biosynthesis
- Clinical: Complicated SPG
- Onset age: 1.5 years
- Spasticity
- Tendon reflexes: Absent
- Gait: Non-ambulatory
- Sensory loss
- Intelligence: Borderline
- Contractures: Pes equinovarus
- Laboratory
- NCV: Sensory-Motor neuropathy
- MRI: Corpus callosum & Cerebellar hypoplasia, Colpocephaly
- SPG67: Spastic Paraplegia
97
● Post-GPI attachment to proteins 1 (PGAP1);
Chromosome 2q33.1; Recessive
- Nosology: Neurodevelopmental disorder + Dysmorphic features, Spasticity, Brain abnormalities (NEDDSBA)
- Epidemiology: 5 families
- Genetics
- Mutation: c.1952+1G>T; Splice
- PGAP1 protein
- Endoplasmic reticulum
- GPI biosynthesis
- GPI inositol deacylase
- Catalyzes inositol deacylation of glycosylphosphatidylinositol (GPI)
- ER-to-Golgi transport of GPI-anchor proteins
- Clinical
- Onset age: 4 months to 4 years
- Motor delay
- Cognition: Borderline to normal
- Spasticity
- Tendon reflexes: Increased in legs
- Tremor
- MRI: Variable
- Corpus callosum agenesis
- Cortical atrophy
- Vermis atrophy
- Nosology: Neurodevelopmental disorder + Dysmorphic features, Spasticity, Brain abnormalities (NEDDSBA)
- SPG69: Spastic Paraplegia
97
● RAB3 GTPase activating protein subunit 2 (RAB3GAP2);
Chromosome 1q41; Recessive
- Epidemiology: 1 patient
- Genetics
- Mutation: c.T1955G; p.L252X; Stop codon
- Allelic disorders
- Martsolf syndrome 1
- Warburg micro syndrome 2
- Muscular dystrophy/Short stature
- Martsolf syndrome 1
- RAB3GAP2 protein function
- Exocytosis of neurotransmitters & hormones
- Autophagy: Positive modulator
- GTPase activating complex subunit: Specificity for RAB3 Rab-GTPase activating proteins
- Clinical: Complicated SPG
- Onset age: 6 months
- Developmental delay: Global
- Spasticity
- Dysarthria
- Tendon reflexes: increased in legs
- Plantar reflex: Extensor
- Deafness
- Cataracts
- Cognition: Intellectual disability
- Brain MRI: Normal
- RAB3GAP2 variant: Muscular dystrophy/Short stature
134
- Epidemiology: Mennonite sibling pair
- Genetics
- Inheritance: Recessive
- Mutation: Missense; Homozygous; Arg420Cys
- Clinical
- Onset age: 2nd decade
- Skeletal: Microcephaly; Short stature
- Tracheomalacia
- Face: Inexpressive; Eyebrows arched; Philtrum long; Upper lip thin
- Eyes: Ptosis
- Weakness: Proximal; Arms, Scapulae & Legs; Dysphagia
- Muscle mass; Reduced
- Laboratory
- EMG: Myopathic
- Serum CK: 3,200
- SPG71: Spastic Paraplegia
97
● Zinc finger RNA binding protein (ZFR)
;
Chromosome 5p13.3; Recessive
- Epidemiology: 1 patient
- Genetics
- Mutation: c.T956C; p.L319P; Missense
- ZFR protein function
- ? RNA localization
- Clinical: Uncomplicated SPG
- Onset age: 1 year
- Spasticity
- Gait: Scissors or Lost
- Tendon reflexes: Increased in legs
- Plantar reflex: Extensor
- Cognition: Normal
- Laboratory
- MRI: Corpus callosum thin
- EMG/NCV: Normal
- SPG75: Spastic Ataxia 75
97
● Myelin Associated Glycoprotein (MAG);
Chromosome 19q13.12; Recessive
- Epidemiology: 12 patients
- Genetics
- Mutations: Missense (Cys430Gly, Ser133Arg) & Nonsense
- Allelic disorders
- Pelizaeus-Merzbacher-like
- Cerebellar Ataxia + Oculomotor Apraxia
- MAG protein
- Other disorder: MAG neuropathy
- Clinical
- Onset age: 1 to 3 years
- Developmental delay
- Spasticity: Gait; Tendon reflexes increased
- Ataxia: Gait; Dysarthria; Dysmetria; Tremor
- Amyotrophy
- Sensory loss: Legs
- Tendon reflexes: Reduced
- Dystonia
- Intellectual disability
- Eyes: Nystagmus; Optic atrophy; Oculomotor Apraxia in 1 family
- Laboratory
- Brain MRI: Optic nerve, Cerebellum & Corpus callosum atrophy
- NCV: Axon loss
- MAG variant: Pelizaeus-Merzbacher-like (PML) Infant-onset disorder
- Epidemiology: 5 families; 7 patients
- Genetics
- Mutations: Missense (c.399C>G, p.S133R; Homozygous); Null
- Inheritance: Recessive
- Clinical
- Onset age; Infancy
- Mental retardation
- Spastic paraparesis: Legs > Arms; Dysarthria
- Tendon reflexes: Reduced
- Ataxia
- Eye: Nystagmus; Optic atrophy
- Extrapyramidal
- Course: Slow progression
- Laboratory
- NCV
- Distal motor latencies: Prolonged
- Velocity: Reduced
- Brain MRI
- Corpus callosum & Cerebelum atrophy
- White matter hyperintensities
- Nerve pathology
- MAG: Absent
- Onion-bulbs: Ill-formed
- Myelin sheath: Thin
- NCV
- SPG76: Spastic Paraplegia 76
109
● Calpain 1 (CAPN1);
Chromosome 11q13.1; Recessive
- Nosology: Spastic ataxia
- Epidemiology: 35 families
- Genetics
- Mutation types: Nonsense, Missense, Frameshift, Splice-site
- Mutation locations: Functional domains of CAPN1 protein; No hotspot
- Allelic disorder: Spinocerebellar ataxia in Parson Russell Terrier dogs
- CAPN1 protein
127
- Location: Central nervous system; Muscle
- Heterodimer: With small subunit CAPNS1
- Protease
- Calcium-dependent
- Neutral
- Non-lysosomal: Not degredative
- Cleaves vesicle fusion protein dysferlin
- Role in: Repair of mechanical membrane damage
- Overlap with Calpain-2
- Loss of both CAPN1 & CAPN2
by knockout of CAPNS1
: Myopathy
- No effect of calpains on recovery from membrane perforation by streptolysin-O or saponin
- Clinical: Complicated or Pure HSP
- Onset age: 19 to 38 years; Mean 28 years
- Spasticity
- Legs > Arms
- Gait
- Hyperreflexia: Legs ± Arms
- Extensor plantar response (80%)
- Weakness (60%): Legs ± Arms; Distal
- Dysarthria (80%)
- Bladder dysfunction (20%)
- Foot deformity (60%): Pes cavus
- Ataxia (70%): Limb; Gait
- Sensory: May be normal
- Polyneuropathy (20%): Sensory loss
- Ocular: Saccades slow in 1 family
- Course
- Progressive
- Females: More likely to develop complicated HSP
- Laboratory
- NCV: Normal or Axonal sensory neuropathy
- MRI: Normal or Cervical spinal cord atrophy or Cerebellar atrophy
- CAPN1 variant syndrome: Spinocerebellar ataxia in Parson Russell Terrier dogs
- SPG83: Spastic Paraplegia
● 4-Hydroxyphenylpyruvate Dioxygenase-like (HPDL);
Chromosome 1p34.1; Recessive
- Epidemiology: 15 families
- Genetics
- Mutations: Gly50Asp
- Allelic disorder: NEDSWMA
more with Truncating mutations
- HPDL protein
- Mitochondrial
- Oxygenase: Vicinal oxygen chelate (VOC) superfamily
- Metalloenzyme: Iron-containing, non-heme
- Clinical
- Onset age: Mid-Teens
- Gait: Unsteady
- Muscle: Cramps; Myalgia, Poor exercise tolerance
- Spastic paraparesis: Leg DTRs increased; Plantar response extensor; Bladder urgency
- Course: Progressive; May lose walking
- Other: Dysarthria, Dysphagia
- Cognition: Normal
- Laboratory
- Brain & Spine MRI: Normal
- SPG84: Spastic Paraplegia
● Phosphatidylinositol (PI) 4-kinase, Catalytic α (PI4Ka);
Chromosome 22q11.21; Recessive
- Epidemiology: 2 patients
- Genetics
- Mutations: Hypomorphic; Deletion & Missense
- Allelic disorder
- Polymicrogyria, perisylvian + Cerebellar hypoplasia & Arthrogryposis (PMGYCHA)
- Polymicrogyria, perisylvian + Cerebellar hypoplasia & Arthrogryposis (PMGYCHA)
- PI4Ka protein
- Catalyzes 1st step in biosynthesis of Phosphatidylinositol 4,5-bisphosphate
- Clinical
- Onset age: Childhood to Teens
- Spastic paraparesis
- Legs
- Tendon reflexes: Increased
- Hand weakness
- Pes cavus
- Nystagmus
- Cognitive: Impairment with younger onset
- Infections, Recurrent
- GI: inflammatory bowel disease; Multiple intestinal atresia
- Laboratory
- Brain MRI: Cervical spinal cord atrophy
- Immune: B-Cell Lymphopenia & Hypogammaglobulinemia 147
- SPG86: Spastic Paraplegia
● ABHydrolase Domain-containing Protein 16A, phospholipase (ABHD16A);
Chromosome 6p21.33; Recessive
- Epidemiology: 9 families; 18 patients
- Genetics
- Mutations: Missense & Stop
- ABHD16A protein
- Endoplasmic reticulum membrane protein
- Main brain phosphatidylserine (PS) hydrolase
- Colocalizes with ABHD12
- General
- Lipid metabolism
- Intracellular signaling
- Nosology
- Phosphatidylserine lipase ABHD16A
- α/β Hydrolase domain-containing protein 16A
- Clinical
- Onset age: Infancy or Early childhood
- Spasticity
- Seizures: Some patients
- PNS: Axon loss in some patients
- Developmental delay: Global
- Face: Dysmorphic
- Skeletal: Scoliosis; contractures
- Skin pigmentation: Increased or Decreased
- Course: Progressive
- Laboratory
- Brain imaging: White matter & corpus callosum Δ;
- SPG87: Spastic Paraplegia
● Transmembrane protein 63C (TMEM63C);
Chromosome 14q24.3; Recessive
- Epidemiology: 3 families, 7 patients
- Genetics
- Mutations: Deletion, Duplication, Stop
- TMEM63C protein
- Channel subunit: Hyperosmolarity-activated ion currents
- ER & Mitochondrial morphologies & dynamics
- Clinical
- Onset: Infancy to 19 mo
- Spasticity: Paraparesis; DTRs brisk
- Spinal: Lumbar lourdosis
- Other CNS: Intellectual disability; Speech delay
- Laboratory
- Nerve conductions & EMG: Normal
- Brain MRI: Normal
- SPG88: Spastic Paraplegia
● Karyopherin α-3 (KPNA3);
Chromosome 13q14.2; Dominant
- Epidemiology: 6 families; 11 patients
- Genetics
- Mutations: Missense; Often Leu
- KPNA3 protein
- Subunit of a nuclear transport receptor (NTR)
- Nucleocytoplasmic trafficking
- Transport HNRNPK
& PCAF (KAT2B)
- Clinical
- Onset age: Infant
- Spasticity
- Walking: Delayed or None
- Tendon reflexes: Brisk
- Intellectual disability: Some patients
- Course: Slow progression
- Laboratory
- Brain MRI: White matter Δ; Cerebellar atrophy; Some normal
- SPG89: Spastic Paraplegia, Childhood onset
● Autocrine Motility Factor Receptor (AMFR; GP78);
Chromosome 16q13; Recessive
- Epidemiology: 20 patients, 8 families
- Genetics
- Mutations: Loss of function; Often homozygous
- AMFR protein
- RING-H2 finger E3 ubiquitin ligase
- Anchored at endoplasmic reticulum (ER)
- Mediates polyubiquitination: HMGCR & INSIG1
- ER-associated degradation (ERAD)
- Clinical
- Onset age: Childhood
- Spasticity
- Tendon reflexes: Increased
- Plantar response: Extensor
- Gait: Unsteady
- Paraparesis: Most
- Quadriparesis: Severe patients; May also have seizures
- Muscle cramps
- Motor delay: Late walking
- Developmental delay (50%): Intellectual; Learning disabilities
- Laboratory
- Brain MRI: Corpus callosum thin
- SPG: Spastic paraplegia & Psychomotor retardation ± Seizures (SPPRS)
● HECT Domain- and ankyrin repeat-containing E3 ubiquitin protein ligase 1 (HACE1; KIAA1320);
Chromosome 6q16.3; Recessive
- Epidemiology: 6 families; 14 patients
- Genetics
- Mutations: Often stop
- Allelic disorders
- Lung cancer mutations
- Ataxia, Norwegian elkhound, black
- HACE1 protein
133
- E3 ubiquitin ligase
- Regulates activity of cellular GTPases
- Tumor suppressor
- Mutations: Disordered autophagy, mitophagy & oxidative function
- Clinical
- Onset: Birth
- Psychomotor development: Delayed
- Spasticity: Legs; Gait disorder; Dysarthria; Slow progression
- Seizures (60%): Especially myoclonic
- Ataxia: Gait
- Other: Some patients
- Ocular: Strabismus, Myopia, Retinal dystrophy
- Face: Hypotonia
- Dystonia
- Hearing loss: Sensorineural
- Skeletal: Kyphosis, Scoliosis, Hip dislocation, Foot deformities; Large head
- Genitalia: Hypoplastic in males
- Laboratory
- Brain imaging: Cerebral atrophy; Corpus callosum thin
- SPG 90: Spastic paraplegia, Complex
139
● Serine palmitoyltransferase, small subunit, A (SPTSSA);
Chromosome 14q13.1; Recessive or Dominant de novo
- Epidemiology: 3 patients
- Genetics
- Mutations: Thr51Ile (Dominant); Gln58X (Recessive)
- Allelic disorders
- SPG90A
: Dominant
- SPG90B
: Recessive
- SPG90A
- SPTSSA protein
- Location: Endoplasmic reticulum membrane
- Catalyzes 1st, & Rate-limiting, step in sphingolipid biosynthesis
- Small SPT subunit
- Stimulates SPT activity
- Confers Acyl-CoA preference (C14/C16) to SPT catalytic heterodimer of SPTLC1 + SPTLC2 or SPTLC3
- Role in MBOAT7
location to mitochondria-associated membranes
- SPTSSA Mutants: Impaired ORMDL regulation; Excessive sphingolipid synthesis
- Clinical
- Onset age: Early childhood
- Failure to thrive
- Spastic paraplegia
- Language/Cognitive dysfunction
- Hearing loss: Sensorineural
- Short stature
- GERD
- Skin: Vessel malformation
- Laboratory
- EEG: Spikes; Slowing
- Brain MRI: Volume loss; White matter changes
- SPG 92: Spastic paraplegia ± Mild cognitive Defects
● FIC Domain-containing protein Adenylyltransferase (FICD: HYPE);
Chromosome 12q23.3; Recessive
- Epidemiology: 5 patients, 4 families
- Genetics
- Mutations: Arg374His, 2 bp deletion
- FICD protein
- Endoplasmic reticulum
- Bifunctional enzyme
- AMP transferase: Posttranslationally attaches AMP moiety to target proteins
- Phosphodiesterase: De-AMPylates AMPylated proteins to release AMP moiety
- Regulates activity of BiP (HSPA5/GRP78)
: Chaperone & Regulator of Unfolded protein response (UPR)
- Clinical
- Onset age: 1 to 16 years; Median 5 years
- Spasticity
- Legs > Arms
- Gait disorder
- Bladder dysfunction (60%): Urgency
- Tendon reflexes: Increased in legs
- Plantar response: Extensor
- Sensation: Vibration reduced in legs in some patients (60%)
- Cognitive impairment (60%): Mild; Later onset
- Cerebellar: Saccadic pursuit; Tremor (Postural)
- Course: Slow progression
- Laboratory
- NCV: Motor ± Sensory polyneuropathy; Axon loss
- Brain MRI: Often normal
Spasticity + Systemic Disorders
- Sjögren-Larsson Syndrome (SLS)
17
● Fatty aldehyde dehydrogenase (ALDH3A2; ALDH10; FALDH)
;
Chromosome 17p11.2; Recessive
- Epidemiology
- Common in Northern Sweden
- Other areas 0.4 per 100,000
- Genetics
- ~ 50 different mutations
- Missense & Deletion most common
- FALDH protein
- Carboxyl terminal hydrophobic: Microsome membrane anchor
- Catalyzes medium & long chain fatty aldehydes to carboxylic acids
- Deficiency
- ? Increased fatty alcohols or aldehyde modified molecules
- Abnormal cell membrane integrity
- High levels of biologically active lipids
- Clinical
- Generally homogeneous phenotype
- Onset: Pre-term birth
- Spasticity
- Quadriparesis: Onset < 2 years
- Spastic dysarthria
- Slow progression: Disability; Contractures
- Other CNS
- Mental Retardation: Non-progressive
- Seizures
- Systemic
- Skin
- Ichthyosis
- Pruritis
- Color: Brownish-yellow
- Eye
- Pigmentary Retinal degeneration (Macular dystrophy)
- Reduced visual acuity
- Crystalline deposits in retina
- Photophobia
- Skin
- Severity
- 90% with severe disability
- Most with some walking, but use wheelchair
- 10% with mild syndromes
- Treatment: Leucotriene B4 (LTB4) synthesis inhibition
- Laboratory
- EEG: Slow background activity
- MRI: Retarded myelination; Hyperintense periventricular
- Urine: High LTB4 & 20-OH-LTB4
- Epidemiology
- Ichthyosis, Intellectual Disability & Spastic Quadriplegia (ISQMR)
85
● Elongation of very long chain fatty acids-like 4 (ELOVL4);
Chromosome 6q14.1; Recessive
- Epidemiology: 3 families, 5 patients
- Genetics
- ELOVL4 mutations
- Stop: Tyr26*; Arg216X; Ile230Metfs*22 (c.690del); Homozygous
- Heterozygous mutations cause: Macular degeneration (SGDT3)
- Allelic disorders
- SCA34
- Stargardt disease 3
- ISQMR
- Other elongase disorders: SCA38 - ELOVL5
- ELOVL4 mutations
- ELOVL4 protein
- Very long chain fatty acid synthesis
- Component of fatty acid elongation system
- Mutation: Deficiency of VLCFAs >28 carbons long (30% of brain myelin)
- Clinical
- Onset age: Birth
- Ichthyosis
- Variable
- Especially neck & diaper areas
- More severe with cold
- CNS: Some patients
- Seizures: Myoclonic epilepsy
- Mental retardation
- Spastic quadriplegia
- Head circumference: Small
- Laboratory
- Brain MRI: Delayed myelination; Atrophy
- ELOVL4 variant disorder: SCA34
99
- Nosology: Erythrokeratodermia with Ataxia
- Epidemiology: > 60 patients
- Genetics
- Inheritance: Dominant, Incomplete penetrance
- ELOVL4 mutations
- Often missense: Leu168Phe, Ile171Thr, Trp246Gly
- Deficient Very Long Chain-Saturated FA biosynthesis
- Clinical
- Onset: Infant to Adult
- Skin disorder (30% to 90%)
- Onset age: Infancy
- Papulosquamous erythematous ichthyosiform plaques
- Similar to erythrokeratodermia variabilis (EKVP)
- Tend to be on extremities
- Subside during summer
- Disappear by age 25
- May reappear after age 40: With onset of ataxia
- Erythrokeratodermia: Other (GJB3)
- Ataxia
- Onset age: Mean 51 years; Range = 3rd to 8th decade
- Gait disorder
- Eyes: Nystagmus; Slow pursuit or saccades
- Dysarthria
- Limbs
- Polyneuropathy (50%)
- Tendon reflexes: Reduced (50%)
- Axon loss: Mild
- Autonomic involvement
- Other
- Retinitis pigmentos
- Pyramidal tract signs
- Cognitive Δ
- Course
- Progression: Slow
- Cane after 10 years
- Walker by 7th or 8th decade
- Severity: Mild to Moderate
- Laboratory
- Brain MRI
- Atrophy: Cerebellum, Pons & Cortex
- Hot Cross Bun Sign (30%)
- Brain pathology
- Pons
- Macrophages (PAS+, Lipopigment, autofluorescent; Trilaminar spicules)
- Storage lipid: Accumulates within neuronal lipofuscin
- White matter: Vacuolar; Degenerated oligodendroglia
- Four repeat tau: Aggregation; Tangles
- Pons
- Brain MRI
- SPG: Ichthyotic Keratoderma, Spasticity, Hypomyelination & Dysmorphic features (IKSHD)
● Elongation of Very long chain Fatty acids-like 1 (ELOVL1);
Chromosome 1p34.2; Recessive
- Epidemiology: 1 family, 2 patients
- Genetics
- Mutation: Ser165Phe
- ELOVL1 protein
- Biosynthesis of C26 fatty acids & sphingolipids
- Clinical
- Ichthyotic keratoderma: Epidermal hyperproliferation & Increased keratinization
- Spastic paraparesis
- Eye: Optic atrophy; Nystagmus
- Face: Dysmorphic features
- Laboratory
- Brain MRI: Hypomyelination
- Spastic paraplegia with Evans syndrome
- Spasticity
- Early childhood onset
- Legs predominantly involved
- Evans syndrome
- Hemolytic anemia: Coombs-positive
- Thrombocytopenia: Immune
- Spasticity
- Fitzsimmons Syndrome
- Epidemiology: 2 families; 6 patients
- Genetics
- Possibly X-linked
- Clinical
- CNS
- Spastic Paraplegia: Progressive
- Dysarthria: Nasal speech
- ± Mental Retardation
- Skeletal disorders: Hands & Feet
- Brachydactyly
- Cone shaped epiphyses
- Abnormal metaphyseal-phalangeal pattern
- Palmoplantar hyperkeratosis
- CNS
- Mothers
- Tendon reflexes: Brisk
- Hand tremor, postural
- Learning difficulties, moderate
- Plantar hyperkeratosis
- SPG23: Spastic paraplegia with pigmentary abnormalities (Lison)
115
● Dual serine/threonine & tyrosine protein kinase (DSTYK; RIP5; RIPK5; DUSTYPK); Chromosome 1q32.1; Recessive
- Epidemiology: Arabian, Israeli & Palestinian-Jordanian families
- Genetics
- Mutation: Complex homozygous 3' 4-kb deletion/20-bp insertion
- Allelic with: Congenital urological developmental disorders, Dominant (CAKUT1)
- DSTYK protein
- Membrane-associated
- Protein kinase
- Regulation of cell death
- Epithelium
- Urinary tract development
- Clinical
- Onset
- Early childhood
- Spastic paraparesis
- Skin
- Facial appearance: Prematurely aged
- Scalp hair: White from birth
- Eyebrows and eyelashes: Premature graying
- Skin
- Covered areas: Hypopigmented
- Sun-exposed areas: Patchy, vitiligo-like depigmentation
- Spastic paraparesis
- Weakness: Legs
- Spasticity: Legs
- Tendon reflexes: Brisk in legs
- Plantar reflexes: Extensor
- Disability: Difficulty walking
- CNS, other
- Mental retardation: Mild
- Head circumference: Reduced in some patients
- Scoliosis: Some patients
- Onset
- Laboratory
- NCV: Axonal neuropathy
- Sensory-Motor
- Leg predominant
- Muscle: Type 1 fiber predominance
- MRI: Mild ventricular enlargement in 1 patient
- NCV: Axonal neuropathy
- Paraparesis, Hypermanganesemia, Polycythaemia & Cirrhosis
● Solute carrier family 30, Member 10 (SLC30A10);
Chromosome 1q41; Recessive
- Epidemiology: 1 patient
- Genetics
- Mutations: c.585del, p.Thr196Profs*17
- Allelic with: Hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC)
- SLC30A10 protein: Manganese transporter
- Clinical
- Onset age: 14 years
- Paraparesis: Spastic; Progressive
- Weakness: Distal legs
- Sensory loss: Distal legs
- Tendon reflexes: Increased in arms; Reduced in legs
- Plantar reflex: Extensor
- No extrapyramidal signs
- Laboratory
- Brain (basal ganglia), liver & blood manganese: High
- Brain MRI: High signal in lenticular & dentate nuclei, brainstem & pituitary
- Polycythemia
- Hepatic dysfunction: Micronodular cirrhosis
- Cardiomyopathy: Hypertrophic
Spasticity + PNS
- SPG17: Silver syndrome; Spastic paraplegia with amyotrophy of hands & feet
● BSCL2 gene (Seipin);
Chromosome 11q12.3; Dominant
- Epidemiology: > 10 families
- Genetics
43
- Mutations
- Missense
- Exon 3
- N88S; S90L
- Mutation effects
- Alter N-glycosylation site
- Aggregate formation
- BSCL2 Allelic disorders
- Berardinelli-Seip congenital lipodystrophy, Type 2: Null mutations
- Hereditary distal motor neuropathy, 5C (HMN5C)
- SPG17
- CMT2-like
- Progressive encephalopathy (PELD)
: Truncating mutations; c.985C-T
- Asymptomatic 4%
- Mutations
- Seipin protein
- Integral membrane protein
- Glycosylated
- Subcellular location: Endoplasmic reticulum
- Expression: Neurons in Spinal cord & Frontal lobe cortex
- Function: Lipid Droplets
- Mutations result in
- Accumulation of unfolded protein in endoplasmic reticulum
- Unfolded protein response
- Clinical
- General: Variable phenotype within families
- Onset
- Age: 2 to 40 years
- Amyotrophy
- Some families with early leg spasticity
- Spastic paraparesis
- Especially legs (100%)
- Tendon reflexes: Brisk
- Wasting & Weakness (83%)
- Distal
- Arms & Legs
- Pes cavus (83%)
- Bladder disorder (18%)
- Sensory: Usually normal; Occasional reduced vibration at ankles
- Course: Slow progression
- Silver syndromes: Other
- SPG20: Troyer syndrome
28
● Spartin;
Chromosome 13q13.3; Recessive
- Epidemiology: Kuwait & Old Order Amish families
- Genetics
- Mutations: 1110delA; 2-BP del, 364AT
- Hypermethylation of the SPG20/spartin promoter: Biomarker of colorectal carcinoma
- Spartin protein
- Sequence similarities: Spastin, SNX15, VPS4, Skd1
- Functions
- Associates with Cardiolipin: via Plant-Related Senescence Domain
- Regulates Mitochondrial Ca++ Homeostasis
- Postulated functions: Other
- Intracellular protein trafficking of late endosomal components
- Association with microtubules & tubulin
- Functions in degradation of epidermal growth factor receptor
- Localization: Mitochondria & Cytoplasm
- Mono-ubiquitinated
- Clinical
- Onset
- Age: Early childhood
- Dysarthria
- Late walking: Mean 16 months
- Upper motor neuron
- Spastic paraparesis: Legs > Arms
- Bulbar: Dysarthria (Spastic); Drooling
- Incontinence: Occasional
- Tendon reflexes: Brisk in legs; Arms increased late in course
- Plantar response: Extensor
- Lower motor neuron
- Weakness: Distal in hands & feet
- Wasting: Distal
- Sensory: Normal
- Cerebellar: Mild signs
- Dysdiadochokinesia
- Terminal dysmetria
- No nystagmus
- Extrapyramidal: Advanced cases
- Dystonic limb posturing
- Choreoathetoid movements
- Cortical
- Developmental delay: Mild
- Emotional lability & Affective disorders
- IQ reduced
- Skeletal
- Short stature
- Contractures: Legs; DIP joints
- Hyperextensible joints: PIP; Wrist
- Progression
- Slow
- Difficulty walking in 4th & 5th decades
- Onset
- MRI: White matter abmormalities
- Temporoparietal periventricular
- Posterior limbs of internal capsules
- Corpus callosum: Normal
- SPG30B: Paraplegia with Ataxia, mild & Sensory neuropathy, Recessive
56
● ATSV (KIF1A); Chromosome 2q37.3; Recessive or Dominant or de novo
- Epidemiology: Algerian & Pakistani families
- Genetics
- Inheritance: Recessive
- Mutations
- Missense: A255V, R350G
- Homozygous, often
- General location: Motor domain of kinesin 1A
- Allelic disorders
- ATSV protein
- Clinical: Pure or complicated SPG
- Onset
- Age: Mean 17.5 years; 12 to 21 years
- Spastic paraparesis
- Spastic gait
- Tendon reflexes: Increased in legs
- Plantar response: Extensor in 75%
- Sphincter involvement: Mild; 50%
- Functional: Inability to run
- Peripheral neuropathy
- Sensory loss: Legs; Panmodal; 50%
- NCV: Axon loss; Legs > Arms
- Ataxia: Mild
- Limb
- Eye: saccadic pursuit 50%
- Onset
- Laboratory
- CT scan: Cerebellar atrophy in 3 patient
- ATSV (KIF1A) variant: SPG30A Dominant or de novo
103
- Epidemiology: 27 families
- Genetics
- Inheritance: Dominant or Sporadic
- Mutations: S69L; T99M; G102S; R167C; I1127T
- Clinical: SPG, Pure or Complicated
- Onset age: 1 to 63 years; Intrafamilial variation
- Spasticity
- Paraparesis (Legs > Arms
- Tendon reflexes: Often brisk
- Plantar reflexes: Extensor
- Intellect: Normal
- Sensation: Normal
- Pes cavus
- Laboratory
- NCV: Axon loss or Normal
- Brain imaging: Uaually normal
- ATSV (KIF1A) variant: NESCAVS Dominant or de novo
- Nosology: NEurodegeneration, Spasticity ± Cerebellar Atrophy, Cortical Visual impairment Syndrome
- Epidemiology: > 40 patients
- Genetics
- Inheritance: Dominant or de novo
- Mutations: Missense
- ATSV (KIF1A) protein
- Clinical: Heterogeneous
- Onset: Infancy or Early childhood
- Developmental delay: Global, Walking, Speech, learning
- Spasticity: Legs; Loss of ambulation
- Visual impairment: Cortical; Optic atrophy, Oculomotor apraxia
- Polyneuropathy: Axonal, Dysautonomia
- Ataxia
- Extrapyramidal: Dystonia, Athetosis
- Skeletal: Scoliosis, Kyphosis, Joint contractures
- Course: Progressive
- Laboratory
- Brain MRI: Cerebellar atrophy, especially vermis; Corpus callosum thin
- SPG39: Spastic Paraplegia with Distal Arm & Leg Wasting
64
● Patatin-like phospholipase domain-containing protein 6 (PNPLA6; Neuropathy target esterase (NTE)); Chromosome 19p13.2; Recessive
- Epidemiology: Ashkenazi-Jewish & Northern European (German) families
- Genetics
- Mutations: Spastic ataxia
- Missense: Met1012Val & Arg890His
- Frameshift insertion: c.2946_2947insCAGC
- General location: N-terminal side of the EST domain (Gly840–Ser1031)
- Allelic with
- Ataxia & Hypogonadism syndromes: Gordon–Holmes; Boucher–Neuhäuser
- Ataxia + Retinal changes
- Ataxia
- Oliver-McFarlane syndrome
- Laurence-Moon syndrome
- Mutations: Spastic ataxia
- PNPLA6 Protein
- Nosology: Also called Neuropathy target esterase & Neurotoxic esterase
- Family: Patatin-like phospholipase domain-containing proteins
- Involved in neuronal development
- Cell-signaling pathway controlling interactions between neurons and accessory glial cells
- Target for neurodegeneration induced by organophosphorus pesticides & chemical warfare agents
- Phospholipid esterase domain (EST): Altered by organophosphorous intoxication
- Can hydrolyze intrinsic membrane lipids
- Esterase activity: De-esterifies phosphatidylcholine
- Lysophospholipase activity: Catalysis of 2-arachidonoyl lysophosphatidylinositol
- Neurons: High expression
- Peripheral nerve
- Expression
- Mature non-myelinating Schwannn cells: Enriched areas
- Schmidt-Lanterman incisures
- Around Nucleus
- Myelin ovoids with axon degeneration
- Not in: Promyelinating Schwann cells
- Mature non-myelinating Schwannn cells: Enriched areas
- Required for: Ensheathment of unmyelinated axons (Remak fibers)
- Expression
- Mutations: Reduced NTE activity
- Clinical
Gordon Holmes Ataxia
Cerebellum: Control
Cerebellum: Patient
Medulla: PatientHolmes, Brain 1907;30:466-489
- Onset
- Age: Childhood; ≤ 7 years
- Gait disorder: Spasticity
- Paraplegia
- Spastic
- Especially hamstrings
- Gait impairment
- Tendon reflexes
- Knees brisk
- Ankles often reduced
- Plantar response: Extensor
- Symmetric
- Progression: Slow
- Spastic
- Sensation reduced: Distal legs; Vibration
- Weakness: Hands; Iliopsoas; Tibialis anterior
- Muscle wasting: Distal hands & feet
- Urinary urgency
- Onset
- Laboratory
- MRI: Spinal cord atrophy, especially thoracic
- NCV
- Motor axonopathy: Arms & Legs
- CMAP amplitudes: Reduced
- Sensory: Normal
- EMG: Denervation, Chronic & Ongoing
- PNPLA6 Variant syndromes: Ataxia & Hypogonadism
95
- Genetics
- Mutations: General location:
- C-terminal end of EST domain (Ser1031–Pro1122)
- Inheritance: Recessive
- Allelic with: Spastic ataxia & SPG syndromes
- Mutations: General location:
- PNPLA6 protein
- Boucher-Neuhäuser syndrome
- Mutations: Missense or Stop
- Clinical
- Onset age: 1 to 6 years
- Visual impairmant
- Gait ataxia: Onset 6 to 27 years
- Hypogonadotropic hypogonadism
- Primary amenorrhoea
- Puberty: Delayed
- Chorioretinal dystrophy
- Spasticity: Few patients
- Muscle wasting, distal (50%)
- Tendon reflexes: Reduced
- Cognitive impairment: Mild
- Laboratory
- Brain imaging: Atrophy of cerebellum ± pons
- Gordon Holmes (Spastic) ataxia syndrome
: 1 patient
- Genetics
- Mutation: Frameshift; c.3084_3085insGCCA
- Other Gordon Holmes syndrome mutations: RNF216
- Clinical
- Onset
- Age: 14 years
- Delayed puberty
- Hypogonadotropic hypogonadism
- Spasticity: Legs
- Gait disorder: Onset age 30 years
- Onset
- Laboratory
- Brain imaging
- Cerebellar atrophy
- Empty sella
- Brain imaging
- Genetics
- Genetics
- PNPLA6 Variant syndrome: Cerebellar ataxia
108
- Epidemiology: 1 Zoroastrian (Parsi) family
- Genetics
- Inheritance: Recessive
- Mutation: D1310V; Homozygous
- Clinical
- Onset age: 2nd decade
- Ataxia
- Gait & Limb coordination
- Slow saccades
- Tendon reflexes: Brisk in legs
- Course: Slow progression
- Laboratory
- Brain MRI: Cerebellar & Midbrain artrophy
- NCV: Normal
- Spastic paraparesis, Optic atrophy & Polyneuropathy (SPOAN)
52
● Kinesin light chain 2 (KLC2); Chromosome 11q13.2; Recessive
- Epidemiology: Brazilian families
- 70 patients
- Common in Serrinha dos Pintos (1/250; Carriers 1 in 9)
- 2 Egyptian siblings
- Genetics
- Mutation: chr11.hg19:g.66,024,557_66,024,773del; non-coding upstream region of the KLC2 gene
- Mutation effect: KLC2 over-expression
- Allelic, or same, disorder: SPG68
- Also see: SPOAN-like syndrome-IBA57
- KLC2 protein
- Kinesin light chain
- Kinesin protein-1 complex
- Binds to kinesins heavy chain in stoichiometric ratio of 1:1
- Expressed in Schwann cells & Axons
- Anterograde axoplasmic transport
- Kinesins
- Molecular motor
- Generates ATP-dependent movement of vesicles & organelles along microtubules
- Other disorders
- Clinical
- Onset: Infancy
- Spastic paraparesis
- Onset: Infancy
- Legs > Arms
- Motor delay: Toe walking; Some never walk
- Tendon reflexes: Increased proximally; Reduced distally
- Clonus: Spontaneous > Evoked
- Plantar responses: Often no response
- Progressive
- Optic atrophy
- Congenital
- Visual loss: Non-progressive
- Fixation nystagmus
- Pale optic disks
- Polyneuropathy
- Onset: Late childhood/early adolescence
- Motor & Sensory
- Distal amyotrophy: > 20 years of age
- Hyperhidrosis
- Vibration & joint position sense: Reduced
- Pain & temperature sensation: Normal
- Axonal
- Skeletal
- Joint contractures
- Spine deformity: Scoliosis
- Progressive
- Other
- ? Extrapyramidal: Speech disorders
- Dysarthria: Onset in 3rd decade
- Dysphonia
- Cogwheel rigidity (20%)
- Exacerbated acoustic startle response
- Cognitive: Normal
- Hearing: Normal
- ? Extrapyramidal: Speech disorders
- Course
- Wheelchair bound by 15 years
- Laboratory
- NCV: Axonal sensory-motor neuropathy
- Nerve biopsy
- Axon loss
- Occasional: Abnormally folded myelin; Onion bulbs
- Spine MRI: Mild cord atrophy
- Differential diagnosis: SPG 57
- Epidemiology: Brazilian families
- SPG68: See SPOAN
97
- Epidemiology: 2 patients, 1 family
- Genetics
- Original description: Mutations in FLRT1
- Re-assesment: KLC2 mutations
- Original description: Mutations in FLRT1
- Clinical: Complicated SPG
- Onset age: 2 to 3 years
- Gait: Disordered or Lost
- Tendon reflexes: Increased
- No spasticity
- Motor: Foot drop; Amyotrophy, mild
- Eye: Nystagmus, Optic atrophy
- Cognition: Normal
- Laboratory
- VEP: Abnormal
- MRI: Normal brain
- NCV/EMG: Polyneuropathy
- Hereditary sensory neuropathy with spastic paraparesis (Cavanagh's variant)
● Chaperonin containing T-complex polypeptide 1, subunit 5 (CCT5); Chromosome 5p15.2; Recessive
- Allelic with: HSN with Spastic paraparesis
- Clinical
- Sensory neuropathy
- Loss of pain & temperature
- Relatively preserved vibration & joint position sense
- Pathology: Axon loss, Small > Large fiber
- Acromutilation
- Spasticity
- Sensory neuropathy
- See: Hereditary sensory neuropathy
- HMSN 5
Spasticity + Ocular disorders
- Spastic paraplegia with retinal degeneration (SPG15)
:
- Spasticity with Pigmentary tapetoretinal degeneration & Mental retardation
: 15q24
- Sjögren-Larsson Syndrome
- Friedreich ataxia
- Spastic paraplegia, Optic atrophy, Microcephaly & XY sex reversal
- Infantile optic atrophy with chorea & spastic paraplegia (MGCA3)
: OPA3
- SPOAN
- Also see: Optic atrophy
Spasticity + CNS
- See: Spastic ataxia syndromes
- Friedreich ataxia
- Intermediate number of trinucleotide repeats
- Spastic ataxia
- Leukodystrophies:
MLD &
Krabbe
- Late onset disorders may present with spasticity & polyneuropathy
- DRPLA:
Homozygotes with intermediate # (40 or 41) of repeats
- Cerebrotendinous xanthomatosis
- Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH syndrome)
- Cerebral palsy, Spastic Quadriplegic (CPSQ)
- Spastic paraplegia + Myoclonic epilepsy
● Autosomal Recessive- Onset: Prenatal to 10 years
- Spastic paraplegia
- Epileptic myoclonus
- Muscle atrophy: Distal
- Mental retardation
- Ataxia
- Hearing loss
- Course: Progressive
- SPG21: Spastic paraplegia with dementia & extrapyramidal signs (Mast syndrome)
42
● Acidic cluster protein, 33-KD (ACP33; Maspardin); Chromosome 15q22.31; Recessive
- Epidemiology: Ohio Amish; Japanese
- Genetics (ACP33 gene)
- Mutations
- Amish: Homozygous 601insA
- Japanese: Ala108Pro
- Mutations
- Maspardin protein
- Localizes to intracellular endosomal/trans-Golgi transportation vesicles
- May function in protein transport and sorting
- Clinical features
- Onset
- Age
- Amish: 2nd & 3rd decades
- Japanese: 6th & 7th decades
- Amish: Subtle changes in childhood
- Delayed motor milestones
- Awkward running
- Mild incoodination
- Age
- Spastic paraparesis
- Legs > Arms
- Gait disorder
- Jaw Jerk: May be brisk
- Bulbar
- Dysphagia: May need G-tube
- Speech disorders: Mild dysarthria
- Cortical function
- Personality/Psychiatric disorders: Shy; Nervous
- Dementia: May be severe
- End stage: Akinetic mutism
- Extrapyramidal signs: Late
- Rigidity
- Oromandibular dyskinesia
- Athetoid movements of the fingers or limbs
- Cerebellar ataxia: Late
- Tendon reflexes: Reduced at ankles
- Sensation: Normal
- Course: Slow progression
- Variant
- Japanese patients: No extrapyramidal, cerebellar, or bulbar signs
- Onset
- MRI
- Corpus callosum: Thin
- White-matter abnormalities
- Phenylketonuria: Adult onset Spastic paraparesis
+ Dementia
20
● Phenylalanine hydroxylase (PAH); Chromosome 12q23.2; Recessive
- Onset: 5th & 6th decade
- Spastic paraparesis
- Gait disorder
- Tendon reflexes: Brisk
- Dementia
- Strength: Normal
- Cranial nerves: Normal
- Fair Hair & Skin
- Treatment: Dietary restriction of phenylalanine
- SPG9A: Cataracts, Gastroesophageal Reflux, & Spastic Paraparesis with Amyotrophy
102
● delta-1-pyrroline-5-carboxylate synthase (ALDH18A1; P5CS); Chromosome 10q24.1; Dominant
- Epidemiology: Italian & British families
- Genetics
- Mutations: c.727G4C; c.755G4A
- Allelic disorders
- SPG Dominant: SPG9A
- SPG Complex or Pure (SPG9B): Dominant or Recessive
- Motor Neuronopathy with Cataracts & Skeletal abnormalities
- Cutis laxa, autosomal recessive, type IIIA
- Similar locus: Recessive SPG27
- Protein
- Clinical
- Onset
- Infancy to 4th decade
- Anticipation
- Cataracts (100%): Bilateral; Congenital
- GE Reflux (100%): Persistent vomiting; Hiatus hernia
- Spastic paraparesis
- Onset: 1st to 3rd decade; Some during pregnancy
- Penetrance: Incomplete
- Muscle wasting
- Hands & Forelegs
- Motor neuropathy with axon loss
- Skeletal: Growth impairment; Pes cavus
- Onset
- Laboratory
- MRI: Spinal cord atrophy
- Plasma Citrulline: Low
- SPG9B: Hereditary Spastic paraparesis, Complex or Pure
102
● delta-1-pyrroline-5-carboxylate synthase (ALDH18A1; P5CS); Chromosome 10q24.1; Recessive or Dominant
- Nosology: Aldehyde dehydrogenase 18 family, member A1
- Epidemiology: 7 families
- Genetics
- Mutations
- Dominant: Val120Ala; Arg252Gln; Ser652Phe; Arg665Leu
- Recessive: Asp715His; Arg128His, Leu637Pro
- Allelic disorders
- Mutations
- ALDH18A1 protein
- δ-1-pyrroline-5-carboxylate synthase (P5CS)
- Catalyses 1st common steps of arginine, proline & ornithine biosynthesis from glutamate
- Clinical
- Recessive
- Onset age: <1 to 7 years
- Cognitive impairment: Progressive
- Upper motor neuron
- Tetraparesis
- Pseudobulbar palsy
- Tendon reflexe: Increased in arms & legs
- Plantar response: Extensor
- Urinary incontinence
- Course: Progressive; Ambulation often lost
- Cerebellar: Postural tremor in arms (30%)
- Skeletal: Microcephaly; Facial dysmorphism; Short stature
- Dominant
- Onset age: Range 14 to 59 years
- Cramps
- Upper motor neuron
- Leg stiffness & Spasticity
- Spastic gait
- Tendon reflexes: Increased in arms & legs
- Plantar response: Extensor
- Dysarthria
- Weakness
- Distal > Proximal
- Motor neuropathy (45%)
- Sensory: Vibration loss in some
- Pes cavus (50%)
- Urinary symptoms (50%)
- Cognition: Normal
- Recessive
- Laboratory
- Amino acids: Blood
- Dominant families
- Citrulline: Low
- Proline, Ornithine, Arginine: Variably low
- Recessive: Normal
- Dominant families
- Amino acids: Blood
- SPG78: Spastic Ataxia
110
● ATP13A2;
Chromosome 1p36.13; Recessive
- Nosology: PARK-ATP13A2
- Epidemiology: Multiple families
- Genetics
- ATP13A2 protein
- Locations: Lysosomal; Late endosome; Endoplasmic reticulum
- P5-type subfamily of P-type transport ATPases
- Transporter
- Cations
- Polyamines: Especially spermidine
- Across membranes
- Endocytosis into cytosol
- Endolysosome system
- Interaction with heavy metals: In postmitotic neurons
- Expressed in brain
- ATP13A2 mutations: Polyamine-induced cell toxicity
- Lysosomal dysfunction & rupture
- Cathepsin B
activation
- Clinical
- Onset age: Juvenile & Adult
- Spastic quadraplegia
- Gait disorder
- Tendon reflexes: Increased
- Spasticity
- Plantar response: Extensor
- Loss of ambulation: 8 to 18 years after disease onset
- Cognitive
- Decline
- Psychiatric syndromes
- Pes cavus: Bilateral
- Eye
- Strabismus
- Supranuclear: Upgaze reduced; Gaze paresis
- Cerebellar
- Ataxia (30%): Limb; Gait
- Nystagmus, Lateral gaze
- Extrapyramidal
- Parkinsonism: May respond to levodopa
- Dystonia
- Polyneuropathy: Sensory-Motor
- Laboratory
- Brain MRI
- Cerebral & Cerebellar atrophy
- Basal ganglia disorder
- NCV: Axon loss
- Brain MRI
- ATP13A2 (PARK9) variant: ALS
122
- Epidemiology: 2 patients
- Genetics
- Mutations: p.Glu613Ter, p.Ile411Met
- Clinical
- Onset age: 4th to 5th decade
- Spasticity: Legs > Arms; Gait
- Tendon reflexes: Brisk
- Bulbar: 1 patient
- Tongue: Atrophy with Fasciculations
- Dysphagia
- Cognitive disorder: Mild in 1 patient
- Course: Progressive
- Laboratory
- Electrodiagnostic
- Motor unit potentials: Polyphasic
- Axonal sensory-motor polyneuropathy
- MRI: Normal
- Brain scans: Striatal pathololgy
- Electrodiagnostic
- SPG79B: Neurodegeneration with Optic atrophy, Childhood-onset (NDGOA); Spastic Ataxia
● Ubiquitin carboxyl-terminal esterase L1 (UCHL1; PGP9.5);
Chromosome 4p13; Recessive
- Epidemiology: Norwegian & Turkish families, 6 patients
- Genetics
- UCHL1 protein
- Hydrolyze: Small C-terminal adducts of ubiquitin to generate the ubiquitin monomer
- Expression: Neurons; Unmyelinated axons; Neuroendocrine cells, nomal & neoplasm; Testis/Ovary
- Binds to: Ubiquitin
- Mutation: Reduced enzyme activity
- Clinical
- Onset age: 5 to 10 years
- Vision loss: to blindness
- Upper motor neuron
- Spasticity
- Tendon reflexes: Increased
- Cerebellar ataxia
- Inability to stand
- Intention tremor
- Head tremor
- Nystagmus, gaze evoked
- Sensory: Vibration ± Position loss
- Fasciculations: 50%
- Strength: Normal or Reduced
- Cognition: Normal
- Pes cavus
- Course: Progressive
- Laboratory
- EMG: Myokymia
- NCV: Axon loss, Sensory & Motor
- Eye
- VEP: Reduced or Absent response
- Electroretinogram (ERG): Normal
- SSEP: Dorsal column dysfunction
- Brain MRI: Cerebral, Optic nerve & chiasm + Cerebellar atrophy
- Muscle biopsy: Normal or Chronic denervation
- Mouse model: gracile axonal dystrophy (gad)
- UCHL1 variant: SPG79A
- Epidemiology: 44 patients; 21 families
- Genetics
- Inheritance: Dominant
- Mutations: Loss of function
- Clinical
- Onset age: Median 49 years; Range Childhood to 70 years
- Ataxia: Gait disorder; Dysarthria
- Spasticity: Legs > Arms; Tendon reflexes brisk
- Some patients
- Optic atrophy
- Neuropathy: Sensory (Vibration loss); Axon loss
- Course: Slow progression
- Laboratory
- Brain MRI: Cerebellum small or normal
- Spastic paraplegia, Intellectual disability, Nystagmus & Obesity (SINO)
113
● Kinase D-interacting substrate, 220-kD; (KIDINS220/ARMS);
Chromosome 2p25.1; Sporadic, Dominant
- Nosology: ARMS (Ankyrin Repeat-rich Membrane Spanning)
- Epidemiology: 4 patients
- Genetics
- Mutations: de novo; Nonsense; Heterozygous
- Mutation locations: Last two exons of gene
- Allelic Disorder: Ventriculomegaly & Arthrogryposis, Recessive
- KIDINS220 protein
- Scaffold protein
- Coordinates neurotrophin signal pathways in neurites
- Controls axonal & dendritic maturation
- Mutation effect: Truncated isoforms
- Clinical
- Onset age: Congenital or Prenatal
- Spastic paraplegia
- Axial hypotonia (1 patient)
- CNS: Global delay, moderate
- Dysmorphism
- Brachyplagiocephaly
- Macrocephaly
- Forehead: Bossed or Prominent
- Eyes: Deep set
- Eyes
- Nystagmus
- Reduced acuity
- Squint
- Hypermetropia
- Astigmatism
- Obesity
- Laboratory
- Brain imaging
- Lateral & 3rd ventricle dilation
- White matted reduced
- Atrophy, mild
- Brain imaging
- KIDINS220 variant: Ventriculomegaly & Arthrogryposis, Recessive (VENARG)
- Epidemiology: 3 families
- Genetics
- Inheritance: Recessive
- Mutations: Frame-shift or In-frame deletion
- Clinical
- Prenatal
- Ventriculomegaly
- Arthrogryposis
- Face: Dysmorphic
- Subcutaneous edema
- Cardiac defects: Some patients
- Intrauterine death
- Pathology
- Cortical & Cerebellar hypoplasia
- Corpus callosum: Thin
- Spastic Paraplegia, Complicated (SPG81)
114
● Ethanolaminephosphotransferase 1 (EPT1; Selenoprotein I; SELENOI)
;
Chromosome 2p23.3; Recessive
- Epidemiology: 2 Arab family, 5 patients
- Genetics
- Mutations: c.335G>C (p.Arg112Pro); c.732-2A-G (Splice site)
- EPT1 protein
- Final step in phosphatidylethanolamine synthesis
- Kennedy pathway phospholipid cascade
- Clinical
- Onset age: Infancy/Early childhood
- Motor
- Delayed gross motor development<
- Motor function: Gradual decline
- Dysarthria
- Spastic paraperesis
- Spasticity
- Tendon reflexes: Increased
- Plantar response: Extensor
- Progressive
- Arms involved later in course
- Peripheral neuropathy (Oldest patient): Axon loss; ?? Demyelinating
- Cortical & CNS
- Intellectual impairment
- Language delay
- Microcephaly
- Seizures
- Eye
- Retinal pigment disorder
- Cone-rod dysfunction
- Visual acuity: Reduced
- Bifid uvula
- Laboratory
- Brain MRI: Increased T2 signal intensity in periventricular white matter
- NCV: CMAPs normal or reduced amplitude & dispersed
- Cataracts, Spastic Paraparesis & Speech Delay (CSPSD)
● Fatty Acyl CoA Reductase 1 (FAR1);
Chromosome 11p15.3; Dominant
- Epidemiology: 12 patients
- Genetics
- Mutations: Arg480 residue; Heterozygous
- Allelic disorder: Peroxisomal fatty acyl-CoA reductase 1 disorder
- FAR1 protein
- Converts fatty acyl-CoA into a fatty alcohol & CoASH
- Wax monoester synthesis
- Mutations: Loss of plasmalogen-dependent feedback on FAR1 protein levels
- Clinical
- Onset age: Early childhood
- Spastic paraparesis
- Seizures (65%)
- Speech delay (80%)
- Cataracts: Bilateral; Often congenital
- Constipation (45%)
- Course: Ambulatory, but requiring walking aids
- Laboratory
- Brain imaging: Usually normal
- SPG, Complex with Ataxia
141
● RAD50-interacting protein 1 (RINT1);
Chromosome 7q22.3; Recessive
- Epidemiology: 3 patients
- Genetics
- Mutations: Stop or Deletion
- Allelic disorder: Infantile liver failure syndrome 3
- RINT1 protein
- Autophagy
- Lipid homeostasis: Neutral & Phospholipid metabolism
- Mitochondrial dynamics
- Regulation of membrane traffic between the Golgi & Endoplasmic reticulum (ER)
- Telomere length control
- Clinical: Spastic-Ataxia
- Onset age: Early childhood
- Motor & Intellectual development: Delayed
- Spasticity
- Ataxia: Gait; Dysmetria; Nystagmus
- Optic atrophy
- Strabismus
- Dysmorphic face: Low set ears
- Hepatitis
- Laboratory
- Brain MRI
- Posterior periventricular white matter hyperintensity
- Corpus callosum: Thin
- Cerebellar atrophy
- Optic chiasm atrophy
- Hepatic dysfunction
- Brain MRI
- Spastic paraplegia, Epilepsy & Mental retardation
36
● Autosomal Dominant- Onset: < 40 years
- Spastic paraplegia: Legs > Arms
- Epilepsy: At presentation
- Mental retardation: Variable
- Lawrence-Moon syndrome
● PNPLA6; Chromosome 19p13.2; Recessive- Genetics
- Clinical
- Spastic parapaesis
- Pigmentary retinopathy
- Mental retardation
Cerebral palsy, Spastic Quadriplegic (CPSQ)
|
CPSQ1 (DEE89): GAD1; 2q31 CPSQ2: KANK1; 9p24 CPSQ3: ADD3; 10q25 CPSQ4 (SPG51): AP4E1; 15q21 CPSQ5 (SPG47): AP4B1; 1p13 CPSQ6 (SPG52): AP4S1; 14q12 CPSQ (SPG50): AP4M1; 7q22 NEDSBAS: WDR45B; 17q25 NEDSGA: GRIA4; 11q22 NMIHBA: PRUNE1; 1q21 SLS-like: ELOVL4; 6q14 SPATCCM: SLC1A4; 2p14 Cerebral palsy, Ataxic KCNC3 ITPR1 SPTBN2 |
CPSQ1: Developmental and epileptic encephalopathy 89 (DEE89)
● Glutamate decarboxylase 1 (GAD1; GAD67)
;
Chromosome 2q31.1; Recessive
- Genetics
- Mutation: Ser12Cys
- Allelic disorder: Developmental and epileptic encephalopathy 89
- Epidemiology
- Pakistani families
- No recognizable adverse pre- or postpartum events
- GAD1 protein
- Catalyzes conversion of glutamic acid to gamma-aminobutyric acid (GABA)
- Clinical
- Onset age: Infancy
- Symmetry of neurological signs
- Spasticity: Legs > Arms; Tendon reflexes increased
- Cortical: Mental retardation; Seizures, Occasional
- Microcephaly: Some patients
- Scoliosis
CPSQ2
● KN motif and ankyrin repeat domains 1 (ANKRD15; KANK1)
;
Chromosome 9p24.3; Recessive with parental effect
- Epidemiology: Israeli family of Jewish Moroccan origin
- Genetics
- Mutation: Deletion containing only ANKRD15 gene
- Inheritance dependent on parental gender: All affected children born to related clinically healthy fathers
- Paternal transmission (to affected children): Region is hypomethylated in child
- Maternal transmission: Region is hypermethylated
- Affected patients: Have deletion from father & maternal allele with gene repressed from mother
- Allelic disorders: KANK1 mutations increased (but low) frequency in ALS vs controls 132
- ANKRD15
- Ubiquitous expression
- Component of AP-4 complex
- Involved in the recognition and sorting of cargo proteins with tyrosine-based motifs
- From trans-golgi network to endosomal-lysosomal system
- KANK1: Related to ALS cytoskeletal genes (PFN1, KIF5A, TUBA4A)
- Clinical
- Onset
- Congenital
- Hypotonia
- Spastic quadriplegia: Evolves over 1st year
- Mental retardation
- Nystagmus: Transient
- Onset
- Laboratory
- MRI: Brain atrophy; Ventriculomegaly
Spastic Paraplegia 50, Recessive (CPSQ3; SPG50)
130
● Adaptor-related protein complex 4, Mu-1 subunit (AP4M1; MU-ARP2)
;
Chromosome 7q22.1; Recessive
- Epidemiology: 60 families
- Genetics
- Mutation: Stop
- AP4 proteins
- Clinical
- Onset
- Infancy: Ventricular diatation in 20th week of pregnancy
- Hypotonia
- Strabismus
- Spastic quadriplegia
- Progressive over 1st year
- Pseudobulbar signs
- No ambulation
- Hypertonia, generalized
- Hyperreflexia
- Plantar responses: Extensor
- Sphincter control: Absent
- Mental retardation: Absent speech
- Microcephaly
- Adducted thumbs
- Course: Minimal change after 1st year
- Onset
- Laboratory
- MRI: Ventriculomegaly; White matter changes; Cerebellar atrophy
- Pathology
- Reduced myelin
- Gliosis
- Dendritic arborization
- Abnormal morphology
- Aberrant GluRdelta2 glutamate receptor localization
Cerebral Palsy with Microcephaly & Intellectual Disability 4 (CPSQ4; SPG51)
130
● Adaptor-related protein complex 4, Epsilon-1 subunit (AP4E1)
;
Chromosome 15q21.2; Recessive
- Epidemiology: 25 families
- Genetics
- Mutations: Nonsense, Deletion, Insertion; Stop
- Allelic disorder: Stuttering, familial persistent, 1 (Dominant) (STUT1)
- AP4 proteins
- Clinical
- Spastic cerebral palsy
- Early infancy: Hypotonia
- Tetraplegic
- Tone: Increased
- Tendon reflexes: Increased
- Plantar reflex: Extensor
- Intellectual
- Disability: Severe
- Speech: Very dleayed
- Laughter: Stereotypic
- Microcephaly
- Epilepsy
- Eye & Ear: Normal
- Course: Live to adulthood
- Spastic cerebral palsy
- Laboratory
- MRI: Dilated ventricles; Cerebellar atrophy; White matter abnormal
Cerebral Palsy with Microcephaly & Intellectual Disability 5 (CPSQ5; SPG47)
130
● Adaptor-related protein complex 4, Beta-1 subunit (AP4B1)
;
Chromosome 1p13.2; Recessive
- Epidemiology: 53 families
- Genetics
- Mutations: Truncating
- Allelic with: SPG 47
- AP4B1 protein
- Subunit of heterotetrameric adaptor protein (AP) complex
- Intracellular transport of proteins: Especially neurons
- Adaptor protein complexes (AP1-4)
- Expression: Ubiquitous
- Heterotetrameric complexes
- Mediate
- Vesicle formation
- Selection of cargo molecules for inclusion into vesicles
- Brain development
- AP4 disorders
- Clinical
- Onset age: Birth
- Microcephaly
- Muscle tone: Hypotonic early; Hypertonic with development
- Spastic paraplegia
- Inability to walk unaided
- Hyperreflexia
- Waddling gait
- Other CNS
- Cognitive deficit: Severe
- Speech delay
- Adaptive impairment
- Stereotypic laughter
- Shy character
- Skeletal
- Palate: High
- Nasal bridge: High
- Short stature
- Joints: Hyperlaxity
- Genu recurvatum
- Pes planus
Spastic paraparesis with Intellectual Disability, Shy Character & Short Stature (CPSQ6; SPG52)
130● Adaptor-related protein complex 4, Sigma-1 subunit (AP4S1)
Chromosome 14q12; Recessive
- Epidemiology: 26 families
- Genetics
- Mutations: Nonsense; Frameshift; Splice
- AP4 proteins
- Clinical
- CNS
- Intellectual disability, severe
- Speech: Absent
- Shy character
- Stereotypic laughter
- Motor
- Muscle mass in legs: Reduced
- Inability to walk
- Early: Hypotonia
- Late: Spastic paraparesis
- Skeletal
- Microcephaly
- Foot deformity
- Growth retardation
- CNS
Cerebral palsy, Spastic quadriplegic (CPSQ3)
● Adducin 3 (ADD3; ADDL; Gamma adducin)
Chromosome 10q25.1-q25.2; Recessive
- Epidemiology: 1 Jordanian family, 4 patients
- Genetics
- Mutation: Homozygous; Missense; G367D
- Adducin 3 protein
- Expression: Ubiquitous
- Actin-capping
- Modulate fast-growing end of actin filaments
- Control actin molecule length
- Upregulated in chemoresistant glioblastoma cells
- Adducin family
- α-Adducin (ADD1)
: Roles in maintaining axon diameter & endocytosis
- α-Adducin (ADD1)
- Clinical
- Onset age: Early childhood
- Spastic quadriplegia: Moderate to Severe
- Pyramidal signs
- Dysarthria
- Dysphagia
- Cognitive impairment
- Eye: Exotropia, Supranuclear gaze palsy, Strabismus, Nystagmus
- Seizures: 1 patient
- Microcephaly: Borderline
- Laboratory
- Brain MRI
- T2-weighted hyperintensities: Grey matter heterotopia
- White matter reduced, especially frontoparietal
- May be normal
- Muscle biopsy
- Type 2 muscle fiber atrophy
- Mitochondrial oxidative enzymes: Complex I activity mildly reduced
- Brain MRI
Neurodevelopmental Disorder with Spastic Paraplegia & Microcephaly (NEDSPM)
● Glutamate Pyruvate Transaminase 2 (GPT2)
Chromosome 16q11.2; Recessive
- Epidemiology: 8 families
- Genetics
- Mutations: Missense & Stop
- GPT2 protein
- Alanine transaminases
- Pyridoxal enzyme
- Catalyzes: Reversible transamination between alanine & 2-oxoglutarate to form pyruvate & glutamate
- High expression: Muscle, Fat, Kidney, Brain
- Clinical
- Onset: Infancy & Early childhood
- Hypotonia
- Developmental delay: Global
- Spasticity: Legs > Arms; Gait disorder
- Seizures
- Bulbar: Dysarthria; Drooling
- Microcephaly
- Course: Progressive
- Laboratory
- Brain imaging: Normal or Corpus callosum thin
- Alanine: Reduced in CSF
Neurodevelopmental disorder + Motor regression, progressive Spastic Paraplegia & Oromotor dysfunction (NEDRSP)
● Small nuclear RNA-activating protein complex, polypeptide 4 (SNAPC4)
Chromosome 9q34.3; Recessive
- Epidemiology: 8 families
- Genetics
- Mutations: Loss of function
- SNAPC4 protein
- Subunit of snRNA-activating protein complex (SNAPc)
- Transcription of RNA polymerase II & III snRNA genes
- Clinical
- Onset ages: 6 to 36 months
- Spasticity: Appendicular
- Cognitive: Impaired
- Ataxic gait: Some patients
- Oromotor dysfunction: Slow speech, Dysarthria, Drooling
- Ocular: Nystagmus, Optic nerve pallor, Strabismus, Astigmatism, Oculomotor apraxia, Retinopathy
- Skeletal: Short stature; Microcephaly
- Laboratory
- Brain imaging; Cerebellar & Cerebral atrophy
Spastic tetraplegia, Thin corpus callosum & Progressive microcephaly (SPATCCM)
● Solute carrier family 1 (Glutamate/Neutral amino acid transporter), Member 4 (SLC1A4)
Chromosome 2p14; Recessive
- Epidemiology: Ashkenazi Jewish & Pakistani families
- Genetics
- Mutations: c.944_945delTT; E256K (Ashkenazi); Arg457Trp (Pakistani)
- SLC1A4 protein
- Neutral amino acid transporter (ASCT1)
- L-serine, L-alanine, L-cysteine, L-threonine
- Brain: L-serine
- Synthesized by astrocytes
- Shuttled into neurons by SLC1A4 transporter
- Neutral amino acid transporter (ASCT1)
- Clinical
- Onset: Birth
- Psychomotor development delay: No speech; Inability to walk,
- Microcephaly: Postnatal, Progressive
- Spasticity: Legs > Arms
- Febrile seizures: Infancy; 1 patient
- Laboratory
- Brain MRI
- Corpus callosum: Thin
- Myelination: Delayed
- White matter: Nonspecific abnormalities
- Brain MRI
Neurodevelopmental disorder ± Seizures & Gait abnormalities (NEDSGA)
● Glutamate receptor, ionotropic, AMPA 4 (GRIA4)
Chromosome 11q22.3; Dominant or Sporadic
- Epidemiology: 5 patients
- Genetics
- Mutations: de novo; Heterozygous; Missense
- GRIA4 protein
- L-glutamate-gated ion channel
- Mediate fast synaptic excitatory neurotransmission
- Responsive to glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate (AMPA)
- Clinical
- Onset
- Age: Neonatal
- Irritability
- Stiffness & Hypertonia
- Startle reflex: Increased
- CNS
- Seizures
- Spastic quadriplegia: Gait disorder
- Choreiform movements
- Developmental delay: Absent speech, Inability to follow commands
- Other: Some patients
- Sleeping problems
- Feeding difficulties
- Optic nerve hypoplasia
- Stereotypic hand movements
- Eye: Nystagmus, Strabismus
- Skeletal: Contractures, Short stature, Microcephaly
- Onset
- Laboratory
- Brain MRI: Cortical atrophy; Corpus callosum thin
Neurodevelopmental Disorder with Spastic Quadriplegia & Brain abnormalities ± Seizures (NEDSBAS)
● WD Repeat-containing protein 45B; (WDR45B)
Chromosome 17q25.3; Recessive
- Epidemiology: 3 families, 6 patients
- Genetics: Stop mutations
- WDR45B protein
- WD40 repeat protein
- Regulate assembly of multiprotein complexes
- Presenting β-propeller platform for simultaneous & reversible protein-protein interactions
- Clinical
- Onset: Neonatal
- Cortical: Developmental delay; Intellectual disability
- Seizures: Some patients
- Spastic quadriplegia
- Axial hypotonia
- Skeletal: Contractures, Kyphoscoliosis, Microcephaly
- Course: Progressive
- Laboratory
- Brain MRI: Large ventricles, Thin cortex & Corpus callosum, Hypoplastic cerebrum, Reduced white matter
Neurodevelopmental Disorder with Spastic Quadriplegia, Hypotonia & Seizures (NMIHBA)
144● Prune Exopolyphosphatase 1 (PRUNE1)
;
Chromosome 1q21.3; Recessive
- Epidemiology
- 64 patients
- Neurodegeneration, childhood, in Manitoba Cree families
- Genetics
- Mutations
- Missense, Stop, Splice
- Most: Loss of function
- Manitoba Cree: c.521-2A>G
- Genotype-phenotype correlation: Poor
- Allelic disorder: Metastatic subgroups of medulloblastoma
- Mutations
- PRUNE1 protein
- Aspartic acid-histidine-histidine (DHH) protein superfamily
- Phosphoesterase
- Functions
- Nucleotide phosphodiesterase
- Exopolyphosphatase
- Induction & Regulation of cell motility & migration
- Role in brain development
- Cancer cell metastasis
- Mutations: Abnormal cytoskeletal rearrangements & Microtubule polymerization
- Clinical
- Onset age: Congenital to 3 months
- Spasticity: Quadriparesis; No independent ambulation
- Developmental delay: Global, No speech
- Seizures (80%)
- Dysphagia
- Skeletal: Scoliosis; Joint contractures
- Microcephaly: Some patients
- Polyneuropathy (50%): Demyelinating
- Tendon reflexes: Reduced or Absent in some patients
- NCV: Slow in some patients (15 to 29 M/s)
- Course: Progressive; Death in many < 20 years
- Laboratory
- Brain MRI: Cerebral atrophy; Brainstem lesions, T2 hyperintense
- Muscle: Denervation/Reinnervation
- Brainstem: β-Amyloid precursor protein inclusions
- Spinal cord: Motor neuron loss
Familial Spastic Paraplegia: X-linked
|
Adrenomyeloneuropathy: ALDP; Xq28 Mental retardation Infantile spasms: ARX; Xp22 Psychosis, & Macroorchidism: Xq28 Rett syndrome: MECP2; Xq28 Small testes: ATRX; Xq13 SPG1: L1CAM; Xq28 SPG2: PLP; Xq21 Strabismus: X Woods-Black-Norbury Syndrome: Xq26 SPG 16: Xq11 SPG 22: SLC16A2; Xq13 SPG 34: Xq25 |
- SPG1
● L1 Cell Adhesion Molecule (L1CAM)
;
Chromosome Xq28; Recessive
- L1 syndrome epidemiology: 1/3000–1/25,000 live birth males
- Gene features
- Mutations
- > 300 described
- Multiple types: Missense, Nonsense, Splice, Small deletions
- Locations: All along gene; No hotspots
- Gene-Clinical correlations
- Truncation: Earlier death than missense
- Allelic disorders
- SPG1
- MASA Syndrome
- Mental Retardation; Adducted Thumbs; Shuffling Gait; Aphasia
- CRASH syndrome
- Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia & Hydrocephalus
- X-linked hydrocephalus
- X-linked partial corpus callosum agenesis: Missense mutations in extracellular domain
- Gene mutation data base: HGMD
- Mutations
- L1CAM protein
- Transmembrane glycoprotein
- Immunoglobulin (Ig) superfamily
- Development
- Neurite outgrowth guidance
- Neuron cell migration
- Axon bundling
- Synaptogenesis
- Myelination
- Long-term potentiation
- Malignancy: Progression & Metastatic cascade
- Clinical
- Spasticity: Paraplegia
- Ataxia
- Mental Retardation: Often severe
- Muscle: Absent extensor pollicis longus
- Female carriers: May have adducted thumbs & learning disability
- Laboratory
- Brain imaging: Corpus callosum abnormal; Hydrocephalus
- SPG2
137
● Proteolipid protein 1 (PLP1; Lipophilin)
;
Chromosome Xq22.2; Recessive
- SPG2 Epidemiology: 39 families
- Genetics
- Gene: Highly conserved among species
- Mutations
- PLP1: > 390 described
- SPG2: 35 mutations
- Spastic paraparesis: Point mutations (His139Tyr, Ser169Phe, Ile186Thr, Phe236Ser)
- Gene duplication
- Most common mutation (50% to 75%) in Pelizaeus Merzbacher
- Milder phenotype: Slow progression; No dementia
- Originates more 9 times frequently in male germ cells
- Duplicated gene may be inserted in variant locations on X-chromosome
- Point mutation: 15% to 20% of mutations
- Gene deletion
- Mechanisms
- Insertional translocation event
- Sister-chromatid exchange: In male meiosis
- Complex genomic rearrangement
- Clinical: PMP null syndrome
- Mechanisms
- Genetic duplication downstream of PLP gene: May silence PLP gene
- Allelic variants
- Pelizaeus-Merzbacher
- Hypomyelination of Early Myelinating Structures (HEMS)
- Proteolipid protein null syndrome
- PLP gene duplication syndrome ± Neuropathy
- SPG2 + Axonal neuropathy
- Multiple sclerosis: Predisposition
- Autism
- Neurodevelopmental disorders
- Early onset neurological disease trait (EONDT)
- Female SPG2: PLP1 mutation heterozygotes
- 16 patients described
- Gait disorders: Late onset
- EONDT: Large deletions
- Animal disorders
- Murine: Jimpy (Ala38Ser)
- PLP lacks amino acids 208-232; Hypomyelination; Absent mature oligodendrocytes
- Murine: Rumpshaker (Ile186Thr); Hypomyelination; Normal oligodendrocytes & longevity
- Rat: Myelin deficient (MD; Thr75Pro); Severe phenotype; PLP & DM20 both abnormal
- Chinchilla rabbits: Paralytic tremor (pt); CNS hypomyelination
- Murine: Jimpy (Ala38Ser)
- PLP1 protein
- Properties: Very hydrophobic; Integral membrane
- Most abundant protein in CNS myelin (50%)
- Roles
- Formation & maintenance of multilamellar structure of myelin
- Stabilize & Maintain myelin sheath and in the development
- Oligodendrocyte precursor development
- DM20 from alternative splicing of PLP gene: Affected in some families
- PLP1 deletions
- Physically fragile myelin sheath
- Susceptibility to subsequent demyelination
- PLP1 overexpression
- Myelination: Abnormal
- Oligodendrocytes: Reduced viability
- Clinical
- General
- Complicated SPG: 80%
- Onset
- Usually 1 to 5 years
- Varies with
- Allelic variant
- Specific mutation
- Sex
- Males: 2 years to Adult
- Females: Later than males in same family
- Gait disorder
- Spasticity
- Paraparesis: Legs > Arms
- Gait disorder
- Bladder
- Tendon reflexes: Increased
- Plantar reflex: Extensor
- Cognition: Normal or Cognitive disorders
- Progression
- Slow
- Life span: Normal
- Additional CNS signs: Present after paraparesis; Varies according to mutation
- Cognitive: Mental retardation (Common); Dementia (Occasional)
- Optic atrophy
- Cerebellar
- Ataxia
- Tremor: Kinetic; Arms > Legs
- Nystagmus
- General
- Laboratory
- Demyelinating neuropathy
- Clinical: Only mild manifestations
- NCV: Demyelinating
- Abnormal in 64%
- Motor nerve conduction velocity Δ
- Slow
- Non-uniform
- Motor > Sensory Δ
- Distal motor & F wave latencies: Prolonged
- MRI
- CNS myelination: Deficient; Leukoencephalopathy
- WM lesions: Periventricular, Parieto-occipital, Internal capsule, Corpus callosum, Subcortical, Medulla, Brainstem
- Pathology: Dysmyelination
- Demyelinating neuropathy
- Allelic variant syndromes
- Connatal Pelizaeus-Merzbacher
- Genetics
- Mutations produce misfolding of PLP & DM20
- Proteins accumulate in ER
- Clinical: Severe CNS changes
- Onset: Birth
- Hypotonia
- Spasticity: Severe
- Cerebellar: Ataxia; nystagmus
- Cognitive disorders
- No peripheral neuropathy
- Genetics
- Proteolipid protein null syndrome
142
- Epidemiology: > 20 patients
- Genetics: Mutation types
- Total PMP gene deletion
- Mutation in exon 1 (start codon)
- Deletions: 4th G of PLP coding region; Distal enhancer region
- PLP1 Protein Δ: Absent PLP/DM20
- Clinical
- Onset age: 1 to 5 years
- Motor development: Delay
- Intellectual disability
- Spastic paraplegia (70%)
- Ataxia
- Peripheral neuropathy
- Clinically mild
- Demyelinating
- Mild cognitive change
- Gastroesophageal reflux
- Survival: 5th to 7th decade
- Laboratory
- Brain MRI: Hypomyelination
- NCV: Demyelinating neuropathy (70%)
- Typical Pelizaeus-Merzbacher (HLD1)
- Genetics: Most often gene duplication
- External link: Gene clinics
- PLP gene duplication syndrome + Neuropathy
15
- Protein: Increased PLP/DM20
- Clinical
- CNS: Moderate to severe disease
- Peripheral neuropathy: Some patients
- Weakness: Hands & Feet
- Sensory loss ?
- Tendon reflexes: Reduced at ankles
- NCV: Absent sensory potentials
- Nerve pathology: Loss of large myelinated axons
- SPG2 + Axonal neuropathy: Genetic duplication downstream from PLP gene
55
- Clinical
- Gait: Awkward, Frequent falls, Steppage
- Dysarthria
- Muscle atrophy
- Weakness: diffuse; distal > Proximal
- Spastic paraplegia
- DTRs: Absent at ankle jerks
- Dystonic posture: With arms outstretched
- Mental retardation: Mild, Since infancy
- NCV
- Motor & Sensory amplitudes: Reduced
- Conduction velocity: Normal
- Nerve biopsy
- Reduced numbers of large & small myelinated axons
- Spheroids: Accumulations of normal and large sized mitochondria & tubulovesicular profiles
- Clinical
- Adrenomyeloneuropathy (AMN)
● Adrenoleukodystrophy protein (ALDP; ABCD1))
;
Chromosome Xq28; Recessive
- Epidemiology
- Incidence: 1: 20,000 to 1:100,000
- Genetics
- Multiple point mutations & deletions (6%): > 100 different
- No correlation with phenotype
- Allelic with
- Adrenoleukodystrophy
- Other syndromes
- ? Modifier gene: Some differences in phenotypes in identical twins
- ALDP protein
- ATP binding transporter: ABC transporter superfamily
- Location: Peroxisomal membranes
- Absent in 70% of X-ALD patients: No correlation with phenotype
- AMN: Clinical features
- Onset age: 2nd to 4th decade
- Spastic paraparesis: Mainly legs
- Motor: Spastic gait; Increased tone in legs
- Sensory loss: Panmodal with proprioceptive loss
- Tendon reflexes: Increased in legs
- Neuropathy
- Specific clinical signs due to neuropathy uncertain
- Usually primary axonal degeneration
- Reduced large & small myelinated axons
- Little sprouting
- Demyelinating changes: mild
- Occasional onion bulbs reported
- Thinly myelinated axons: Some
- Schwann cell inclusions: Pi granules
- Autonomic
- Impotence: May be preservation of ejaculation & Orgasm
- Bladder: Urgency; Frequency; Incontinence
- Adrenal insufficiency:
1° adrenocortical insufficiency (70%)
- Weakness
- Weight loss
- Skin: Hyperpigmentation
- Nausea & Vomiting
- Gynecomastia
- Testicular atrophy
- Prognosis
- Progression to wheelchair over 5 to 15 years
- Better with normal brain MRI (50%): Less cognitive impairment
- Worse with cerebral involvement
- All X-ALD patients who survive to adulthood eventually develop AMN
- Electrophysiology
- Primary axonal neuropathy
- Variable demyelinating features: Male > Female
- Somatosensory evoked potentials
- Males: Central & Peripheral pathway changes
- Females: Central changes
- BAERs: Abnormal in males (100%) & females (50%)
- CSF: Normal until cerebral involvement
- Female carriers
- Later onset myelopathy (20% to 50%)
- Onset 20 to 55 years
- Biochemistry
- Increased saturated, unbranched very long-chain (> 24 carbon) fatty acids (VLCFA)
- VLCFA accumulation
- Location: In all tissues
- No change with age
- 2° to: Defective formation of Coenzyme A derivative during oxidation
- C26:0 VLCFA may impair mitochondrial Complex V function
- Other peroxisomal syndromes with increased VLCFA: Zellweger; Infantile Refsum
- Carrier females: 85% with increased VLCFA
- Pathology: 2 types
- Distal axonopathy: 'Pure' AMN
- Inflammatory demyelinating CNS: Rapidly progressive cerebral forms
- Treatment
- Adrenal insufficiency: Steroid replacement
- Neurological: None; Dietary therapy or marrow transplant not clearly effective
- Other ALDP syndromes
- Childhood cerebral adrenoleukodystrophy
- Onset < 10 years
- Cognitive deficits
- CNS demyelination: Inflammatory
- Disability: Often < 3 years
- Adolescent cerebral: Onset 10 to 21 years
- Adult cerebral: Rapid CNS progression; Onset > 21 years
- Addison's disease
- Heterozygotes
- Mineralocorticoid insufficiency: Isolated
- Nonsteroidal anti-inflammatory agents: Cause hypoaldosteronism
- Glucocorticoid reserve: Subclinical reduction
- Adrenal cortical insufficiency rare
- Asymptomatic
- Childhood cerebral adrenoleukodystrophy
- Epidemiology
- Spastic diplegia with Mental retardation & Small testes (MRXS3; Sutherland-Haan)
● ATRX;
Chromosome Xq21.1; Recessive
- ATRX (Helicase 2)
- Location: Nuclear
- Function: Regulation of gene expression
- ATRX mutations also produce
- α-Thalassemia/Mental retardation syndrome
- Juberg-Marsidi mental retardation
- α-Thalassemia/Mental retardation syndrome
- Clinical
- CNS: Mental retardation
- Skeletal: Short stature; Microcephaly; Brachycephaly
- Testes: Small
- Spastic diplegia
- ATRX (Helicase 2)
- SPG 16: Spastic paraplegia, Pure
12
● Chromosome Xq11.2; Recessive- Genetics: Nucleus organizer region (NOR) insertion at Xq11.2
- Clinical
- Walking: Late or None
- Spastic paraplegia
- Spasticity: Legs
- Tendon reflexes: Brisk in lower extremities
- SPG 22: Allan-Herndon-Dudley Syndrome (AHDS)
● Solute Carrier Family 16 (Monocarboxylic acid transporter), Member 2 (SLC16A2; MCT8);
Chromosome Xq13.2; Semi-Dominant
- Genetics
- Mutations: Missense & Deletions (In & Out of frame)
- SLC16A2 protein
- Location: Choroid plexus & ventricular epithelium
- Iodothyronine transport
- Clinical
- Onset age: Birth
- Head & Neck
- Microcephaly
- Face: Elongated; Bitemporal narrowing
- Ears Large; Simple; Pinna abnormal; Antihelix prominent & flat
- Eyes: Disconjugate movements; Nystagmus, rotary (Some patients)
- Chest: Pectus excavatum
- Skeletal
- Contractures: Large & Small joints
- Scoliosis
- Feet: Flat; Great toe lateral deviation
- Neurologic
- Neonatal: Hypotonia
- Mental retardation
- Spasticity
- Paraplegia or Quadriplegia
- Tendon reflexes: Brisk
- Plantar reflex: Extensor
- Ataxia
- Dystonia
- Muscle: Atrophy
- Thyroid dysfunction: No clinical signs
- Laboratory
- MRI, Brain: Delayed myelination; Leukodystrophy
- Thyroid: T4 reduced; T3 increased; TSH normal or increased
- Carrier females
- Common clinical: Mild thyroid phenotype; No Neurologic features
- Occasional: AHDS with non-random X-inactivation
- Pregnancy: Child may have neonatal hypothyroidism
- Genetics
- Spastic paraplegia: Mental retardation & Strabismus
13
● Chromosome X; Recessive- Spastic paraparesis: Lower extremities; Slowly progressive
- Mental retardation: Severe
- Cranial nerves: Strabismus; Facial hypotonia
- Skeletal: ? Short & thick distal phalanges in some patients
- Woods-Black-Norbury Syndrome
● Chromosome Xq26-qter; Dominant- Females
- Males with congenital hypotonia & early death
- Rett syndrome
32
● Methyl-CpG-Binding protein 2 (MECP2); Chromosome Xq28; Dominant (or Sporadic) with male lethality
- Epidemiology
- Frequency: 1/15,000 females
- Sex distribution
- Females: Typical clinical syndrome
- Hemizygous males: Lethal or Neonatal encephalopathy
- Genetics
- Most mutations occur de novo
- Mutations: Missense, Nonsense, Frameshift
- C to T transition mutations: 70% at eight different CpG dinucleotides in MECP2 gene
- Non-affected females with mutation have skewed X-inactivation
- MECP2 mutation frequency
- Sporadic cases: 70% to 90%
- Familial cases: 50%
- Variant forms: 20% to 40%; More common with preserved speech variant
- Clinical-Genetic correlations
- X chromosome inactivation: Explains some clinical variabiltiy
- Inactivation of mutated chromosome: Unaffected carrier females
- Inactivation of normal chromosome: Severe disorder
- Severe phenotype: Truncation mutations early in gene
- Speech preserved: Missense or late truncation mutations
- Males
- Correlation with mutation type is especially clear
- Missense mutations with nonspecific X-linked retardation syndromes
- X chromosome inactivation: Explains some clinical variabiltiy
- MECP2 protein
- Selectively binds CpG dinucleotides in DNA
- Mediates transcriptional repression
- Target genes: Retroviral, Tissue-specific (Leukosialin; Multi-drug resistance), Imprinted (Ube3a)
- Interactions: Histone deacetylases; Corepressor SIN3A complex; c-Ski; N-CoR
- Location: Higher levels in brain, especially neurons
- Clinical
- Course
- Normal development until 6 to 18 months
- Arrested development & decline over 10 to 15 years
- Mortality rate is 1.2% per year
- Deaths may be sudden & unexplained (25%)
- Cortical
- Mental retardation: Severe
- Cognitive: Absent language
- Seizures (50%)
- Grinding of teeth
- Loss of purposeful hand skills
- Other CNS
- Spastic paraparesis: Late
- Gait disorder: Ataxia/Apraxia
- Breathing patterns: Irregular, especially in waking state
- Autonomic
- Vasomotor disturbances: Legs
- Sialorrhea
- Constipation
- Skeletal
- Microcephaly
- Growth retardation
- Scoliosis or Kyphosis
- Cardiac: Long QTc interval
- Course
- Laboratory
- EEG: High amplitude spike & wave
- Brain: Low weight; Dendrites with reduced length & complexity
- Variant Rett (MECP2) syndromes
- Mild
- forme fruste: Worndown form
- Late regression
- Preserved speech
- Severe
- Congenital
- Encephalopathy
- Early seizure onset
- Males
- Genetics: Hemizygous MECP2 mutations
- Typical clinical
- Neonatal encephalopathy
- Death: 1–2 years; May be prenatal
- Occasional patients: Typical Rett syndrome
- Associated with somatic mosaicism or partial or complete Klinefelter (47,XXY) karyotype
- Mental retardation with psychosis, Pyramidal signs & Macroorchidism (MRXS13)
● MECP2; Chromosome Xq28; Recessive
- Genetics: Allelic with Rett syndrome
- Clinical
- Mental retardation
- Manic-depressive episodes
- Increased muscle tone
- Hyperactive tendon reflexes
- Tremor
- Shuffling gait
- Macroorchidism
- Spasticity, Progressive & Mental retardation
14
● MECP2; Chromosome Xq28; Recessive
- Genetics
- Allelic with Rett syndrome
- Truncation mutation C1216T in exon 3
- Clinical
- Sex distribution: Males
- Cortical
- Cognitive: Absent language
- Seizures
- Grinding of teeth
- Motor
- Delayed development: Walking at 2 to 5 years
- Spastic paraparesis
- Facial hypotonia
- Ataxia: Gait
- Autonomic
- Sialorrhea
- Diarrhea
- Head circumference: Larger than average
- Genetics
- Mild
- Epidemiology
- Infantile spasms, Mental retardation & Spasticity (Epileptic Encphalopathy, Early-onset; EIEE1)
● Aristaless-related homeobox (ARX); Chromosome Xp21.3; Recessive
- Genetics: Mutations
- Types
- Polyalanine repeats
- Missense
- Deletion
- Clinical correlations
- Malformation phenotypes: Associated with protein truncation mutations & missense mutations in homeobox
- Non-malformation phenotypes: Missense mutations outside of homeobox & expansion of PolyA tracts
- Longer repeat mutations: Early Infantile Epileptic Encephalopathy With Suppression-Burst Pattern (Ohtahara Syndrome)
- Types
- Allelic disorder: X-linked infantile spasm syndrome (ISSX1; West syndrome)
- Genetics: Mutations
- Onset: Neonatal
- Clinical: Varied manifestations
- Mental retardation (100%): Most often moderate to severe
- Seizures (58%): Especially infantile spasms
- Hypotonia
- Spasticity
- Ataxia
- Dystonia: Episodic
- Macro- or Microcephaly
- Variant syndromes
- X-linked myoclonic epilepsy with spasticity and intellectual disability
- Infantile spasms with severe dyskinetic quadriparesis: Expansion of the first PolyA tract
30● Chromosome Xq24-q25; Recessive
- Epidemiology: Brazilian family, 12 affected members
- Genetics
- Different locus from initial publication
- Clinical
- Onset
- Age: 10 to 25 years
- Gait: Shuffling
- Spastic paraplegia
- Predominantly legs
- Reflexes
- Tendon: Brisk
- Plantar: Extensor
- Clonus: Ankles
- Sensation
- Vibration: Reduced in legs after 6th decade
- Pain: Spontaneous; Legs
- Normal: Bladder & Bowel; Mental
- Course
- Progressive
- Wheelchair in 3rd or 4th decades
- Onset
93● ATPase, H+ transporting, lysosomal, accessory protein 2 (ATP6AP2)
Chromosome Xp11.4; Recessive
- Epidemiology: 1 Danish & German American family
- Genetics
- Mutation: Synonymous variant; c.345C>T (p.S115S); Markedly increases exon 4 skipping
- Allelic disorders
- X-linked mental retardation Hedera type (MRXSH)
- Congenital Disorder of Glycosylation, Type IIr (CDG2R)
- X-linked mental retardation Hedera type (MRXSH)
- ATP6AP2 protein
- Clinical
- Onset ages: 14 to 58 years; Mean 39; Variable
- Spasticity (60%)
- May be onset symptom
- Paraparesis
- Tendon reflexes: Increased in 50%
- Plantar response: Extensor in 50%
- Parkinsonism (100%)
- Resting tremor
- Masked facies
- Bradykinesia
- L-dopa responsive
- Seizures: 1 patient
- Course: Slowly progressive
- Laboratory
- MRI: Diffuse atrophy; Ventricular enlargement
- CNS pathology: Aβ depositis; tau (4R)+ & GFAP+ processes
● Recessive
- Onset: ~10 years
- Clinical
- CNS
- Spastic paraparesis
- Tremor
- Deafness
- Cataracts
- Short stature
- Endocrine: Hypogonadism
- CNS
- Lab: Normal very-long-chain fatty acids
● Arginase, liver (ARG1)
;
Chromosome 6q23.2; Recessive
- Genetics
- Mutations: Missense; Deletion; Stop
- Clinical
- General
- Growth failure
- Anorexia
- Vomiting
- Neurologic
- Spastic quadriplegia: Progressive
- Seizures
- Developmental delay
- Mental retardation
- Behavioral: Hyperactivity; Irritability
- General
- Laboratory
- Hyperammonemia
- Hyperarginemia
- Diaminoaciduria (Arginuria, Lysinuria, Cystinuria, Ornithinuria)
- Orotic aciduria
- Pyrimidinuria
- CSF amino acids: High
Syringomyelia
|
Familial syringomyelia: with Arnold-Chiari & Scoliosis
● ? Autosomal Dominant Cleidocranial dysplasia ● Runt-related transcription factor 2 (RUNX2) ;
Chromosome 6p21.1; Dominant
● Growth/differentiation factor 5 (GDF5) ; Chromosome 20q11.2; Recessive
|
Cleidocranial dysplasia
  from A Kornberg MD |
Familial Spine Disorders & Myelopathy
|
Achondroplasia: FGFR-3; 4p16 Ankylosing spondylitis: 6p21 Atlanto-Axial instability Cleidocranial dysplasia: RUNX2; 6p21 Coffin-Lowry: RPS6KA3; Xp22 Collagen, type II disorders Disk disease: Multiple loci Dyggve-Melchior-Clausen: FLJ90130; 18q21 Hypophosphatemia; Rickets Larsen: Filamin B; 3p14 Lumbar stenosis Morquio Oculodentodigital Dysplasia: GJA1; 6q22 Opsismodysplasia: INPPL1; 11q13 Posterior longitudinal ligament Ossification Thickening Pseudoachondroplastic dysplasia: COMP; 19p13 Scheuermann disease Spondyloepiphyseal dysplasia variant Spondylometaepiphyseal dysplasia: DDR2; 1q23 Spina bifida Spinal Stenosis Tethered cord Trisomy 21 |
Also see: Acquired systemic causes of spine disorders Aggrecan mouse Radiology: Spine; Cervical spine 
|
Spine disorders, Familial
- Coffin-Lowry Syndrome
● Ribosomal Protein S6 kinase, 90 kD, Polypeptide 3;
Xp22.12; Dominant
- Genetics: Multiple mutation types
- Missense; Nonsense mutations; Splicing errors; Deletions or Insertions, Short
- RSK6 protein: Growth factor-regulated serine/threonine kinase
- Clinical features
- Cervical myelopathy: Due to hypertrophy ± calcification of ligamentum flavum
- CNS: Mental retardation; Deafness; Drop episodes
- Visceral neuropathy
- Skeletal
- Short, hyperextensible fingers & Flat feet
- Short stature
- Face: Pugilistic nose, Thick lips, Hypertelorism, Broad ears
- Systemic
- Mitral regurgitation
- Hydronephrosis
- Emphysema
- Female heterozygotes: Mild expression
- Learning disability
- Dysmorphism: Facial & Digital; Mild
- Laboratory
- Single-membrane-limited inclusions in fibroblasts
- Proteodermatan sulfate storage
- External link & Image: Coffin-Lowry Syndrome Foundation
- Genetics: Multiple mutation types
- Morquio's Syndrome
- Type A
● Galactosamine sulfatase; Chromosome 16q24.3; Recessive
- Type B
● β-galactosidase deficiency;
Chromosome 3p22.3; Recessive
- Clinical features
- Cervical myelopathy: Due to atlanto-axial dislocation
- Corneal opacities
- Hearing loss
- Joint laxity
- Growth retardation
- Hip dysplasia
- Type A
- Achondroplasia
● Fibroblast growth factor receptor-3;
Chromosome 4p16.3; Dominant
- Genetic
- Homozygotes with more severe disease
- Most cases new mutations (> 75%)
- Clinical features
- Myelopathy: Cervical & lumbar; Due to spinal stenosis
- CNS: Occasional hydrocephalus
- Skeletal
- Short stature
- Large head
- Brachydactyly
- Hearing loss
- Respiratory insufficiency
- Obesity
- Contractures
- Genetic
- Type II Collagenopathies (Cartilage & Vitreous collagen)
2
● Collagen type II, α-1 chain (COL2A1); Chromosome 12q13.11; Dominant
- Achondrogenesis II
: Lethal
- Hypochondrogenesis
: C1-C2 dyslocation
- Spondyloepiphyseal dysplasia (SED) congenita
: C1-C2 dyslocation
- Spondyolo-epi-metaphyseal dysplasia (SEMD) Strudwick
: C1-C2 dyslocation
- Kneist dysplasia
: C1-C2 dyslocation
- Stickler dysplasia
: Spinal stenosis
- Other Stickler syndrome dominant mutations: COL11A1
;
COL11A2
- Stickler syndrome recessive mutations: COL9A1
;
COL9A2
- Other Stickler syndrome dominant mutations: COL11A1
- Type II collagen absent in herniated human intervertebral disc samples
- Achondrogenesis II
- Spondyloepiphyseal dysplasia (SED) with atlantoaxial instability
:
C1-C2 dyslocation
● Autosomal Dominant- Cervical myelopathy due to atlanto-axial dislocation
- Spondylometaepiphyseal dysplasia, Short limb-hand type
● Discoidin domain receptor family, member 2 (DDR2); Chromosome 1q23.3; Recessive- Cervical myelopathy due to atlanto-axial dislocation
- Bone dysplasia: Severe short-limb
- Short stature
- Face: Short nose; Ocular hypertelorism; Retro/micrognathia
- Chest: Narrow; Abnormal sternum; Short ribs
- Pseudoachondroplastic dysplasia
● Cartilage oligomeric matrix protein;
Chromosome 19p13.11; Dominant
- Dwarfism: Short-limb
- Limbs: Brachydactyly; Telescoping fingers
- Joints: Limited elbow and hip extension; Ligamentous laxity
- Cervical myelopathy due to atlanto-axial dislocation
- Recessive type pedigrees due to gonadal mosaicism
- Cytoplasmic metachromasia of fibroblasts
- Dyggve-Melchior-Clausen disease
34
● Dymeclin (DYM; FLJ90130)
; Chromosome 18q21.1; Recessive
- Genetics
- Allelic with: Smith-McCort dysplasia (SMC)
- Allelic with: Smith-McCort dysplasia (SMC)
- Clinical
- Skeletal
- Dwarfism: Short trunk
- Head: Prominent jaw; Microcephaly
- Limbs: Claw hand; Restricted joint mobility; Hip subluxation
- Chest: Barrel; Protuding sternum
- Spine: Osteochondrodysplasia
- Cervical myelopathy: Due to atlanto-axial dislocation
- CNS: Mental retardation
- Skeletal
- Laboratory
- Mucopolysacchariduria
- Abnormal cartilage (Growth plate) histology
- Disordered chondrocyte columns: Degenerating cells; Rough ER inclusions
- Brain: Hypomyelination
- Genetics
- Larsen syndrome (Osteochondrodysplasia)
45
● Filamin B; Chromosome 3p14.3;Dominant
- Filamin B disorders
- Perinatal lethal atelosteogenesis I
& III
- Spondylocarpotarsal syndrome
- Perinatal lethal atelosteogenesis I
- Genetics: Missense mutations
- Filamin B protein
- Filamins: Cytoplasmic; Crosslink actin into 3D networks
- Filamin B: Growth plate chondrocytes; Developing vertebral bodies
- Clinical
- Short stature
- Face: Flat; Frontal bossing; Hypertelorism
- EENT: Cataract; Cleft-palate
- Spine & Skeletal
- Scoliosis
- Abnormal vertebral segmentation & development: Kyphosis
- Joint dislocations: Knee
- Arthrogryposis
- Limbs
- Multiple congenital joint dislocations
- Brachydactyly
- Carpal or phalangeal abnormalities
- GU: Cryptorchidism; Genital anomalies
- CNS
- Myelopathy
- Cervical spine
- 2° to abnormal vertebral segmentation: Hypoplastic C4 or C5
- Infantile onset
- Hydrocephalus
- Myelopathy
- Variant: Larsen syndrome, Recessive
● β-1,3-Glucuronyltransferase 3 (B3GAT3); Chromosome 11q12.3; Recessive
- Filamin B disorders
- Opsismodysplasia
● Inositol Polyphosphate Phosphatase-like 1 (INPPL1); Chromosome 11q13.4; Recessive
- General classification: Severe spondylodysplastic dysplasias (group 14)
- INPPL1 protein
- Inositol-1,4,5-trisphosphate 5-phosphatase family
- Negative regulation of insulin signaling & glucose homeostasis
- Docking protein
- Endochondral ossification
- Polymorphisms associated with predisposition to insulin resistance
- Clinical
- Cervical myelopathy due to atlanto-axial dislocation
- Hypotonia
- Craniofacial: Prominent brow, Depressed nasal bridge, Small anteverted nose, Long philtrum
- Death
- Respiratory failure in 1st few years in some
- Some long-term survivors
- Skeletal dysplasia: Late bone maturation
- Dwarfism
- Short hands & Feet
- Radiology
- Platyspondyly
- Metacarpals: Square
- Skeletal ossification: Delayed
- Metaphyseal cupping
- Spina bifida
- Associated with
- Anencephaly
- Hydrocephalus
- Lipoma
- Sacral: Hairy patch, dimple, agenesis (caudal regression)
- Meningocele
- Posterior
- Anterior: Autosomal dominant
- Onset: Symptoms in young adults with obstructive labor
- GI: Constipation & rectal fistula & abscess
- Meningitis
- Onset: Symptoms in young adults with obstructive labor
- Posterior
- Clinical
- Weakness: Legs
- Sensory loss: Sacral
- Urinary incontinence
- Mouse model: Double heterozygotes for undulated
& patch
- Rule out: Sacral dysgenesis or hemisacrum
-
● X-linked Dominant
● Autosomal Dominant
- Associated with
- Trisomy 21
- Cervical myelopathy due to atlanto-axial instability
- Familial intervertebral disc disease
- Intervertebral disc disease: General
67
- Prevalence of degenerative intervertebral discs increases linearly with age
- 80% of all lumbar discs abnormal at 70 years of age
- 43.8% of patients with lumbar disc herniation have family history in patients younger than 17 years old
- Lumbar disc herniation in juvenile patients 5x greater with positive family history
- Family history associated with more severe disc disease
- Similar familial predisposition for cervical & lumbar disc disease
- Monozygotic twins
- Heritability of disc height & bulge = 60% to 74%
- Association between lumbar disc degeneration on MRI & propensity to report pain in lumbar spine
- SPG25: Disc herniation & Spastic paraplegia
27
● Chromosome 6q23.3-q24.1; Recessive- Epidemiology: Family from Northeastern Italy
- Clinical
- Onset age: 30 to 46 years
- Spine pain
- Early in disease course
- Cervical & Lumbar
- Radiates to extremities
- Spastic paraparesis: Legs
- Disc herniations: Cervical, Thoracic & Lumbar
- Neuropathy: Mild; Sensory or Motor
- Treatment: Surgical
- Radiology
- Disk herniations
- Intervertebral disc disease: Increased risk
● Collagen IX α2 (COL9A2);
Chromosome 1p34.2; Dominant
- Mutation: Gln326Trp
- Allelic COL9A2 disorders
- Multiple epiphyseal dysplasia, Type2
- Stickler syndrome, type V
- Epiphyseal dysplasia + Myopathy
- Multiple epiphyseal dysplasia, Type2
- Intervertebral disc disease: Increased risk
● Collagen IX α3 (COL9A3);
Chromosome 20q13.33; Dominant
- Mutation: Arg103Trp
- Present in 12.2% of lumbar disc disease cases and in 4.7% of controls
- Increased the risk of lumbar disc disease about 3-fold
- Allelic COL9A3 disorders
- Multiple epiphyseal dysplasia, Type3
;
- Epiphyseal dysplasia + Myopathy
- Multiple epiphyseal dysplasia, Type3
- Mutation: Arg103Trp
- Intervertebral disc disease: Increased risk
● Cartilage intermediate layer protein (CLIP);
Chromosome 15q22.31; Dominant
- CLIP protein
- Expressed abundantly in intervertebral discs
- Colocalizes with TGFB1
in clustering chondrocytes & territorial matrices
- Inhibits TGF-β1-mediated induction of cartilage matrix genes
- Expression increases as lumbar disc degeneration progresses
- Mutation: Ile395Thr
- Increased frequency with lumbar disc disease
- CLIP protein
- Intervertebral disc disease, lumbar: Increased risk in Japanese population
66
● Thrombospondin II (THBS2);
Chromosome 6q27
● Matrix metalloproteinase-9 (MMP9);
Chromosome 20q13.12
- THBS2
- Mutation: Intronic SNP (IVS10-8C to T)
- Present in Japanese populations
- Located in a polypyrimidine tract upstream of 30 splice site of intron 10
- Exerts allelic differences on exon 11 skipping rates in vivo
- Susceptibility allele shows increased skipping
- Skipping of exon 11 results in: Decreased THBS2 interaction with MMP2 and MMP9
- Increased the risk of lumbar disc disease: ~1.4-fold
- THBS2 protein
- High levels in intervertebral discs
- Interacts with MMP2 & MMP9 (Gelatinases)
- Promotes LRP
-mediated endocytosis of MMP2 & subsequent lysosomal degradation
- Thrombospondin family
- Family of five secreted, modular glycoproteins
- Location: Extracellular matrix
- Mutation: Intronic SNP (IVS10-8C to T)
- MMP9
- MMP9 Mutation
- Missense: Q279R missense
- Increased risk: ~1.3-fold
- MMP9 mutation also associated with: Lung cancer metastasis & Trachoma
- MMP9 Mutation
- MMP9 protein
- THBS2
- Combined risk for lumbar disc herniation of THBS2 + MMP9 mutations: ~3-fold
- Intervertebral disc disease: General
67
- Lumbar disc disease: Association with severe degeneration
53
● Aggrecan; Chromosome 15q26.1
- Mutation: Polymorphism
- Exon 12 is candidate marker for severe lumbar disc disease
- Shorter number of repeats with multilevel and severe disc degeneration
- Disorders associated with severe disc degeneration
- Collagen II
● Col2A1; Chromosome 12q13.11-q13.2
- Spondyloepiphyseal dysplasia
- Achondrogenesis
- Stickler syndrome
- Spondyloepiphyseal dysplasia
- Cartilage oligomeric matrix protein
● COMP; Chromosome 19p13.1
- Pseudoachondroplasia
- Multiple epiphyseal dysplasia, Fairbank type
- Pseudoachondroplasia
- Collagen II
 Ankylosing Spondylitis Limited back flexion |
● Chromosome 6p21.3; Dominant
- Onset
- 15 to 30 years
- Back pain
- Large joints
- Epidemiology
- Male predominant: 75%
- Prevalence: 1% to 2% of population
- Clinical
- Cervical myelopathy
- 86% Male
- 2° Atlanto-axial instability: 20%
- Disease duration > 10 years
- Skeletal
- Back
- Pain: Variable
- May radiate to legs 2° cauda equina fibrosis
- Better with activity
- Worse with rest
- Worse in AM
- Tenderness over sacroiliac joints
- Stiffness: Limited flexion & amp; extension
- Progression: Upward from lumbar spine
- Pain: Variable
- Chest wall
- Limited movement
- Costochondral joint involvement
- Joint arthritis: Transient 50%; Permanent 25%
- Back
- Systemic features
- Cardiac (3% to 5%): AV block; Aortic insufficiency
- Pulmonary fibrosis: Late in disease
- Iridocyclitis: 20%
- Amyloidosis
- Progression
- 10% Disability in 10 years
- Worse prognosis: Hip disease in 1st 2 years
- Cervical myelopathy
- Laboratory
- HLA-B27 haplotype association: 90%
- Erythrocyte Sedementation Rate: High
- X-ray: Earliest changes in sacroiliac joints; Bamboo spine
- Anemia: Mild
- Radiology: Changes are Bilateral & Symmetric
- Pathology
- Inflammation at sites of insertion of ligaments & tendons in bones
- Reactive bone growth
- Treatment: Exercise; NSAIDs
- External links
- eMedicine
- MedMedia
- Images: Sacroiliac joints; Facet joints
35● Connexin 43 (GJA1)
; Chromosome 6q22.31; Recessive
- Dysmorphisms
- Craniofacial
- Ocular: Microphthalmia, Microcornea, Iris abnormalities, Cataracts, Glaucoma, Optic atrophy
- Nasal
- Dental
- Limb
- Syndactyly type III: Occasional
- Craniofacial
- CNS
- Spastic paraplegia
- Onset age: 2nd decade
- Gait disorder
- Spastic bladder
- Mental retardation: Mild
- MRI: Leukodystrophy in subcortical cerebral white matter
- Course: Slowly progressive
- Spastic paraplegia
- Conductive deafness: Occasional
- Cardiac abnormalities: Rare
59● Multiple susceptibilty loci; Recessive
 OPLL: Compression of cervical spinal cord
(MRI T2 signal) |
- Epidemiology
- Common in Asia
- Frequency in Japan
- 2%–4% of general population > 30 years of age
- 10% of males > 60 years of age
- Male predominant: 2:1
- Similar high prevalence in Korea and Taiwan
- Frequency in Japan
- Frequency in Caucasians: 0.1% to 1.7%
- Most cases in North America are sporadic
- Increased frequency after 50 years of age
- Common in Asia
- OPLL Genetics: Multiple susceptibiltiy loci
40,
60
- Mutation types: Single nucleotide polymorphisms (SNPs) & Missense
- COL6A1
Chromosome 21q22.3
- Strongly associated OPLL mutation: T to C substitution at intron 32 [-29]
- Other associated SNPs: Numerous
- Exon 15 (+39): T to C substitution
- Intron 33 (-20): A to G substitution
- Mutations in glycine residues of triple-helix domain of COL6A1 in
- Myosclerosis: COL6A2 mutation
- COL11A2
: Chromosome 6p21.32
- Genetics
- Mutation: Intron 6 (-4), T to A substitution, is protective
- Single nucleotide substitution int exon 6: Higher prevalence in men, but not in women
- No association with OPLL in Japanese study
- XI collagen protein
- Collagen
- Found in the cartilage matrix
- Coassembles with Type II collagen in fibril network
- Overproduction in some surgical specimens of OPLL
- Genetics
- TGFB3 (14q24.3)
: Intronic SNP
- Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)
: Chromosome 6q23.2
- R-spondin 2 (RSPO2)
- Secreted agonist of canonical Wnt-β-catenin signaling
- Other susceptibility
- Loci: 1p, 11q, 16q
- TLR5: 1q41
- HLA haplotype: 6p21
- RXRB: 6p21
- RUNX2: 6p21
- CDC5L: 6p21
- IL-1β: 6q13
- ESR1: 6q25
- IL-15RA: 10p15
- BMP9: 10q11.22
- CCDC91
: 12p11
- VDR: 12q13
- BMP4: 14q22-q23
- TGFB3: 14q24
- TGFB1: 19q13
- BMP2: 20p12.3
- OPLL secondary (Syndromic): Hypophosphatemic rickets/osteomalacia
- Phosphate regulating endopeptidase homolog, X-linked (PHEX)
: XLHR
- Fibroblast growth factor 23 (FGF23)
: ADHR
- Chloride channel, voltage-sensitive 5 (CLCN5)
: HR X-linked
- Dentin matrix acidic phosphoprotein 1 (DMP1)
: ARHR1
- Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1)
: ARHR2
- Phosphate regulating endopeptidase homolog, X-linked (PHEX)
- Other causes: Hypoparathyroidism; Acromegaly/gigantism
- Clinical
- Onset
- Neck: Pain or Stiffness (42%)
- Arm: Dysesthesias (48%)
- Gait: Spastic
- Hand dysfunction
- Spinal levels: Cervical (C4-C6) 75%; Thoracic 15%; Lumbar 10%
- Progression
- Symptomatic patients: To severe myelopathy in some
- Size: Enlargement laterally, posteriorly, and longitudinally
- Signs begin when: 50-60% of AP diameter of spinal canal is occupied
- Acute deterioration in during disease course in 20%
- May be related to falls or ossification of thoracic ligamentum flavum
- Asymptomatic patients
- Myelopathy-free rate at 30-years: 71%
- May not require surgery
- Minority of patients with OPLL are symptomatic
- Associated disorders
- Other skeletal
- Ossification of ligamentum flavum
- Diffuse idiopathic skeletal hyperostosis
- Diabetes: Association with fasting serum insulin level
- Obesity
- Hypoparathyroidism
- Hypophosphatemic rickets
- Diet: High-salt & low-protein
- Other skeletal
- Onset
- Diagnostic tests
- MRI
- Low signal on T1 & T2 anterior to spinal cord
- CT myelogram: Average of 3 segments involved
- MRI
- Treatment of symptomatic patients
- Surgical decompression
- Approaches
- Anterior
- Removal of ossified mass
- Complication: CSF leak
- Posterior
- Decompression with laminectomy
- Continuous-type OPLL without kyphotic deformity.
- Compression of > 4 levels
- Anterior
- ? More improvement with less severe myelopathy
- Approaches
- Surgical decompression
- Mouse model: Twy ('tip-toe' walking Yoshimura) mouse
- Mutation in nucleotide pyrophosphatase
- Mutation in nucleotide pyrophosphatase
- Image: UCSD
- Other cause of thickening
- Maroteaux-Lamy Syndrome (Mucopolysaccharidosis type VI)
- Maroteaux-Lamy Syndrome (Mucopolysaccharidosis type VI)
- Genetic associations
- HLXB9
- Currarino triad
:
Anal abnormalities, Anterior meningocele, Sacral abnormalities
- Currarino triad
- VATER & VACTERL syndromes
- CHARGE
- Chromosome 22: Deletion 22q11.2
; Ring chromosome
- DiGeorge syndrome: Clinical; No chromosome abnormality
- Chromosome 21: Trisomy 21
; Trisomy 21q + Monosomy of 6q
- Other chromosomes: Trisomy 8; Partial monosomy 4p15.2-pter + Partial trisomy 13q32-qter
- Other syndromes:
Klippel-Trenaunay-Weber
,
Klippel-Feil
, Dandy-Walker, Fuhrmann
- FG syndromes
- HLXB9
- Anatomic associations: Various spinal dysraphic states
- Spinal lipomas
- Diastematomyelia
- Dermal sinus
- Myelocystocele
- Tight filum terminale
- Loosely defined "tethered cord"
- Onset of signs
- Most common in children or young adults
- May occur at any age
- May be associated with exercise or growth
- Weakness
- Legs
- May be asymmetric
- Pain
- Lower back
- Radiation: To the legs, perineum, or genitals
- Flexion of the back: Increased pain
- Lordotic posture or pelvic tilting: Decreased pain; Worse gait
- Other neurologic
- Gait disorders: Associated with weakness or spasticity
- Urinary incontinence: Failure to toilet train
- Sensory loss: Early in perineal region
- Tendon reflexes: May be reduced or increased
- Scoliosis
- Cutaneous changes: May be prominent or absent
- Hairy patch: Commonly associated with diastematomyelia
- Nevus
- Appendage or skin tag
- Small dimple with pinhole: Especially at lumbosacral junction; Associated with dermal sinus
- Large subcutaneous fat collection: Associated with spinal lipomas
- Treatment: Surgery
- Most likely to improve: Pain
- Worst prognosis: Bladder function
- Early: Dwarfism, mild
- Age-related: Lordosis; Spastic paraparesis
- Pathology
- Herniation & degeneration of vertebral disks
- Degeneration of disc chondrocytes
|
Arnold-Chiari Malformation ● Autosomal Recessive or Sporadic ● With Syringomyelia
|
 Arnold-Chiari malformation + Hydromyelia
Cerebellar vermis projects below foramen magnum (Arrow) |
 From: Simon Kornberg Canine ACM + Hydromyelia
|
Spastic Ataxia Syndromes
87
|
Hereditary Dominant SCA SPAX Recessive SPAX SPG X-linked Acquired |
Spastic Ataxia, Dominant
|
Spastic Ataxia, Recessive
|
|
Spastic Ataxia: X-linked
Spastic Ataxia: Acquired
|
Spastic Ataxia 1, Hereditary (SPAX1)
21● Vesicle-related membrane protein 1 (VAMP1; Synaptobrevin; SYB1)
;
Chromosome 12p13.31; Dominant
- Epidemiology: Newfoundland families
- Genetics
- Mutation: Splice site, c.340+2T>G; Ser114Arg
- Mutation leads to: Loss of VAMP1A isoform
- Allelic disorder: Congenital Myasthenic Syndrome, Presynaptic
- VAMP1 protein
- General: Synaptic vesicle cycle at Presynaptic nerve terminals
- Family: VAMP/Synaptobrevin
- Location: Post-Golgi vesicular compartments
- Anchored in vesicle membrane by: C-terminal domain
- Interact with: Synaptophysin prior to docking of vesicle
- After docking: Bind to SNAP-25-syntaxin complex
- Forms: Synaptic core complex
- Exocytosis, Regulated
- Starts cascade of protein interactions leading to: Neurotransmitter exocytosis
- Cleaved by some botulinum toxins
- Clinical
- Severity variable within families
- Onset
- Age
- Variable
- Typical: 10 to 20 years
- Range: Early childhood to 20's
- No anticipation
- Leg spasticity
- Age
- Spasticity
- Legs
- Severe
- Tendon reflexes: Brisk
- Cerebellar
- Involuntary head jerks
- Dysarthria
- Dysphagia
- Gait disorder
- Ocular: Supranuclear gaze palsy
- Sensory: Vibration loss in legs
- Not affected: Life span; Cognition
- Pathology
- Degeneration of: Corticospinal tracts & Posterior columns
- VAMP1 variant disorder: Congenital Myasthenic Syndrome, Presynaptic 25 (CMS 25)
116
- Epidemiology: 11 families
- Genetics
- Inheritance: Recessive
- Mutations: Frameshift or Missense; Most loss of function
- Allelic disorder: SPAX1, Dominant
- Clinical
- Onset age: Birth
- Early motor: Hypotonia; Feeding difficulties; Developmental delay
- Weakness: Diffuse; bulbar; Respiratory
- GI: Dysphagia; Aspiration with chest infections
- Eye: Ophthalmoparesis; Strabismus
- Joints: Contractures or Laxity
- Pyridostigmine treatment: Mild improvement
- Laboratory
- Serum CK: Normal
- Muscle biopsy: Myopathic; Atrophy, especially type 2; Hypertrophy, Type 1
- EMG: Myopathic
- NCV: CMAP small amplitude
- RNS: 2x Increment at 20 Hz or Normal
- Leg MRI: Mild change in adductors & quadriceps
Hereditary Spastic Ataxia (SPAX7)
● Autosomal Dominant
- Epidemiology: 3 families
- Clnical
- Onset age: Congenital to 18 years
- Eye
- Optic atrophy
- Pupils: Miosis; Reduced reactivity to light
- Ptosis
- Ataxia: Limbs; Gait; Dysarthria
- Pyramidal
- Spastic paraparesis
- Tendon reflexes: Brisk in legs
- Plantar response: Extensor or Flexor
- Extrapyramidal: Chorea
Spastic Ataxia 2 (SPAX2; SPG 58)
62
● Kinesin family member 1C (KIF1C)
; Chromosome 17p13.2; Recessive
- Nosology: SPG58
- Epidemiology: Moroccan, Algerian, Palestinian & French families
- Genetics
- Mutations: Gly102Ala; Arg731*; Arg169Trp; Pro176Leu; G183A (Splice); rg301Gly; R731X (Stop); Deletion
- Allelic disorder
- KIF1C heterozygote: Mild syndrome
- KIF1C protein
- Axon transport, Anterograde
- Kinesins: Other disorders
- Clinical
- Onset
- Age: Range 1 to 69 years; Often 6 to 18 years
- Dysphagia
- Falling
- Cerebellar ataxia
- Dysarthria
- Gait disorder
- Nystagmus: Horizontal; Some patients
- Tremor & Head titubation
- Pyramidal
- Spasticity: 1 of 3 families; All limbs
- Tendon reflexes: Brisk in legs
- Plantar response: Extensor
- Arms: Often normal
- Weakness: Some patients
- Distal
- Hands & Feet
- Fasciculations
- Sensation: Normal or Reduced (Panmodal; Posterior column)
- Bladder: Often normal
- Progression
- Over few years or Slow
- Often still walking after 2 decades
- EOM: Saccadic pursuit; Dysmetric saccades; Upgaze paresis (1 patient)
- Cognition: Intact
- Onset
- Laboratory
- Brain MRI: Normal or Internal capsule demyelination; T2 hyperintensities
- VEP: Normal or Increased latency
- NCV: Demyelination in some
- KIF1C heterozygotes
- Genetics: Semidominant inheritance
- Clinical
- Weakness: Hip abductors; Proximal legs
- UMN: Tendon reflexes brisk; Extensor plantar responses
- NCV: Neuropathy
Branchial Myoclonus with Spastic paraparesis & Cerebellar ataxia
● Glial fibrillary acidic protein (GFAP)
; Chromosome 17q21.31; Dominant
- Nosology: Adult onset Alexander disease
24
- Genetics
- Mutation: Val87Gly; Missense
- GFAP protein
- Intermediate-filament (IF) protein
- Location: Cytoplasm
- Specific for cells
- Astroglial lineage
- Lacking fibronectin
- GFAP immune disorder: Astrocytopathy
- Clinical
- Onset age: 12 to 71 years
- Branchial (Palatal) myoclonus
- Cerebellar
- Truncal ataxia
- Nystagmus
- Bulbar: Dysarthria; Dysphagia; Dysphonia
- Spastic paraparesis (50%)
- Reflexes
- Tendon: Mildly increased
- Plantar: Extensor
- Autonomic: Bladder dysfunction in some
- Cognitive: Normal
- Progression: Death or severe disability 5 to 10 years after onset
- Pathology (MRI)
- Medulla & Spinal cord: Severe atrophy
- Cerebral & Cerebellar cortex: Mild atrophy
- Periventricular: Intensity on T2
- Inferior olive: Hypertrophy (30%)
- GFAP immune disorder: Astrocytopathy
138
- Clinical
- Onset
- Antecedent: Flu-like symptoms (90%)
- Course: Subacute
- Ages: 28 to 72 years; Mean 53 years
- Polyradiculopathy (10% to 20%)
- Meningoencephalomyelitis
- Pyramidal signs
- Brainstem
- Tremor
- Psychiatric Δ
- Neoplasm association: Ovary, Teratoma, CNS lymphoma
- Course: Acute monophasic or Chronic
- Treatment: Immunothereapy, corticosteroid or other
- Onset
- Laboratory
- MRI: Linear gadolinium meningeal enhancement
- CSF: Pleocytosis
- GFAP Antibody
- Cell target: Astrocytes
- Antigen target: GFAPα
- May be present without CNS astrocytopathy
- Other antibodies: NMDAR in 20%
- Neuropathology: CD8 lymphocytes
- Other: Antibody related CNS syndromes
- Clinical
Spastic ataxia, congenital, with Mental retardation & Osmiophilic skin vessels (GAMOS1; SCAR5)
18● WDR73
; Chromosome 15q25.2; Recessive
- Nosology: Galloway-Mowat Syndrome 1
- Epidemiology: > 50 patients
- Genetics
- Mutation: H347Y; Homozygous
- Initially misidentified as ZNF592
mutation
- WDR73 protein
- Clinical
- Onset: Congenital
- Ataxia
- Spasticity: Brisk tendon reflexes; Speech disorder
- Strength: Mildly reduced in legs
- Gait: 60% never walk
- Mental retardation: Severe; Little speech
- Eye: Optic atrophy; Oculomotor apraxia
- Sensory: Normal
- Skeletal: Microcephaly; Short stature
- Course: Non-progressive
- Laboratory
- Skin vessels: Osmophilic endothelium
- MRI: Cerebellar atrophy
- Muscle biopsy: Normal morphology & mitochondrial studies
Neurodegeneration with Optic atrophy, Childhood-onset (NDGOA)
● Ubiquitin carboxyl-terminal esterase L1 (UCHL1; PGP 9.5)
; 4p14
- Epidemiology: Turkish family
- Genetics
- Mutation: Homozygous; Missense; Glu7Ala
- UCHL1 protein
- Clinical
- Onset
- Age: Childhood
- Visual loss at 5 years
- Early development: Normal
- Eye: Optic atrophy, Nystagmus, Blindness
- Cerebellar ataxia: Inability to stand
- Sensory loss: Vibration; Joint position
- Spasticity
- Legs
- Tendon reflexes: Increased
- Plantar responses: Extensor
- IQ: Mildly decreased
- Seizures: 1 patient
- Onset
- Laboratory
- EEG: 3.5- to 4-Hz spike activity
- NCV: Normal
- EMG: Myokymia or Myotonia
- Brain MRI: Cerebral & Cerebellar atrophy
Spastic Paraplegia, Ataxia ± Mental Retardation (SPAR)
23● Autosomal Dominant
- Epidemiology: Michigan family
- Onset: 15 to 35 years; ? Anticipation
- Clinical: Variable phenotype
- Spastic paraplegia (100%)
- Leg spasticity
- Bladder dysfunction
- Dorsal column sensory loss: Reduced vibration & proprioception
- Tendon reflexes: Brisk in legs
- Plantar responses: Extensor
- Course: Progressive; Disabling
- Ataxia (65%)
- Limb
- Dysarthria
- EOM: Saccadic intrusions; Hypermetric saccades
- Dystonia (60%): Mild; Hands & Feet
- Mental retardation (30%): Mild; Non-progressive
- Spastic paraplegia (100%)
- Laboratory
- MRI: Spinal cord ± Cerebellar atrophy
- NCV & EMG: Normal
- SSEP: Conduction delay between spinal cord & cortex
- See: Spastic ataxias
Spastic Paraplegia, Epilepsy & Mental Retardation (SPERM)
● Autosomal Dominant
- Epidemiology: 1 Italian family
- Genetics: Incomplete penetrance
- Onset: < 40 years
- Clinical
- Motor (83%)
- Distribution: Lower limb involvement
- Weakness
- Spastic paraplegia
- Progressive defecit
- Epilepsy (100%)
- Mental retardation: Variable severity
- Motor (83%)
Lipodystrophy with Spastic-Ataxia & Congenital cataracts (LCCNS)
25● Caveolin 1 (CAV1)
;
Chromosome 7q31.2; Dominant
- Epidemiology: Kentucky family
- Genetics
- Mutation: Heterozygous; Truncating; 1- BP deletion
- Clinical: Variable neurologic phenotype
- Onset
- Age: Congenital
- Lipodystrophy
- Cataracts
- Lipodystrophy: Partial
- Absence of subcutaneous fat over entire body except buttocks, hips, and thighs
- Ocular
- Retinitis pigmentosa
- Iris deposits
- Spastic paraplegia
- Leg spasticity
- Bladder dysfunction
- Dorsal column sensory loss: Reduced vibration; Legs > Arms
- Tendon reflexes: Brisk in legs; Clonus
- Plantar responses: Extensor
- Course: Progressive & Disabling in 2nd & 3rd decade in some patients
- Cerebellar
- Spastic-Ataxic gait
- EOM: Gaze-evoked horizontal nystagmus; Upbeat nystagmus; Ocular dysmetria
- Orthostatic hypotension
- General: Neurologic involvement varied; Some patients with mild ataxia
- Onset
- Laboratory
- MRI: Spinal cord with increased T2 signal
- NCV & EMG: Normal
- SSEP: Conduction delay
- Lipids: High serum cholesterol & triglycerides
- Vitamin E & β-Tocopherol: Markedly elevated
- Carbohydrate metabolism: Insulin resistance; Impaired glucose tolerance
- Body fat
- Absent subcutaneous fat: Upper body & Trunk
- Preservation of subcutaneous fat: Between waistline & Knees
- Visceral fat accumulation
- Muscle biopsy: No mitochondrial changes
- See: Spastic ataxias
Paroxysmal Choreoathetosis/Spasticity (CSE; DYT9)
● SLC2A1 (GLUT1)
; Chromosome 1p34; Dominant- Epidemiology: 4 families
- Genetics
- Mutations: Deletion, Stop & Missense
- Allelic disorders
- GLUT1 deficiency syndrome-1 (GLUT1DS1)
- GLUT1 deficiency syndrome-2 (GLUT1DS2)
- Idiopathic generalized epilepsy-12, susceptibility (EIG12)
- Dystonia 9
- GLUT1 deficiency syndrome-1 (GLUT1DS1)
- SLC2A1 protein
- Glucose & Dehydroascorbic acid transporter
- Clinical features
- Onset: 2 to 15 years
- Spasticity between episodes: 30%
- Episodes
- Involuntary movements & Dystonic postures
- Perioral & leg paraesthesias
- No ataxia
- Duration: 20 minutes
- Frequency: 2x/day to 2x/year
- Precipitated by: Exercise; Stress; Alcohol; Lack of sleep
- Treatment: ? Acetazolamide & Phenytoin
- Cognition: Impaired
- Laboratory
- EEG: Generalized slowing
- CSF Glucose & Lactate: Low
Hypomyelinating Leukodystrophy 6 (HLD6; HABC)
146● Tubulin β4A (TUBB4A)
;
Chromosome 19p13.3; DominantHypomyelinating Leukodystrophy 9 (HLD9)
● Arginyl-tRNA Synthetase (RARS1)
; Chromosome 5q34; Recessive
- Epidemiology: 33 patients
- Genetics
- Mutations: Heterozygous; Missense, Splice, Stop; Loss of function
- RARS protein
- tRNA synthetase: Cytoplasmic
- Clinical: Spastic ataxia
- Onset age: Birth to 1 year; Mean 6 months
- Spasticity: Legs > Arms; Gait disorder; Pseudobulbar
- Cerebellar: Intention tremor, Dysmetria, Dysarthria, Nystagmus
- Cognition: Impaired; Language delay
- Course: Progressive
- Laboratory
- Brain MRI: Atrophy; Loss of myelin, supra- & infratentorial
Hypomyelinating Leukodystrophy (Spastic-Ataxia) 120
● Glutamyl-Prolyl-tRNA Synthetase (EPRS)
; Chromosome 1q41 Recessive
- Epidemiology: 5 patients, 4 families
- Genetics
- Mutations: Missense & Stop
- EPRS protein
- Amino-acyl-tRNA synthetase (ARS): Bifunctional
- Catalyzes aminoacylation of glutamic acid & proline tRNA
- Part of GAIT (γ-interferon-activated inhibitor of translation) comple
- Involved in selective translational silencing
- Components
- Ribosomal protein L13a (RPL13A)
- EPRS
- Synaptotagmin-binding cytoplasmic RNA-interacting protein (SYNCRIP, NSAP1)
- Glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
- Ribosomal protein L13a (RPL13A)
- Clinical
- Onset age: Infant to 14 years
- Cognitive regression
- Spasticity
- Ataxia: Intention tremor; Dysarthria; Nystagmus
- Dystonia
- Dysphagia
- Optic atrophy: Visual loss
- Course: Progression to disability
- Laboratory
- Brain MRI: Hypomyelinating leukodystrophy; Thin corpus callosum
Leukoencephalopathy with Ataxia, UMN signs & Polyneuropathy (RPIAD)
44● Ribose-5-Phosphate Isomerase (RPIA)
; Chromosome 2p11.2; Recessive
- Epidemiology: 4 patients
- Genetics
- Mutations: Missense & Stop
- RPIA protein
- Pentose phosphate pathway: Non-oxidative phase
- Converts ribulose-5-phosphate to ribose-5-phosphate
- Location: Cytosol & Membrane-bound organelles
- Deficiency: Leads to accumulation of pentoses & pentose phosphates
- Clinical
- Onset
- Infancy: 4 days to 6 months
- Psychomotor retardation: Slow walking & Speech
- Developmental & Speech delay
- Seizures: Onset 4 years
- Ataxia
- Arms & Legs
- Dysarthria
- Nystagmus: Lateral gaze
- Upper motor neuron
- Spasticity
- Hyperactive tendon reflexes: Except at ankles
- Plantar reflexes: Extensor
- Eyes: Optic atrophy; Retinitis pigmentosa
- Peripheral nerve
- Tendon reflexes at ankles: Reduced
- Motor: Mild distal atrophy & weakness
- Sensory loss: Distal
- Course: Progression after age 5 to 7
- Onset
- Laboratory
- Brain imaging
- MRI: Leukoencephalopathy; Cerebellar atropy
- Proton MRS: Ribitol & D-Arabitol peaks
- Ribitol & D-Arabitol high: Serum, Urine & CSF
- Lactate & Pyruvate: Normal
- Nerve conduction testing: Axon loss in some patients
- Motor: Mildly reduced velocities
- Sensory: Mildly reduced velocities
- Serum CK: Mildly high
- EEG: Slowing; Epileptic activity
- Brain imaging
Leukoencephalopathy with Cortical involvement & Peripheral neuropathy
112
● Folate receptor 1, adult (FOLR1)
; Chromosome 11q13.4; Recessive
- Nosology
- Neurodegeneration due to cerebral folate transport deficiency
- Cerebral folate deficiency
- Epidemiology: 13 families
- Genetics
- Mutations: c.466T>G (p.W156G); Gln118Ter; Cys175Ter; 18-BP Dup, NT130
- FOLR1 protein
- High affinity for folic acid & several reduced derivatives
- Mediates delivery of 5-methyltetrahydrofolate to cell interior
- Clinical
- Onset: Late infantile to 3 years
- Psychomotor regression, severe
- Hypotonia
- Epilepsy: Myoclonic
- Ataxia
- Spasticity
- Tendon reflexes: Increased or Decreased
- Polyneuropathy
- Treatment: Folinic acid
- Laboratory
- Brain MRI
- Cortical disturbances
- CNS hypomyelination
- Cerebellar atrophy
- NCV
- Axon loss: CMAPs small amplitude, some temporal dispersion
- NCV: 31 to 37 M/s
- CSF: 5-methyltetrahydrofolate low
- EEG: Multifocal epileptiform
- Brain MRI
Pelizaeus-Merzbacher–Like Disease (PMLD; HLD2)
46
● Gap Junction Protein α12 (Connexin 46.6; Connexin 47; GJA12; GJC2)
; Chromosome 1q42.13; Recessive
- Nosology: Hypomyelinating leukodystrophy 2
- Epidemiology: Turkish & German families
- Genetics
- Missense mutation in one or both alleles; Some nonsense mutations
- Mild phenotype: Ile33Met
- Knockout mouse: Clinically normal
- Allelic with
- SPG 44
- Lymphedema, hereditary, IC
- GJA12 protein
- Gap junction protein
- Higher expression: Brain & Spinal cord
- Low expression: Skeletal muscle
- May play role in oligodendrocyte function
- Functional overlap with GJB1
- Clinical
- Onset
- Age: Early infancy
- Poor head & trunk control
- Nystagmus
- Motor development
- Impaired by age of 8 to 15 mo
- Delayed unaided sitting and/or walking
- Walking at age 5 rare
- Facial weakness: Common
- Cerebellar
- Ataxia
- Nystagmus
- Choreoathetosis
- Dysarthria
- Spasticity: Progressive
- Epilepsy: Focal; Onset prior to adolescence
- Peripheral nerve: Mild neuropathy
- Onset
- Laboratory
- Nerve conductions
- Motor & sensory velocities: Mildly slowed
- Lower limbs more involved
- MRI: Leukodystrophy
- Nerve conductions
- Variant syndrome (SPG44
):
Later onset complicated spastic paraplegia
73
- GJA12 (GJC2) Mutation: Ile33Met; Homozygous
- Mutant protein: Forms gap junction channels with altered functional properties
- Clinical
- Onset
- Age: 1st or 2nd decade
- Gait disorder
- Hand tremor
- Spastic paraplegia
- Legs > Arms
- Walking preserved: Until late
- Sphincter dysfunction: 1 patient late in course
- Sensory loss: 1 patient late in course
- Cerebellar ataxia: Mild; No nystagmus
- Mental impairment: Mild
- Progression: Slow
- Other
- Pes cavus
- Strabismus
- Scoliosis
- Onset
- Laboratory
- MRI: Hypomyelinating leukoencephalopathy
- Evoked potentials: Abnormal
- EMG & NCV: Normal
Pelizaeus-Merzbacher–Like Disease 2
79
● Small inducible cytokine subfamily E, Member 1 (SCYE1; AIMP1)
; Chromosome 4q24; Recessive
- Nosology
- Disease name: Leukodystrophy, hypomyelinating, 3 (HLD3)
- SCYE1 protein: Aminoacyl tRNA synthase (ARS) complex-interacting multifunctional protein 1 (AIMP1); p43
- Epidemiology: Israeli Bedouin family
- Genetics: Frameshift mutation; Gln98ValfsX30
- AIMP1 protein
- Expression: Neurons of Brain & Spinal cord
- Associated with: Neurofilament light chain (NEFL)
- AIMP1 depletion: Neurofilament hyperphosphorylation
- Clinical
- Onset
- Age: 1 to 3 years
- Nystagmus
- Eye
- Nystagmus: Horizontal & Rotary
- Exotropia (50%)
- Fundi: Pale
- Pupillary reflex: Slow
- Visual acuity: Reduced
- Motor
- Axial hypotonia
- Spasticity: Limbs; Legs > Arms
- Leg muscle wasting
- Seizures (50%)
- Mental retardation: Severe
- Skeletal
- Small head
- Kyphoscoliosis
- Joint contractures
- Progression: Rapid
- Onset
- Brain MRI
- Hypomyelination
- Atrophy: Diffuse
Spastic Ataxia with Optic Atrophy (SPAX4)
78
● Poly(A) RNA polymerase, mitochondrial (MTPAP; PAPD1)
; Chromosome 10p11.23; Recessive
- Epidemiology: Old Amish family
- Genetics
- Mutation: Homozygous; Missense; N478D
- MTPAP Protein
- Location: Mitochondria
- Function: Polyadenylation of mitochondrial mRNA
- Clinical
- Onset
- Age: Early childhood
- Delayed speech & walking
- Cerebellar
- Ataxia: Limb, Truncal & Gait
- Nystagmus
- Spasticity
- Tongue: Slow movements
- Paraparesis
- Lower limb tone: Increased
- DTRs
- Knee & Jaw: Brisk
- Arm & Ankle: Reduced
- Plantar response: Extensor
- Dysarthria: Cerebellar & Spastic
- Strength: Normal
- Eye: Optic atrophy
- Cognitive: Learning difficulties; Emotional liability; IQ ~50
- Course: Progressive decline in function
- Onset
Spastic Paraparesis with Brain Stem & Spinal Cord Hypomyelination (Leukoencephalopathy) (HBSL)
94
● Aspartyl-tRNA Synthetase (DARS)
; Chromosome 12q21.3; Recessive
- Epidemiology: 10 patients
- Genetics
- Mutations: Missense; Met256Leu, Ala274Val, Asp367Tyr, Arg460His, Arg487Cys, Arg494Gly, Arg494Cys
- DARS protein
- Expression: High in cortex, Hippocampus + Cerebellar molecular layer & Purkinje neurons
- See
- Clinical
- Onset: 1st year
- Developmental delay: Global; Hypotonia
- Upper motor neuron
- Spasticity: Legs
- Tendon reflexes: Brisk in Arms & Legs
- Plantar: Extensor
- Cerebellum: Nystagmus; Dysarthria (30%); Other usually normal
- Cognition: Mild mental retardation or Normal
- Eye: Optic pallor (30%)
- Course: Progressive; Patients never walked
- Laboratory
- MRI: White matter pathology
- Cerebrum: General atrophy
- Corpus callosum: Increased signal; Thin
- Cerebellar peduncles & Brain stem
- Spinal cord: Corticospinal tracts & Dorsal columns
- NCV: Normal
- MRI: White matter pathology
Progressive Spastic Ataxia & Hypomyelinating Leukodystrophy (SPAX8)
117
● NK6 Homeobox 2 (NKX6-2)
;
Chromosome 10q26.3; Recessive
- Epidemiology: 12 families
- Genetics
- Mutations
- Types: Missense (Arg101Ser; Leu163Val; Phe167Leu; Ala182Val) or Nonsense
- Middle East: 196delC
- Mutations
- NKX6-2 Protein
- Transcriptional repressor with early
- CNS: Early high general & late focused expression
- Regulates oligodendrocyte gene expression
- Clinical
- Onset age: 1 month to 5 years
- Hypotonia: Early
- Cerebellum
- Eyes: Nystagmus; Hypometric saccades; Horizontal EOM Limited; Oculomotor apraxia
- Ataxia: Arms & Legs
- Pyramidal features
- Spasticity
- Tendon reflexes: Increased
- Truncal & Limb
- Legs > Arms
- Dysarthria
- Dystonia (60%): Cervical; Limbs
- Epilepsy
- Polyneuropathy: Distal weakness
- Sensation: Normal
- Cognitive impairment: With early onset disease
- Disease course: Progressive until CNS myelination is complete, then stable
- Laboratory
- Brain MRI
- Hypomyelination: Increased T2W & FLAIR signal in white matter
- Cerebellar atrophy
- Spinal cord: Volume loss; Ventral & dorsal horn T2W hyperintensity
- NCV: Normal motor & sensory
- Brain MRI
5,10-Methylenetetrahydrofolate Reductase Deficiency
● MTHFR
;
Chromosome 1p36.22; Dominant
- Genetics
- Polymorphisms C677T & A1298C: Increased sporadic ALS risk in females
- MTHFR protein
- Methyl donor for homocysteine re-methylation to methionine
- Clinical: Varied syndromes
- Common childhood
- Clinical
- Developmental delay
- Psychiatric features
- Polyneuropathy: Some patients
- Encephalopathy
- Nitrous oxide sensitivity
- Laboratory
- Plasma methionine: Low or Normal
- Homocystinuria
- Clinical
- Spastic paraparesis + CNS
80
- Mutation: Homozygous A195V
- Clinical
- Onset age: Adult
- Spinal syndrome
- Spasticity: 4 limbs
- Incontinence
- Slow Progression
- CNS
- Behavior disorders
- Seizures
- Laboratory
- Fasting homocysteine: High
- Muscle biopsy: Denervation; Complex I deficiency
- Treatment
- Betaine (50 mg/kg twice daily)
- Thiamine (10 mg)
- Riboflavin (100 mg)
- Neural tube defects, Folate sensitive
- Common childhood
Hereditary Sensory Ataxia (SNAX1; ADSA)
48
● Ring Finger Protein 170 (RNF170)
; Chromosome 8p11.21; Dominant
- Epidemiology
- 4 families
- Genetics
- Mutation: Missense; Arg199Cys
- Allelic disorder: Hereditary Spastic Paraparesis, Recessive
- RNF170 protein
- Expressed in spinal cord
- E3 ubiquitin ligase
- Targets inositol 1,4,5-trisphosphate receptors for degradation
- Other inositol 1,4,5-trisphosphate receptors related SPG syndromes: ITPR1; ERLIN1; ERLIN2
- Clinical
- Onset
- Age: Range 3rd to 8th decade
- Symptoms: Gait disorder; Instability in dark
- Sensory
- Loss: 100%
- Legs > Arms
- Distal
- Pan-modal
- Ataxia (66%)
- Wide based gait
- Romberg: Positive
- Dysesthesias: Some patients
- Loss: 100%
- Reflexes
- Tendon
- Legs: Absent
- Arms: Reduced
- Plantar: Flexor 70%; Extensor 30%
- Tendon
- Motor
- Strength: Usually normal
- Hypotonia in some patients
- Ocular: Abnormal saccades
- Sphincter function: Normal
- Cognition: Normal
- Skin: No ulcerations
- Course: Normal life span
- Onset
- Differential diagnosis
- Laboratory
- Nerve conduction studies
- SNAPs: Normal or Reduced amplitude
- CMAPs: Normal
- H-reflexes: Absent
- SSEP: Legs absent; Arms present
- EMG: Normal
- MRI of Brain & Spine: Normal or Posterior column involvement
- CSF: Normal
- Vestibular areflexia
- Pathology: Spinal cord
- Axonal spheroids in dorsal columns
- Spheroids may contain ubiquitin
- Nerve conduction studies
- Also see: Sensory ataxia syndromes
- RNF170 variant syndrome: Hereditary Spastic Paraparesis 85 (SPG85)
124
- Epidemiology: 6 families
- Genetics
- Inheritance: Recessive
- Mutations: Homozygous; Stop or Missense; Ala109Asnfs*9, Cys102Arg, delEx4_7, Arg173Asnfs*49, Tyr114*, c.396+3A>G
- Allelic disorder: Sensory Ataxia, Dominant
- RNF170 protein
- Mutation effect: Reduced ubiquitination & proteasomal degradation of IP3R
- Clinical
- Onset age: 2 to 5 years
- Spinal cord
- Spasticity: Legs ≥ Arms
- Plantar response: Extensor
- Tendon reflexes: Increased, Legs ≥ Arms
- Urinary bladder function: Usually normal
- Eye: Optic atrophy; Saccadic pursuit
- Ataxia: Some patients
- Sensory: Subclinical involvement of sensory tracts
- Course: Slow progression; Loss of ambulation in 3rd or 4th decade
- Laboratory
- NCV: Axon loss in 2 patients
- Brain MRI: Normal or Cerebellar atrophy
Spasticity, Childhood-onset, with Hyperglycinemia (SPAHGC)
: Spastic ataxia
● Glutaredoxin 5 (GLRX5)
; 14q32.13; Recessive
- Epidemiology: Lebanese & Chinese families
- Genetics
- Mutations: K51del; 8-BP ins, NT82
- Allelic disorder: Sideroblastic anemia, pyridoxine-refractory 3 (SIDBA3)
- GLRX5 protein
- Mitochondrial protein
- Iron-sulfur (Fe-S) cluster biogenesis
- Maintenance of intracellular iron homeostasis
- Mitochondrial Fe-S cluster transfer to apoproteins (e.g. lipoate synthetase)
- Clinical
- Onset age: 10 months to 2.5 years
- Pyramidal
- Spastic diplegia: Legs > Arms
- Plantar response: Extensor
- Tendon reflexes: Increased
- Ataxia
- Cognitive: Learning difficulties or Normal
- Optic atrophy
- Laboratory
- Brain MRI: Leukodystrophy; C-spine lesions
- Hyperglycinemia
- Respiratory chain enzymes: Normal
Neurodegeneration with Brain Iron Accumulation 7 (NBIA7)
: Spastic ataxia
● RALBP1-associated EPS domain-containing protein 1 (REPS1)
; 6q24.1; Recessive
- Epidemiology: 1 French family, 2 patients
- Genetics
- Mutations: Compound heterozygous; Missense; V78L, A113E
- REPS1 protein
- Interacts with RALBP1
- Forms endosome recycling compartment
- Interacts with RALBP1
- Clinical
- Onset age: 1 to 10 years
- Motor delay
- Ataxia: Nystagmus, Dysarthria, Dysmetria
- Spasticity: Legs
- Pes cavus
- Course: Progressive
- Laboratory
- Brain imaging: Cerebellar & Cerebral atrophy, Corpus callosum thin, Iron accumulation in globus pallidi & peduncles
Neurodegeneration with Brain Iron Accumulation 8 (NBIA8)
: Spastic ataxia
● Carnitine acetyltransferase (CRAT; CAT1)
; 9q34.11; Recessive
- Epidemiology: 1 Turkish patient
- Genetics
- Mutation: Missense; Homozygous; Arg321His
- Possible allelic disorder: Carnitine acetyltransferase deficiency
- CRAT protein
- Fatty acid metabolism
- Mitochondrial: Inner membrane
- Catalyzes reversible transfer of acyl groups from acyl-CoA thioester to carnitine
- Control of acyl-CoA/CoA ratio in mitochondria, peroxisomes, & endoplasmic reticulum
- Clinical
- Onset age: 2 years
- Speech delay
- Hypotonia
- Ataxia: Gait disorder; Tremor; Dysmetria
- Spasticity: Tendon reflexes brisk
- Neuropathy: Sensory
- Course: Progressive
- Laboratory
- Brain imaging: Cerebellar atrophy; Basal ganglia hyperintensities consistent with iron accumulation
Neurodegeneration with Brain Iron Accumulation 9 (NBIA9)
: Spastic ataxia
● Ferritin heavy chain 1 (FTH1)
; 11q12.3; Dominant; de novo
- Epidemiology: 5 patients
- Genetics
- Mutations
- Heterozygous
- Truncating
- Duplication or Deletion
- Location: Exon 4 (last exon) of FTH1
- Allelic disorder: Hemochromatosis 5
- Mutations
- FTH1 protein
- Ferritin subunit
- Ferroxidase activity: Fe++ → Fe+++
- Allows iron storage ferritin mineral core
- Binds to: TFR1
- Mutation effect: Dominant negative
- Clinical
- Onset: Childhood
- Developmental delay
- Spasticity
- Ataxia
- Dystonia
- Startle response
- Microcephaly
- Laboratory
- Serum iron: Borderline low or Normal
- Brain MRI
- White matter: Loss, Corpus callosum thin
- Cerebellar atrophy
- Basal ganglia: Iron
- Pontocerebellar hypoplasia
- Brain pathology: Inclusions, eosinophilic, FTH1+; Iron deposition
Hereditary Spastic Paraplegia, Complicated (SPG82)
125
● CTP:phosphoethanolamine cytidylyltransferase (ET; PCYT2)
; 17q25.3; Recessive
- Epidemiology: 10 families
- Genetics
- Mutations
- Types: Missense & Stop
- Cys30Gly, His244Tyr, Pro307Leu, Arg377Ter
- General: Most missense in 2nd catyalytic domain; Few in 1st catalytic domain
- Allelic disorder: CNS & PNS Neurodegeneration in Sarlooswolfdogs
- Mutations
- PCYT2 protein
- Etherlipid biosynthesis
- Kennedy pathway: Phosphatidylethanolamine synthesis
- Via CDP-ethanolamine pathway
- Rate limiting enzyme
- Via CDP-ethanolamine pathway
- Strongest expression: Liver, Heart & Skeletal muscle
- Phosphatidylethanolamine: Abundant membrane lipid
- Other etherlipid disorders: Zellweger syndrome; Rhizomelic chondrodysplasia punctata
- Clinical
- Onset age: < 2 years
- Developmental delay, global, with regression
- Spasticity: Para- or Tetraparesis
- Spasticity
- Tendon reflexes: Brisk
- Plantar response: Extensor
- Epilepsy
- Eye: Nystagmus; Optic atrophy
- Polyneuropathy: Some patients
- Sensory loss
- Weakness: Distal
- Laboratory
- Brain MRI: Cerebral & Cerebellar atrophy, progressive
- NCV: Small CMAP & SNAP ampltudes
Spastic dystonia syndromes
- DOPA-responsive dystonia
● GTP cyclohydrolase I; Chromosome 14q22.2; Dominant
● Tyrosine hydroxylase; Chromosome 11p15.5; Recessive
- Mitochondrial:
Hereditary spastic dystonia with Leber's optic atrophy
● NADH Dehydrogenase, Subunit 4
- SPG
- Neuroaxonal dystrophy
- Ataxias
- Triosephosphate isomerase (TIM) deficiency
Mass lesions
- von Hippel-Lindau
:
Hemangioblastoma
- Neurofibromatosis
- Meningioma
- Multiple hamartoma
- Lipoma
Other familial spinal syndromes
| Differential diagnosis of hereditary spastic paraplegia | |
| Category | Disorders |
| Structural abnormality | Spinal:
Spondylosis; Atlanto-axial; Canal stenosis Vascular: Arteriovenous malformation Congenital: Arnold-Chiari; Tethered cord Mass: Neoplasm; Granuloma; Syringomyelia |
| Degenerative disorders | Multiple sclerosis; Amyotrophic lateral sclerosis; Spinocerebellar ataxias |
| Leukodystrophies | Adrenomyeloneuropathy; Krabbe; Metachromatic leukodystrophy |
| Metabolic disorders | Vitamin deficiency: B12; E; Abetalipoproteinemia; Mitochondrial disorders |
| Infections | Syphilis; HTLV; HIV (AIDS); Lyme |
| Other | DOPA-responsive dystonia; Hydrocephalus; Toxins |
Return to Spinal Cord Index
Return to Neuromuscular home page
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