Home, Search, Index, Links, Pathology, Molecules, Syndromes, Muscle, NMJ, Nerve, Spinal, Ataxia, Antibody & Biopsy, Patient Info

FAMILIAL SPINAL CORD SYNDROMES¹

• History
  • 1st cases described in 1880 by Strümpell
  • Later more extensively discussed by Lorrain
• Epidemiology
  • Prevalence: 2 to 10 per 100,000
  • Common types: SPG4; SPG 11
• Classification according to
  • Mode of inheritance & genetic linkage
  • Presence or absence of other features
    • Uncomplicated : Spasticity; No CNS or systemic features
    • Complicated : Spastic paraplegia with other features
    • Exclusion of alternative disorders
• Inheritance: Dominant more common than recessive
• Uncomplicated (Pure) HSP syndromes: Tend to have many similarities regardless of genetic linkage

  Features suggesting diagnosis other than SPG Motor     Weakness > Spasticity     Prominent upper limb spasticity     Asymmetry Peripheral neuropathy Ataxia: Symptomatic Retinal pigmentation Extrapyramidal signs

  • Onset
    • 2 peaks: 2nd to 4th decade & < 6 years
    • Age may vary even within families: 25% of affected patients asymptomatic
    • Disability 2° motor dysfunction: Leg stiffness & Gait disorder
  • Motor
    • Spasticity
      • Most common feature of HSP (> 95%)
      • Predominantly in legs: Hamstrings; Quadriceps; Ankles
      • Symmetric
      • Gait: Circumduction & Toe walking
      • Treatment: Baclofen (oral or intrathecal); Dantrolene (oral)
    • Weakness (50%): Distal; Legs; Usually much milder than spasticity
  • Reflexes
    • Tendon
      • Legs 3+ to 4+ (> 95%): Ankle may be absent in some patients
      • Arms 2+ to 3+
    • Extensor plantars (75%)
  • Sensory loss (10% to 65%)
    • Mild: More common later in disease
    • Modalities
      • Vibration
      • Later in disease course: Joint position & Pansensory
    • Paresthesias may occur
  • Bladder: Variable involvement (40%)
    • Urgency progressing to incontinence
    • More common in longstanding disease
    • Common early: SPG 19
    • Treatment: Oxybutinin
  • Skeletal: Pes cavus & other foot deformities (30%)
  • Dementia: Mild mental status changes not uncommon
  • Normal: Cranial nerves
  • Uncommon features
    • Paresis of upper limbs
    • Distal amyotrophy
  • Laboratory features
    • Nerve conduction studies: Often normal
    • Pathology: Central axonopathy
      • Axonal degeneration: Most prominent in distal regions of longest axons
      • Mainly involves: Corticospinal tract & Fasciculus gracilus (Dorsal Column)
      • Spinocerebellar tracts involved in 50%
      • Cortex: SPG 4
    • CSF: Usually normal
  • Distinctive features
    • Early onset
      • SPG 5: Recessive
      • SPG 10: Dominant
      • SPG 12: Dominant
      • SPG 24: Recessive
      • SPG 28: Recessive
      • SPG 30: Recessive
      • SPG 31: Dominant; Some families
      • SPG 39: Recessive
      • SPG 47: Recessive
      • Leukodystrophy & Dystonia: Recessive
    • SPG 4 (2p24)
      • Most common dominant FSP
      • Adult onset: Also SPG 6 & SPG 8
    • Other uncomplicated SPG
      • SPG 7: Recessive
      • SPG 8: Dominant
      • SPG 16: X-linked
      • SPG 33: Dominant
      • SPG 34: X-linked
      • SPG 37: Dominant
      • SPG 48: Recessive
• Complicated FSP: Features associated with spastic paraparesis
  • Early onset
    • IAHSP: Recessive
    • SPG 9: Dominant
    • SPG 18: Recessive
    • SPG 20: Recessive
    • SPG 26: Recessive
    • SPG 32: Recessive
    • SPG 35: Recessive
    • SPG 43: Recessive
    • SPG 45: Recessive
    • SPG 46: Recessive
    • SPG 47: Recessive
    • SPOAN: Recessive
    • Myoclonic epilepsy: Recessive
    • Leukodystrophy & Dystonia: Recessive
  • SPG + Peripheral neuropathy
  • SPG 2
  • SPG 3A
  • SPG 7
  • SPG 11
  • SPG 21
  • SPG 23
  • SPG 25
  • SPG 26
  • SPG 27
  • SPG 30
  • SPG 36
  • SPOAN
    
  • Adrenomyeloneuropathy
  • Leukoencephalopathy
  • Cavanaugh
  • MTATP6
  • Motor neuropathy
    • SPG 4
    • SPG 9
    • SPG 14
    • SPG 15
    • SPG 17 (Silver syndrome)
    • SPG 20 (Troyer syndrome)
    • SPG 21 (Mast syndrome)
    • SPG 26
    • SPG 38 (Silver syndrome)
    • SPG 39: PNPLA6; 19q13
      
    • SPG 43
  • Spastic ataxia
  • Thin corpus callosum
    

    FSP + Thin corpus callosum From: R Baloh From: M Al-Lozi

    • SPG1
    • SPG11: Most common
    • SPG15
    • SPG18
    • SPG21
    • SPG 46
    • SPG 47
    • Leukodystrophy & Dystonia
  • Epilepsy: Variable types
    • Myoclonic epilepsy
    • Spastic paraplegia, Epilepsy & Mental retardation
    • Infantile spasms, Mental retardation & Spasticity
    • SPERM
    • Pelizaeus-Merzbacher–Like Disease
    • Sjögren-Larsson Syndrome
    • Rett syndrome
    • Leukoencephalopathy with Ataxia, UMN signs & Polyneuropathy
    • SPG15: Occasional
    • SPG18: Occasional
    • Symmetrical spastic cerebral palsy: Occasional
    • Leukodystrophy & Dystonia: Occasional
  • Dementia & Mental retardation
    • Often associated with other CNS signs
    • SPG1
    • SPG2
    • SPG4
    • SPG7
    • SPG11
    • SPG14
    • SPG15
    • SPG 18
    • SPG20
    • SPG21
    • SPG26
    • SPG 45
    • SPG 46
    • SPG 47
    • X-linked SPG
    • Presenilin 1
    • Leukodystrophy & Dystonia
    • Other
  • Other
    • SPG9: Cataracts, Gastroesophageal Reflux, Amyotrophy
    • SPG16: Cranial nerve involvement
    • SPG17: Hand & foot atrophy
    • SPG23: Pigmentary abnormalities
    • SPG25: Prolapsed intervertebral disks
    • SPOAN: Optic atrophy
      
    • SPG29: Esophageal hernia; Hearing loss
    • SPG 2q24: Dystonia
    • SPG 44: Tremor
    • SPG 46: Cataracts
• Protein types
  • Chaperone activity
    • SPG4
    • SPG7
    • SPG13
  • Mitochondrial
    • SPG7
    • SPG13
    • SPG20
    • HHH syndrome
    • SPG31
  • Transport proteins
    • SPG3A: Atlastin; Dynamin role in vesicle recycling
    • SPG4: Spastin; Associates with microtubule cytoskeleton
    • SPG10: KIF5A; Transports cargoes along microtubules in anterograde direction
    • SPG20: Spartin; Trafficking of late endosomal components
    • SPG 30: ATSV (KIF1A); Synaptic vesicle transport
    • ALS2 & IAHSP: Alsin; ? Vesicle transport
  • Golgi
    • SPG 3A: Atlastin
    • SPG 21: Maspardin
  • Endoplasmic reticulum
    • SPG 12: RTN2
    • SPG 18: ERLIN2 (ERAD pathway)
  • Myelination
    • SPG 2: PLP
  • Other
    • SPG 39: PNPLA6
    • SPG 44: GJA12
    • SPG 48: KIAA0415
      

Familial Spastic Paraplegia (Strumpell; FSP): Dominant

• SPG3A (FSP1) ¹⁹
  l Atlastin (ATL1; SPG3A) ; Chromosome 14q22.1; Dominant
  • Epidemiology: Common cause of dominant, early onset FSP
  • Genetics
    • ATL1 Gene mutations
      • > 40 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
    • Allelic with: Hereditary Sensory Neuropathy I syndrome
  • Atlastin protein
    • Homology
      • Dynamin family of large GTPases: Dynamins play role in
        • Synaptic vesicles: Recycling
        • Mitochondria: Maintenance & Distribution
      • Guanylate binding protein 1 (GBP1)
    • Expression: Predominantly in CNS
      • Enriched in cerebral cortex: Especially lamina V
      • Subcellular: Golgi apparatus; Oligomeric integral membrane protein
  • Clinical
    • Onset
      • Age: Early
        • Range: 1 year to 7th decade
        • Mean in 1st or 2nd decade
        • Anticipation & variation within families
      • Spasticity
    • 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: Occasional patients
      • Ataxia
      • Seizures
      • MRI: Hyperintensities
  • 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
    • Laboratory
      • Nerve conduction testing: Axonal loss in most but not all
      • Nerve biopsy: Axon loss
  
  
• SPG4 (FSP2)
  l Spastin ; 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 identified⁹
      • 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
      • Compound heterozygote⁴⁷
        • Mutations: 2 Missense; P361L & S44L
        • More severe disease
        • Infantile onset
        • Parents: Asymptomatic or Paraparesis
      • Homozygous mutations: S44L
        • Adult onset
        • Paraparesis
      • Large exon deletions
        • Onset age: Earlier
        • Clinical syndrome: Similar
        • Frequency: Common
        • Technical: May not be detected by gene sequencing
      • Exon 10-12 duplication
        • Brazilian family
        • Males: Earlier age of onset; More severely affected
        • Females: 50% unaffected
    • 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
  • 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
    • Function²²
      • 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
  • Clinical
    • Onset
      • Typical
        • 3rd to 5th decades; Mean 23-35 years
        • Later than SPG3, SPG5 or SPG7
      • 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
  • Lab³⁸
    • 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
  
  
• SPG6 (FSP3)⁴¹
  l NIPA1 ; Chromosome 15q11.2; Dominant
  • Epidemiology: Families of Irish & Iraqi ancestry
  • Genetics
    • Mutations
      • Missense: Thr45Arg; G106R (316G>A & 316G>C)
      • Probably dominant negative effect
    • Gene probably commonly deleted in Prader-Willi & Angelman syndromes
  • 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 1st decade to 35 years
    • No anticipation
    • Spastic paraparesis: Relatively severe
      • Tendon reflexes: Brisk in Arms & Legs
      • Extensor plantar responses
    • Weakness & Atrophy: Distal in legs
    • Sensory loss: Vibratory in legs; Frequent; Mild
    • Bladder dysfunction (10%)
    • Pes Cavus: Common
    • Progression: May need wheelchair in 30's to 50's
  
  
• SPG8 ⁶¹
  l 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
  • Onset: 22 to 60 years
  • Clinical
    • General
      • Pure spastic paraplegia
      • Intrafamilial phenotypic heterogeneity: Present
    • Pyramidal signs
      • Spasticity
        • Hyperreflexia
        • Extensor plantar responses
        • Gait disorder
      • Relatively severe: 60% use wheelchair by age 40
    • Weakness: Hip flexion; Ankle dorsiflexion
    • Gait: Spastic diplegia
    • Sensory loss: Vibratory in feet
    • Bladder disorders (50%): Urgency; Incontinence
    • Pes cavus
    • Occasional: Dysmetria (Finger-Nose)
  • Muscle biopsy: Normal
  
  
• SPG9: Cataracts, Gastroesophageal Reflux, & Spastic Paraparesis with Amyotrophy
  l Chromosome 10q23.3-q24.2; Dominant
  • Epidemiology: Italian & British families
  • Genetics: Similar locus to Recessive SPG27
  • Onset
    • Infancy to 4th decade
    • Anticipation
  • Clinical
    • Cataracts (100%): Bilateral; Congenital
    • GE Reflux (100%): Persistent vomiting; Hiatus hernia
    • Spastic paraparesis: Incomplete penetrance; Onset 1st to 3rd decade
    • Muscle wasting: Hands & Forelegs; Motor neuropathy with axonal loss
    • Skeletal: Growth impairment; Pes cavus
  • MRI: Spinal cord atrophy
  
  
• SPG10⁶
  l Kinesin Heavy Chain 5A (KIF5A) ; Chromosome 12q13.3; Dominant
  • Genetics
    • Mutation types
      • Missense: Asn256Ser; Arg280Cys; Tyr276Cys; Ala361Val
      • Other: In-frame deletion; Splice site
    • Mutation locations: Often in motor or neck domain of kinesin
  • KIF5A protein
    • Plus-end–directed microtubule motor
    • Involved in anterograde transport of membranous organelles in axons
    • Expressed only in neurons
    • Mutation effects
      • Prevents stimulation of the motor ATPase by microtubule-binding
      • Impairs axonal transport
      • Reduces gross cargo flux: Leads to deficient supply of synapse
    • Other kinesin mutations
      • CMT 2A: KIF1Bβ
      • CFEOM1: KIF21A
  • Epidemiology: 3% of European AD HSP families
  • Onset
    • Age
      • Mean 10 to 23 years
      • Range: Infancy to 51 years
      • Varies within families
    • Gait disorder
  • Clinical
    • 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
    • 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
      • Frequency: 10% of complicated forms of SPG
  • Laboratory
    • Electrophysiology: Subclinical sensory-motor neuropathy in all patients
  
  
• SPG12⁸
  l Reticulon 2 (RTN2) ; Chromosome 19q13.32; Dominant
  • Epidemiology: USA, Welsh, German & Italian families
  • Genetics
    • Mutations: Deletion; Frameshift & Truncation
    • Disease mechanism: Haploinsufficiency
  • Reticulon 2 protein
    • Location: Endoplasmic reticulum
    • Interacts with: Spastin
    • ER-shaping protein
  • Onset
    • Age: Mean 7 to 14 years; Range 5 to 39 years
  • Clinical
    • 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%
  • Laboratory
    • Nerve conduction & EMG: Normal
    • MRI: Spinal cord usually normal
    • SSEP: Delayed
  
  
• SPG13⁷
  l 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
  • Onset: Mean 39 years; Range 17 to 68 years
  • Clinical
    • 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
  • HSP60 Variant: Hypomyelination & Leukodystrophy ⁷
    • Nosology
      • Pelizaeus-Merzbacher–Like Disease (PMLD)
      • Hypomyelinating leukodystrophy 4 (HLD4)
    • Epidemiology: Israeli Bedouin kindred, 23 children
    • Genetics
      • Recessive
      • HSPD1 mutation: D29G; Homozygous
      • Allelic with: SPG 13
    • 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
  
  
• SPG19²⁶
  l 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
  • Laboratory
    • Motor evoked potentials: Slowed central motor conduction velocity in legs
  
  
• SPG29
  l 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
  • Laboratory
    • Hyperbilirubinemia
    • NCV & EMG: Normal
    • Motor evoked potentials: Reduced from lower limbs
    • CNS imaging: Normal
  
  
• SPG31 ⁵⁷
  l Receptor expression–enhancing protein 1 gene (REEP1) ; Chromosome 2p11.2; Dominant
  • Epidemiology
    • > 25 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
  • REEP1 protein
    • Mitochondrial: ? Membrane protein
    • Expression: Ubiquitous; Neuronal & Non-neuronal tissues
    • Rab-mediated vesicle transport
    • ? Involved in chaperone-like activities
  • Clinical
    • Common phenotype: Pure spastic paraplegia
    • Onset age
      • Bimodal
        • 1st & 2nd decade (> 3 years): 71%
        • 31 to 91 years
      • Inter- & Intrafamilial variation
      • Penetrance: Incomplete
    • 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
      • Axon loss
    • 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
  
  
• SPG33 ⁵⁸
  l ZFYVE27 ; Chromosome 10q24.2; Dominant
  • Epidemiology: German family
  • Genetics: Missense mutation; 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
  
  
• SPG 36 ³¹
  l 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
  • Laboratory
    • Brain MRI: Normal
    • Central motor conduction time: Prolonged
    • Motor & Sensory NCV: Abnormal in legs
      • NCV: Mildly slow
      • Motor DL: Prolonged
      • SNAP amplitude: Reduced
  
  
• SPG 37
  l 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)
  • Laboratory
    • MRI: Normal
    • EMG: Normal
    • Evoked potentials: Normal
  
  
• SPG 38: Silver syndrome 2 ⁶⁹
  l 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
  • Laboratory
    • CMAP amplitudes: Variably reduced, Median > Ulnar
    • EMG: Chronic denervation, Distal
    • Evoked potentials: Normal
  • Also see: SPG17 (Silver syndrome)
  
  
• SPG 41 ⁶⁵
  l 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
  
  
• SPG 42 ⁷¹
  l Solute carrier family 33 (Acetyl-CoA Transporter), Member 1 (SLC33A1) ; Chromosome 3q25.31; Dominant
  • Epidemiology: Single Chinese family
  • Mutation
    • Missense: Ser113Arg
    • Mechanism: ? Haploinsufficiency
  • SLC33A1 protein
    • Cytoplasmic: Endoplasmic reticulum
    • Probable acetyl-CoA transporter necessary for O-acetylation of gangliosides
    • 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
  
  
• SPG 2q24: Spasticity + Dystonia⁷⁰
  l 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
  • Laboratory
    • CNS MRI: Normal
    • Nerve conduction studies: Normal
    • Dystonia treatment: Deep pallidal stimulation
  
  
• Other syndromes
  • Alzheimer's disease: Presenilin 1 ³⁷
    l Chromosome 14q24.3; Dominant
    • Genetics
      • Mutation: Deletion of exon 9
      • Allelic with: CMD 1U
    • 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
  • SOX10
  • Adult-onset Leukodystrophy (ADLD)
  • Multiple exostoses and spastic tetraparesis : 1 family

Familial Spastic Paraplegia (RFSP): Recessive

• SPG5
  l 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
  • Onset: 1 to 40 years
  • Clinical features: Pure HSP with sensory loss
    • Spasticity: Lower limbs
    • 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
  • Laboratory
    • Cortical evoked responses: Abnormal
    • Muscle biopsy
      • Few SDH-positive muscle fibers
      • Normal mitochondrial enzyme analysis
  
  
• SPG5B
  l Recessive
  • Epidemiology: Tunisian family
  • Genetics
    • Not linked to Chromosome 8
    • ? Same as SPG 7
  • Pure spastic pararplegia
  
  
• SPG7 or SPG5C ⁵⁴
  l Paraplegin ; Chromosome 16q24.3; Recessive
  • Epidemiology
    • Frequency: ~1.5% to 6% of SPG families
    • European, Moroccan & Turkish families
    • May present as sporadic HSP: Predominant spasticity in legs
  • Genetics
    • Types
      • Frameshift: Insertion or Deletion
      • Missense: A10S; A572V; G577S; F676L
    • Inheritance
      • Usually recessive
      • Probable dominant: 9 base pair deletion in exon 11; Missense mutations
  • Protein¹
    • 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
      • Proteolytic and chaperone-like activities at the inner mitochondrial membrane
      • Post-translational assembly of mitochondrial proteins
      • Turnover of mistranslated or misfolded polypeptides
      • Chaperone activity: Also see SPG4 & SPG13
    • Mutations: Frameshift
  • Clinical: Pure spastic paraparesis, or Complicated syndromes
    • Onset
      • Age: 2nd to 5th decade
      • Presenting feature: Gait change
    • Clinical features
      • 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
        • ? Distal predominance
      • Sensation: Vibration sense reduced
      • Bladder dysfunction (50%)
      • Skeletal (40%): Scoliosis; Pes cavus
      • CNS (Some families)
        • Optic atrophy (40%)
        • Cerebellar: Limb ataxia; Dysarthria; Nystagmus
      • Severe cases: Dysarthria; Dysphagia
    • Progression
      • Slow over decades
      • May eventually need walking aids
  • 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
  • Mouse model: Paraplegin knock-out
    • Abnormal mitochondria in nerve terminals
    • Distal axonopathy in spinal cord & PNS: Swelling and degeneration
  
  
• SPG 11 : Spastic paraplegia with thin corpus callosum (ARHSP-TCC)⁴
  l Spatacsin (KIAA1840) ; Chromosome 15q21.1; Recessive
  • Epidemiology
    • Relatively common
    • North America, Europe, Japan, Turkey
  • Genetics
    • Mutations: Nonsense, Deletion & Insertion
    • Mechanism: Loss of function
    • Allelic with: Juvenile ALS, Recessive (ALS5)
  • Spatacsin protein
    • Cytosolic & perinuclear distribution: Diffuse & reticular
    • Possibly membrane associated
    • Adult: Distributed throughout brain
  • Onset
    • Age: Usually before 20 years; Range 1 to 50 years
    • Spasticity: Legs
    • Mental slowing
    • Parkinsonism: Occasional patient; Tremor & Akinesia
  • Clinical
    • 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: Commonly normal or Vibration sense reduced
    • Ataxia: Mild
    • CNS: Other
      • Mental retardation: 25%; Progressive disorder
      • Extrapyramidal: Parkinsonism, Juvenile-onset, Levodopa responsive
    • Other occasional features
      • Eye
        • Optic atrophy: May be more prominent on temporal side
        • Retinitis pigmentosa
        • Cataract
        • Movement: Strabismus or Reduced convergence
      • Clinodactyly
    • Course
      • Progressive: Gait disorder & disability
      • Wheelchair in 3rd decade
  • Laboratory
    • Imaging: White matter lesions
      • Corpus callosum
        • Agenesis of, or thin, in 25%
        • More abnormality: Increasing age; Rostral
      • Periventricular
      • Cortical atrophy: Frontal
    • NCV: Motor neuropathy
      • Motor axon loss: Reduced CMAP amplitudes
      • SNAPs: Normal
    • EMG: Denervation in limbs
    • Motor evoked potentials: Central conduction slow
  • Variant syndrome: Juvenile ALS, Recessive (ALS 5)
    • Corpus callosum: Normal
  
  
• SPG 14¹⁰
  l 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
  
  
• SPG 15¹⁶
  l 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
  • Spastizin protein
    • Zinc-finger protein
    • Contains FYVE domain
    • Widely distributed in human tissues: Higher levels in embryo
    • Colocalizes partially with markers of endoplasmic reticulum and endosomes
    • Other ZFYVE family disorders
      • ZFYVE27: SPG33
      • FGD4: CMT 4H
  • 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
  • Laboratory
    • MRI: Atrophy of cerebral hemispheres, corpus callosum, brainstem
    • NCV: Axonal neuropathy (67%)
    • Muscle biopsy: Denervation
    • CSF: Normal
  
  
• SPG 18
  l Endoplasmic reticulum lipid raft-associated protein 2 (ERLIN2; SPFH2) ; Chromosome 8p11.23; Recessive
  • Epidemiology: Arab & Turkish families
  • ERLIN2 mutations: Deletion; Null; Insertion, out of frame ⁸³
  • ERLIN2 protein
    • ERAD pathway
    • Associates with activated IP3 receptors
    • May act as substrate recognition factor
  • Clinical
    • Onset age: Childhood; < 2 to 6 years
    • Gait disorder: Spastic
    • Spasticity: Legs > Arms
    • Reflexes: Tendon brisk; Plantar extensor
    • Skeletal: Joint contractures
    • CNS: Varies among patients
      • Mental retardation: 2 families
      • Language disorders
      • Epilepsy: 2 families
      • Squint
  • Laboratory
    • EMG & Muscle biopsy: Normal
    • CNS imaging: Often normal; Agenesis or hypoplasia of corpus callosum in 1 family
  
  
• SPG, infantile onset (IAHSP)²⁹
  l 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
      • ALS2
      • Juvenile PLS
  • 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 paraplegia³³
    l 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 26⁵⁰
    l Chromosome 12p11.1–12q14; Recessive
  • Epidemiology: Single Kuwaiti family
  • Onset age: 6 to 11 years
  • Clinical
    • Spastic paraparesis
      • Legs: Spastic
      • Tendon reflexes: Brisk in legs
      • Plantar response: Upgoing in 60%
      • Gait: Spastic
      • Progression: Slow; Most walk independently
    • Vibration sense: ?
    • Strength: ?
    • Other features
      • Dysarthria 80%
      • Tongue: Tremor
      • Amyotrophy: Distal Arms & Legs
      • Intellectual
        • Impairment: IQ 50 to 70
        • Emotional lability
  • Laboratory
    • NCV: Normal
    • EEG: Normal
    • MRI: Normal
  
  
• SPG27: Pure spastic paraplegia
    l Chromosome 10q22.1-q24.1; Recessive
  • Genetics: Overlaps with locus for Dominant SPG9
  • Epidemiology: French-Canadian family
  • Onset age: 25 to 45 years
  • Clinical
    • 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
    l Chromosome 14q21.3-q22.3; Recessive
  • Locus: Near SPG 3A
  • Epidemiology: Moroccan family
  • Onset age: 6 to 15 years
  • Clinical
    • 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
  
  
• SPG32: Paraplegia with Mental retardation & Brainstem malformation ⁶³
    l 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
  • MRI
    • Cerebellar & Cortical atrophy
    • Pontine dysraphism
  
  
• SPG35 ⁶⁸
    l Fatty acid 2-hydroxylase (FA2H) ; Chromosome 16q23.1; Recessive
  • Epidemiology: Omani and Pakistani families
  • Genetics
    • Mutations: Arg235Cys; p.Arg53_Ile58del
    • Allelic with: 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
  • Onset
    • Age: 4 to 11 years
    • Clinical: Gait disorder & Foot drop
  • Clinical
    • 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
  • 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
  
  
• SPG43 ⁷⁵
    l Chromosome 19p13.11-q12; Recessive
  • Epidemiology: 1 Mali (Bambra) family
  • Onset age: 7 to 12 years
  • Clinical
    • 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
    • Weakness & Wasting
      • Hands & Feet
      • Proximal leg weakness
    • Contractures: Knees & Ankles
    • Cognition: Normal
    • Ataxia: None
    • Progression: Slow; Ambulation present
  
  
• SPG45: Spastic Paraplegia with Early onset ⁷⁴
    l Chromosome 10q24.3–q25.1; Recessive
  • Epidemiology: Turkish family
  • Clinical
    • Onset age: < 1 year
    • Spastic paraplegia
      • Legs
      • Tendon reflexes: Brisk
      • Plantar reflexes: Extensor
    • Mental retardation
    • Ocular: Optic atrophy; Myopia
    • Strength: Normal
    • Contractures: Some patients; Toes, Knees
  
  
• SPG46: Spastic Paraplegia with Mental impairment & Thin Corpus callosum ⁷⁶
    l Chromosome 9p21.2-q21.12; Recessive
  • Epidemiology: Tunisian family
  • Clinical
    • Onset age: 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
    • Disease progression: Slow
  • Laboratory
    • EMG & NCV: Normal
    • MRI
      • Thin corpus callosum
      • Cerebellar & Cerebral atrophy
  
  
• SPG47: Spastic Paraplegia with Thin Corpus callosum ⁸⁴
    l Chromosome 1p13.2–1p12; Recessive
  • Epidemiology: Arabic family
  • Clinical
    • Onset age: Infancy
    • Spastic paraparesis
      • Gait: Spastic
      • Tendon reflexes: Brisk
      • Plantar reflexes: Extensor
      • Course: Slowly progressive
    • Mental retardation: Delayed psychomotor development
    • Seizures
  • CNS
    • Corpus callosum thin
    • Periventricular white matter abnormalities
    • Ventriculomegaly: Asymmetric
  
  
• SPG48: Spastic Paraplegia ⁷⁷
    l KIAA0415 ; Chromosome 7p22.1; Recessive
  • Epidemiology: French family
  • Genetics: Mutation
    • 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)
  • KIAA0415 protein
    • Putative helicase
    • Interacts with SPG11 & SPG15
    • Mutation: Cells censitive to DNA damaging drugs
  • Clinical
    • Onset age 49 to 50 years
    • Spastic paraparesis
    • Urinary incontinence
    • Progression: Slow
  • Laboratory
    • Brain MRI: Normal
    • Spine MRI: Cord hyperintensities in 1 patient
  
  

• Sjögren-Larsson Syndrome¹⁷
  l Fatty aldehyde dehydrogenase (ALDH3A2; ALDH10; FALDH) ; Chromosome 17p11.2; Recessive
  • 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
  • Epidemiology
    • Common in Northern Sweden
    • Other areas 0.4 per 100,000
  • 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
    • 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
  
  
• Ichthyosis, Intellectual Disability & Spastic Quadriplegia ⁸⁵
  l Elongation of very long chain fatty acids-like 4 (ELOVL4) ; Chromosome 6q14.1; Recessive
  • Epidemiology: 2 patients
  • ELOVL4 mutations
    • Stop: Arg216X; Ile230Metfs*22 (c.690del); Homozygous
    • Heterozygous mutations cause: Macular degeneration (SGDT3)
  • 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
    • Seizures: Myoclonic epilepsy
    • Mental retardation
    • Spastic quadriplegia
    • Head circumference: Small
  • Laboratory
    • Brain MRI: Delayed myelination; Atrophy
  
  
• Spastic paraplegia with Evans syndrome
  • Spasticity
    • Early childhood onset
    • Legs predominantly involved
  • Evans syndrome
    • Hemolytic anemia: Coombs-positive
    • Thrombocytopenia: Immune
  
  
• Fitzsimmons Syndrome
  • Spastic Paraplegia: Progressive
  • Dysarthria: Nasal speech
  • Skeletal disorders: Hands & Feet
    • Brachydactyly
    • Cone shaped epiphyses
    • Abnormal metaphyseal-phalangeal pattern
  • ± Mental Retardation
  • Reported twice in uniovular twins
  
  
• SPG23: Spastic paraplegia with pigmentary abnormalities (Lison)
  l Chromosome 1q24-q32; Recessive
  • Epidemiology: Arabian family
  • Onset
    • Early childhood
    • Spastic paraparesis
  • Clinical
    • 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
  • Laboratory
    • NCV: Axonal neuropathy
      • Sensory-Motor
      • Leg predominant
    • Muscle: Type 1 fiber predominance
    • MRI: Mild ventricular enlargement in 1 patient

• SPG17: Silver syndrome; Spastic paraplegia with amyotrophy of hands & feet
  l BSCL2 gene (Seipin) ; Chromosome 11q12.3; Dominant
  • Epidemiology: > 10 families
  • Genetics⁴³
    • Mutations
      • Missense
      • Exon 3
      • N88S; S90L
    • Same gene mutated in
      • Berardinelli-Seip congenital lipodystrophy, Type 2: Null mutations
      • Hereditary distal motor neuropathy, 5B
    • Mutation effects
      • Alter N-glycosylation site
      • Aggregate formation
  • Seipin protein
    • Integral membrane protein
    • Glycosylated
    • Subcellular location: Endoplasmic reticulum
    • Expression in neurons in the spinal cord and in the frontal lobe cortex
    • Mutations result in
      • Accumulation of unfolded protein in endoplasmic reticulum
      • Unfolded protein response
  • Onset
    • 2 to 40 years
    • Amyotrophy
    • Some families with early leg spasticity
  • Clinical
    • Variable phenotype within family
    • 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
    • SPG 3
    • SPG 4: Frameshift mutation; with Epilepsy & Cognitive disorder
    • SPG 10
    • SPG 31
    • SPG 38
    • Recessive locus
      
      • Onset: 1st decade
      • Spastic paraparesis
      • Wasting & Weakness: Hands & Feet
      • Benign course
  
  
• SPG20: Troyer syndrome²⁸
  l Spartin ; Chromosome 13q13.3; Recessive
  • Genetics: 1110delA mutation
  • 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
  • Epidemiology: Kuwait & Old Order Amish families
  • Onset
    • Age: Early childhood
    • Dysarthria
    • Late walking: Mean 16 months
  • Clinical
    • 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
  • MRI: White matter abmormalities
    • Temporoparietal periventricular
    • Posterior limbs of internal capsules
    • Corpus callosum: Normal
  
  
• SPG30: Paraplegia with Mild ataxia & Sensory neuropathy ⁵⁶
    l ATSV ; Chromosome 2q37.3; Recessive
  • Epidemiology: Algerian & Pakistani families
  • Genetics
    • Mutations: Missense; A255V, R350G
    • Allelic with: Hereditary Sensory > Motor Ulcero-Mutilating Neuropathy (HSN2C)
  • Onset
    • Age: Mean 17.5 years; Range 12 to 21 years
  • Clinical: Pure or complicated SPG
    • 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%
  • Laboratory
    • CT scan: Cerebellar atrophy in 1 patient
  
  
• SPG39: Spastic Paraplegia with Distal Arm & Leg Wasting ⁶⁴
    l Patatin-like phospholipase domain-containing protein 6 (PNPLA6; NTE) ; Chromosome 19p13.2; Recessive
  • Epidemiology: Ashkenazi-Jewish & Northern European (German) families
  • Genetics
    • Mutations
      • Missense: Met1012Val & Arg890His
      • Frameshift insertion: c.2946_2947insCAGC
  • PNPLA6 Protein
    • Nosology: Also called Neuropathy target esterase & Neurotoxic esterase
    • 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
    • Can hydrolyze intrinsic membrane lipids
    • Esterase activity
    • Mutations: Reduced NTE activity
  • Clinical
    • 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
      • Sensation reduced: Distal legs; Vibration
    • Weakness: Hands; Iliopsoas; Tibialis anterior
    • Muscle wasting: Distal hands & feet
    • Urinary urgency
  • Laboratory
    • MRI: Spinal cord atrophy, especially thoracic
    • NCV
      • Motor axonopathy: Arms & Legs
      • CMAP amplitudes: Reduced
      • Sensory: Normal
    • EMG: Denervation, Chronic & Ongoing
  
  
• Spastic paraparesis, Optic atrophy & Polyneuropathy (SPOAN) ⁵²
  l Chromosome 11q13; Recessive
  • Epidemiology: Brazilian families
    • Common in Serrinha dos Pintos (1/250; Carriers 1 in 9)
  • Clinical
    • Onset: Infancy
    • Spastic paraparesis
      • Onst: 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
    • Course
      • Wheelchair bound by 15 years
  • Laboratory
    • NCV: Axonal sensory-motor neuropathy
    • Nerve biopsy: Axonal loss; Occasional abnormally folded myelin & onion bulbs
    • Spine MRI: Mild cord atrophy
  
  
• Hereditary sensory neuropathy with spastic paraparesis (Cavanagh's variant)
    l Autosomal Recessive
  • Sensory neuropathy
    • Loss of pain & temperature
    • Relatively preserved vibration & joint position sense
    • Pathology: Small > large fiber loss
  • Acromutilation
  • Spasticity
  • See: Hereditary sensory neuropathy
  
  
•   HMSN 5

• Spastic paraplegia with retinal degeneration
• Spasticity with Pigmentary tapetoretinal degeneration & Mental retardation
• Sjögren-Larsson Syndrome
• Friedreich ataxia
• Spastic paraplegia, Optic atrophy, Microcephaly & XY sex reversal
• Infantile optic atrophy with chorea & spastic paraplegia : Iraq-Jewish
• SPOAN

• 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
  l 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
  l Maspardin (ACP33) ; Chromosome 15q22.31; Recessive
  • Epidemiology: Ohio Amish
  • Genetics (ACP33 gene)
    • Mutations all homozygous 601insA
  • Maspardin protein
    • Localizes to intracellular endosomal/trans-Golgi transportation vesicles
    • May function in protein transport and sorting
  • Onset
    • 2nd & 3rd decades
    • Subtle changes in childhood
      • Delayed motor milestones
      • Awkward running
      • Mild incoodination
  • Clinical features
    • 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
  • MRI
    • Thin corpus callosum
    • White-matter abnormalities
  
  
• Spastic paraplegia with Leukodystrophy & Dystonia ⁷²
  l 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 with: SPG 35
  • FA2H protein
    • Membrane bound
    • Catalyzes 2-hydroxylation of galactosylceramide & sulfatide
  • Clinical
    • 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
  • 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
  
  
• Phenylketonuria: Adult onset Spastic paraparesis + Dementia ²⁰
  l 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
  
  
• Spastic paraplegia, Epilepsy & Mental retardation³⁶
  l Autosomal Dominant
  • Onset: < 40 years
  • Spastic paraplegia: Legs > Arms
  • Epilepsy: At presentation
  • Mental retardation: Variable
  
  
• Lawrence-Moon syndrome
  l Autosomal Recessive
  • Spastic parapaesis
  • Pigmentary retinopathy
  • Mental retardation

Cerebral palsy, Spastic Quadriplegic (CPSQ)

• Genetics
  • Mutation: Ser12Cys
  • Locus similar to: SPG 13
• Epidemiology
  • Pakistani families
  • No recognizable adverse pre- or postpartum events
• Clinical
  • Symmetry of neurological signs
  • Spasticity: Legs > Arms
  • Cortical: Mental retardation; Occasional seizures
  • Microcephaly: Some patients

• 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
• 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
• Clinical
  • Onset
    • Congenital
    • Hypotonia
  • Spastic quadriplegia: Evolves over 1st year
  • Mental retardation
  • Nystagmus: Transient
• Laboratory
  • MRI: Brain atrophy; Ventriculomegaly

• Epidemiology: Moroccan family
• Genetics
  • Mutation: Intronic; IVS14DS, G-T, +1; Homozygous
• 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
• Laboratory
  • MRI: Ventriculomegaly; White matter changes; Cerebellar atrophy
  • Pathology
    • Reduced myelin
    • Gliosis
    • Dendritic arborization
      • Abnormal morphology
      • Aberrant GluRdelta2 glutamate receptor localization

• Epidemiology: Palestinian-Jordanian consanguineous family
• Genetics: homozygous deletion involving AP4E1
• Clinical
  • Spastic cerebral palsy
    • Early infancy: Hypotonia
    • Tetraplegic
    • Hypertonia
    • Hyperreflexia
    • Plantar reflex: Extensor
  • Intellectual
    • Disability: Severe
    • Laughter: Stereotypic
  • Microcephaly
  • Epilepsy
  • Eye & Ear: Normal
  • Course: Lives to adulthood
• Laboratory
  • MRI: Dilated ventricles; Cerebellar atrophy; White matter abnormal

• Epidemiology: Israeli-Arab family
• Genetics: Truncating mutation
• 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

• Epidemiology: 3 consanguinous families; Syrian
• Mutations: Nonsense; Frameshift; Splice
• Adaptor protein complexes (AP1-4)
  • Expression: Ubiquitous
  • Heterotetrameric complexes
  • Mediate: Vesicle formation; Selection of cargo molecules for inclusion into vesicles
  • Brain development
  • See: CPSQ3
• 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

• SPG1
  l L1 Cell Adhesion Molecule (L1CAM) ; Chromosome Xq28; Recessive
  • Gene features
    • Mutations: Usually missense, nonsense, or small deletions
    • Allelic with
      • MASA Syndrome: Mental Retardation; Adducted Thumbs; Shuffling Gait; Aphasia
      • CRASH syndrome
          Corpus callosum hypoplasia, mental Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus
      • X-linked hydrocephalus
    • Gene mutation data base: HGMD
  • Clinical features
    • Spasticity
    • Ataxia
    • Mental Retardation: Often severe
    • Absence of extensor pollicis longus
    • Female carriers may have adducted thumbs and learning disability
      
  
  
• SPG2
  l Proteolipid protein (PLP; Lipophilin) ; Chromosome Xq22.2; Recessive
  • Genetics
    • Gene: Highly conserved among species
    • 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
    • Genetic duplication downstream of PLP gene May silence PLP gene
    • Allelic variants
    • Allelic with animal diseases
      • 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
  • PLP protein
    • Properties: Very hydrophobic; Integral membrane
    • Role: Formation & maintenance of multilamellar structure of myelin
    • Most abundant protein in CNS myelin (50%)
    • DM20 from alternative splicing of PLP gene: Affected in some families
  • 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
  • Clinical
    • Spastic paraparesis
    • Spastic bladder
    • Normal cognition
    • Progression: Slow
    • Additional CNS signs: Present after paraparesis; Varies according to mutation
      • Cognitive: Mental retardation (Common); Dementia (Occasional)
      • Optic atrophy
      • Cerebellar: Ataxia; Tremor
      • Nystagmus
  • 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
  • Proteolipid protein null syndrome
    • Genetics: Mutation types
      • Total PMP gene deletion
      • Mutation in exon 1 (start codon)
      • Deletion of 4th G of PLP coding region
    • Protein: Absent PLP/DM20
    • Clinical
      • Ataxia
      • Peripheral neuropathy: Clinically mild; Demyelinating
      • Mild cognitive change
      • Onset: 1 to 5 years
      • Survival: 5th to 7th decade
  • Typical Pelizaeus-Merzbacher (HLD1)
    • Genetics: Most often gene duplication
    • External link: Gene clinics
  • PLP gene duplication syndrome with neuropathy¹⁵
    • Protein: Increased PLP/DM20
    • 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
  • SPG syndromes: Pure & complicated
    • SPG2 + Axonal neuropathy: Genetic duplication downstream from PLP gene⁵⁵
      • 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
  • Laboratory
    • Demyelinating neuropathy
      • Clinical: Only mild manifestations
      • Electrophysiology: Demyelinating
        • Motor nerve conduction velocities: Slow
          • Non-uniform; Motor > Sensory
        • Prolonged distal motor & F wave latencies
    • MRI: Deficient CNS myelination
    • Pathology: Dysmyelination
  
  
• Adrenomyeloneuropathy
  l Adrenoleukodystrophy protein (ALDP) ; Chromosome Xq28; Recessive
  
  • Genetics
    • Multiple point mutations & deletions (6%): > 100 different
    • No correlation with phenotype
    • Allelic with adrenoleukodystrophy
    • ? 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
  • Epidemiology
    • Onset: 2nd to 4th decade
    • Incidence: 1: 20,000 to 1:100,000
  • Clinical features of AMN
    • 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
        • Some thinly myelinated axons
    • 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 2° to defective formation of Coenzyme A derivative during oxidation
    • Accumulation in all tissues
    • No change with age
    • 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
  
  
• Spastic diplegia with Mental retardation & Small testes (MRXS3; Sutherland-Haan)
  l 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
  • Clinical
    • CNS: Mental retardation
    • Skeletal: Short stature; Microcephaly; Brachycephaly
    • Testes: Small
    • Spastic diplegia
  
  
• SPG 16: Spastic paraplegia, Pure¹²
  l 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
  
  
• Spastic paraplegia: Mental retardation & Strabismus¹³
  l 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
  l Chromosome Xq26-qter; Dominant
  • Females
  • Males with congenital hypotonia & early death
  
  
• Rett syndrome ³²
  l Methyl-CpG-Binding protein 2 (MECP2) ; Chromosome Xq28; Dominant (or Sporadic) with male lethality
  • 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
  • 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
  • Epidemiology
    • Frequency: 1/15,000 females
    • Sex distribution
      • Females: Typical clinical syndrome
      • Hemizygous males: Lethal
  • 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 QT_c interval
  • Laboratory
    • EEG: High amplitude spike & wave
    • Brain: Low weight; Dendrites with reduced length & complexity
  • Variant Rett syndromes
    • Mild
      • forme fruste: Worndown form
      • Late regression
      • Preserved speech
    • Severe
      • Congenital
      • Encephalopathy
      • Early seizure onset
    • Males
      • Typical: Neonatal encephalopathy; Death at 1–2 years
      • Occasional patients with typical Rett syndrome
        • Associated with somatic mosaicism or partial or complete Klinefelter (47,XXY) karyotype
  
  
• Mental retardation with psychosis, Pyramidal signs & Macroorchidism (MRXS13)
  l MECP2 ; Chromosome Xq28; Recessive
  • Genetics: Allelic with Rett syndrome
  • Clincial
    • Mental retardation
    • Manic-depressive episodes
    • Increased muscle tone
    • Hyperactive tendon reflexes
    • Tremor
    • Shuffling gait
    • Macroorchidism
  
  
• Spasticity, Progressive & Mental retardation¹⁴
  l MECP2 ; Chromosome Xq28; Recessive
  • Genetics
    • Allelic with Rett syndrome
    • Truncation mutation C1216T in exon 3
  • 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
  
  
• Infantile spasms, Mental retardation & Spasticity (Epileptic Encphalopathy, Early-onset)
  l 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)
    • Allelic disorder: X-linked infantile spasm syndrome (ISSX1; West syndrome)
  • 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


• SPG 34: Spastic paraplegia, Pure³⁰
  l Chromosome Xq25; Recessive
  • Epidemiology: Brazilian family, 12 affected members
  • Genetics
    • Different locus from initial publication
  • Onset
    • Age: 10 to 25 years
    • Gait: Shuffling
  • Clinical
    • 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
  
  
• Spastic paraplegia with deafness
  l Recessive
  • Onset: ~10 years
  • Clinical
    • CNS
      • Spastic paraparesis
      • Tremor
    • Deafness
    • Cataracts
    • Short stature
    • Endocrine: Hypogonadism
  • Lab: Normal very-long-chain fatty acids

Cleidocranial dysplasia

from A Kornberg MD

• Familial syringomyelia: with Arnold-Chiari & Scoliosis
  l ?Autosomal Dominant
  
  
• Cleidocranial dysplasia
  l Runt-related transcription factor 2 (RUNX2) ; Chromosome 6p21.1; Dominant
  • Protein
    • Osteoblast-specific transcription factor
    • Regulator of osteoblast differentiation
  • Clinical features
    • Skull
      • Brachycephaly
      • Patent fontanelles
      • Wide sutures
    • Extra teeth
    • Short stature
    • Skeletal dysplasia
      • Clavicular hypoplasia
      • Short middle phalanx of 5th fingers
      • Atlanto-axial subluxation: Myelopathy
    • Joint laxity
    • Syringomyelia: Increased incidence
  
  
• Acromesomelic dysplasia
  l Autosomal recessive
  • Dwarfism
  • Short forearms hands & feet;
  • ± Syringomyelia

Achondroplasia Ankylosing spondylitis Atlanto-Axial dislocation Cleidocranial dysplasia Coffin-Lowry Collagen, type II disorders Disk disease Dyggve-Melchior-Clausen Hypophosphatemia; Rickets Larsen Lumbar stenosis Morquio Oculodentodigital Dysplasia Opsismodysplasia Posterior longitudinal ligament   Ossification   Thickening Pseudoachondroplastic dysplasia Spondyloepiphyseal dysplasia variant Spondylometaepiphyseal dysplasia Spina bifida Spinal Stenosis Tethered cord Trisomy 21

Also see:   Acquired systemic causes of spine disorders   Aggrecan mouse   Radiology: Spine; Cervical spine

• Coffin-Lowry Syndrome
  l 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
  
  
• Morquio's Syndrome
  • Type A
    l Galactosamine sulfatase; Chromosome 16q24.3; Recessive
    
  • Type B
    l 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
  
  
• Achondroplasia
  l 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
  
  
• Type II Collagenopathies (Cartilage & Vitreous collagen) ²
  l Collagen type II, α-1 chain; 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
  • Type II collagen absent in herniated human intervertebral disc samples
  
  
• Spondyloepiphyseal dysplasia (SED) with atlantoaxial instability : C1-C2 dyslocation
  l Autosomal Dominant
  • Cervical myelopathy due to atlanto-axial dislocation
  
  
• Spondylometaepiphyseal dysplasia, Short limb-hand type
  l Autosomal 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
  l 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
  l FLJ90130 gene ; Chromosome 18q21.1; Recessive
  • 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
    • Mental retardation
  • Laboratory
    • Mucopolysacchariduria
    • Abnormal cartilage (Growth plate) histology
      • Disordered chondrocyte columns: Degenerating cells; Rough ER inclusions
  
  
• Larsen syndrome ⁴⁵
  l Filamin B ; Chromosome 3p14.3;Dominant
  • Filamin B disorders
    • Perinatal lethal atelosteogenesis I & III
    • Spondylocarpotarsal syndrome
  • 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
  • Variants: Recessive families also described
  
  
• Opsismodysplasia
  l Autosomal Recessive
  
  • Cervical myelopathy due to atlanto-axial dislocation
  • Hypotonia
  • Dwarfism
  • Late bone maturation
  
  
• 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
  • Clinical
    • Weakness: Legs
    • Sensory loss: Sacral
    • Urinary incontinence
  • Mouse model: Double heterozygotes for undulated & patch
  • Rule out: Sacral dysgenesis or hemisacrum
    l X-linked Dominant
    l Autosomal Dominant
  
  
• Trisomy 21
  • Cervical myelopathy due to atlanto-axial instability
  
  
• Familial intervertebral disc disease
  
  
  • Intervertebral disc disease: General⁶⁷
    • 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 paraplegia²⁷
    l Chromosome 6q23.3-q24.1; Recessive
    • Epidemiology: Family from Northeastern Italy
    • Onset age: 30 to 46 years
    • Clinical
      • 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
    
    
  • Dominant familial intervertebral disc disease
    l ? Collagen IX α2 (COL9A2) ; Chromosome 1p34.2; Dominant
    • Mutation: Gln326Trp
    • Other COL9A2 mutations cause Multiple epiphyseal dysplasia, Type2
    
    
  • Intervertebral disc disease: Increased risk
    l 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
    • Other COL9A3 mutations cause Multiple epiphyseal dysplasia, Type3
    
    
  • Intervertebral disc disease: Increased risk
    l 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
    
    
  • Intervertebral disc disease, lumbar: Increased risk in Japanese population⁶⁶
    l Thrombospondin II (THBS2) ; Chromosome 6q27
    l 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
    • MMP9
      • MMP9 Mutation
        • Missense: Q279R missense
        • Increased risk: ~1.3-fold
        • MMP9 mutation also associated with: Lung cancer metastasis & Trachoma
      • MMP9 protein
    • Combined risk for lumbar disc herniation of THBS2 + MMP9 mutations: ~3-fold
    
    
  • Lumbar disc disease: Association with severe degeneration⁵³
    l 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
      l Col2A1 ; Chromosome 12q13.11-q13.2
      • Spondyloepiphyseal dysplasia
      • Achondrogenesis
      • Stickler syndrome
    • Cartilage oligomeric matrix protein
      l COMP ; Chromosome 19p13.1
      • Pseudoachondroplasia
      • Multiple epiphyseal dysplasia, Fairbank type
  
  

  Ankylosing Spondylitis Limited back flexion

• Ankylosing spondylitis
  l 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
      • Chest wall
        • Limited movement
        • Costochondral joint involvement
      • Joint arthritis: Transient 50%; Permanent 25%
    • 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
  • 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
  
  
• Oculodentodigital Dysplasia ³⁵
    l 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
  • CNS
    • Spastic paraplegia
      • Onset age: 2nd decade
      • Gait disorder
      • Spastic bladder
    • Mental retardation: Mild
    • MRI: Leukodystrophy in subcortical cerebral white matter
    • Course: Slowly progressive
  • Conductive deafness: Occasional
  • Cardiac abnormalities: Rare
  
  
• Lumbar Stenosis
  
  
• Ossification of posterior longitudinal ligament (OPLL) ⁵⁹
  l Multiple susceptibilty loci; Recessive
  

  OPLL: Compression of cervical spinal cord (MRI T2 signal)

  • 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
        • Bethlem myopathy
        • Ullrich myopathy
      • Myosclerosis: COL6A2 mutation
    • Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) : Chromosome 6q23.2
      • ATPase
      • Structure: HPRD
      • Also called: Nucleotide pyrophosphatase (NPPS)
    • 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
        • Found in the cartilage matrix
        • Coassembles with Type II collagen in fibril network
        • Overproduction in some surgical specimens of OPLL
    • TGFB3 (14q24.3) : Intronic SNP
    • Other susceptibility loci: 1p, 11q, 16q
  • 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 Caucasians: 0.2% to 0.7%
    • Most cases in North America are sporadic
    • Increased frequency after 50 years of age
  • Clinical
    • Onset
      • Neck pain (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
  • Diagnostic tests
    • MRI
      • Low signal on T1 & T2 anterior to spinal cord
    • CT myelogram: Average of 3 segments involved
  • 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
      • ? More improvement with less severe myelopathy
  • Mouse model: Twy ('tip-toe' walking Yoshimura) mouse
    • Mutation in nucleotide pyrophosphatase
  • Image: UCSD
  • Other cause of thickening
    • Maroteaux-Lamy Syndrome (Mucopolysaccharidosis type VI)
  
  
• Tethered cord syndromes⁴⁹
  • Genetic associations
    • HLXB9
      • Currarino triad : Anal abnormalities, Anterior meningocele, Sacral abnormalities
    • 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
  • Anatomic associations: Various spinal dysraphic states
    • Spinal lipomas
    • Diastematomyelia
    • Dermal sinus
    • Myelocystocele
    • Tight filum terminale
    • Loosely defined "tethered cord"
  • 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
  • Onset of signs
    • Most common in children or young adults
    • May occur at any age
    • May be associated with exercise or growth
  • Clinical features
    • 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
    • Gait disorders: Associated with weakness or spasticity
    • Urinary incontinence: Failur to toilet train
    • Sensory loss: Early in perineal region
    • Tendon reflexes: May be reduced or increased
    • Scoliosis
• External link: Neurosurgery

Hypophosphatemia, Vitamin D resistant rickets

Aggrecan heterozygosity: Mouse model

• Early: Dwarfism, mild
• Age-related: Lordosis; Spastic paraparesis
• Pathology
  • Herniation & degeneration of vertebral disks
  • Degeneration of disc chondrocytes

---

Arnold-Chiari malformation with Hydromyelia Cerebellar vermis projects below foramen magnum (Arrow)

Arnold-Chiari Malformation
  l Autosomal Recessive or Sporadic
  l With Syringomyelia

• Anatomy: Cerebellar tonsils herniate through foramen magnum
• Clinical
  • Onset: Childhood & Adult
  • Brainstem signs: Downbeat nystagmus
  • Syringomyelia syndromes
  • Respiratory failure
  • Headache: Precipitated by Valsalva maneuver
  • Hydrocephalus: Some patients
• May be associated with: Townes-Brocks Syndrome
• External link

---

Spastic Ataxia Syndromes: Dominant or Recessive

• Dominant
  • Branchial myoclonus with Spastic paraparesis & Cerebellar ataxia (Alexander ): GFAP; 17q21
  • Dentatorubral-Pallidoluysian Atrophy (DRPLA): DRPLA protein; 12p13
  • Episodic ataxia with Choreoathetosis & Spasticity: 1p
  • Rett syndrome: MECP2 protein; Xq28
  • SCA
    • SCA 3: Ataxin-3; 14q32
    • SCA 7: Ataxin-7; 3p14-p21
    • SCA 23: PDYN; 2p13
    • SCA 28: AFG3L2; 18p11
  • Spastic ataxia 1 (SAX1): 12p13
    • Similar locus to: DRPLA
  • Spastic ataxia with congenital miosis : Autosomal
  • Spastic ataxia ± Mental retardation (SPAR): Autosomal
  • Lipodystrophy with Spastic-Ataxia & Congenital cataracts : Autosomal
• Recessive
  • AMACR: 5p13
    
  • Charlevoix-Saguenay : Sacsin; 13q11
  • Cerebellar ataxia, childhood onset (SCAR7): 11p15
  • CLA2 Ataxia syndrome : X-linked
  • DRPLA: Homozygotes for genes with intermediate # (40 or 41) of CAG repeats; 12p13
  • Friedreich ataxia: Frataxin; 9q13-q21
  • Karak syndrome: PLA2G6; 22q13
  • Leukodystrophies
    • Adrenomyeloneuropathy: ALDP; Xq28
    • HLD6
      
    • Krabbe: Galactosylceramide β-galactosidase; 14q31
    • MLD: Arylsulfatase A; 22q13
    • Tremor–ataxia with central hypomyelination (TACH): 10q22
  • Leukoencephalopathy
    • Ataxia, UMN signs & Neuropathy: RPIA; 2p11
      
    • Leukoencephalopathy with brain stem + spinal cord involvement & lactate elevation (LBSL): DARS2; 1
    • Vanishing white matter syndromes
  • Macular corneal dystrophy, Congenital cataracts & Myopia : Autosomal
  • Marinesco-Sjögren: SIL1; 5q31
  • Pelizaeus Merzbacher-like: GJA12; 1q41
  • Spastic ataxia, congenital, with Mental retardation & Osmiophilic skin vessels (SCAR5; CAMOS): ZNF592; 15q25
  • SPAX
    • SPAX2: 17p13
      
    • SPAX3 (Portneuf; ARSAL): 2q33
    • SPAX4 (+ Optic atrophy): MTPAP; 10p11
    • TTC19: 17p12
      
    • Spastic-Ataxia-Neuropathy: AFG3L2; 18p11
  • SPG
    • SPG1: L1 Cell Adhesion Molecule (L1CAM); Xq28
    • SPG2 (Pelizaeus Merzbacher): PLP; Xq21
    • SPG30: 2q37
    • SPG46: 9p21

---

Hereditary Spastic Ataxia (SPAX1) ²¹
  l Chromosome 12p13; Dominant

• Similar locus to: DRPLA
• Epidemiology: Newfoundland families
• Onset
  • Age
    • Variable
    • Typical: 10 to 20 years
    • Range: Early childhood to 20's
    • No anticipation
  • Leg spasticity
• Clinical
  • Severity variable within families
  • Spasticity: Legs; Severe
  • Cerebellar
    • Involuntary head jerk
    • Dysarthria
    • Dysphagia
  • Ocular: Movement Abnormalities
  • Not affected: Life span; Cognition
• Pathology
  • Degeneration of: Corticospinal tracts & posterior columns

---

Spastic ataxia 2 (SPAX2) ⁶²
  l Chromosome 17p13; Recessive

• Epidemiology: Moroccan, Algerian & French families
• Onset
  • Age: Child or Adult
  • Dysphagia
• Clinical
  • Cerebellar ataxia
    • Dysarthria
    • Gait disorder
    • Nystagmus: Horizontal; Some patients
  • Pyramidal
    • Spasticity: 1 of 3 families; All limbs
    • Tendon reflexes: Brisk in legs
    • Plantar response: Extensor
  • Weakness: Some patients
    • Distal
    • Hands & Feet
  • Fasciculations
  • Sensation: Often normal
  • Bladder: Often normal
  • Progression: Over few years or Slow
• Laboratory
  • Brain MRI: Normal

---

Branchial myoclonus with Spastic paraparesis & Cerebellar ataxia
  l Glial fibrillary acidic protein (GFAP) ; Chromosome 17q21.31; Dominant

• Nosology: Adult onset Alexander disease²⁴
• Genetics: Val87Gly point mutation
• GFAP protein
  • Intermediate-filament (IF) protein
  • Location: Cytoplasm
  • Specific for cells
    • Astroglial lineage
    • Lacking fibronectin
• Onset age: 25 to 58 years
• Clinical
  • Branchial (Palatal) myoclonus
    • Palate, pharynx, larynx, and face
    • Differential diagnosis
      • Hereditary ataxias: SCA2; MJD
      • Dentato-rubro-olivary pathway disorders
        • Demyelination; Infarction; Arteritis; Neoplasm; Trauma
  • Cerebellar: Truncal ataxia; Nystagmus; Dysarthria; Dysphagia
  • Spastic paraparesis (50%)
  • Reflexes
    • Tendon: Mildly increased
    • Plantar: Extensor
  • Cognitive: Normal
  • Progression: Death or severe disability 5 to 10 years after onset
• Pathology (MRI)
  • Medulla & spinal cord: Severe atrophy
  • Cerebral and cerebellar cortex: Mild atrophy
  • Periventricular intensity on T2
  • Inferior olive hypertrophy (30%)

---

Spastic ataxia, congenital, with Mental retardation & Osmiophilic skin vessels (CAMOS; SCAR5)¹⁸
  l Zinc-finger protein 592 (ZNF592) ; Chromosome 15q25.3; Recessive

• Epidemiology: Lebanese family
• Genetics: Homozygous missense; Gly1046Arg
• ZNF592 protein
  • DNA binding
  • Transcription regulating
  • Phosphorylated with DNA damage
• 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

---

Spastic Paraplegia, Ataxia ± Mental Retardation (SPAR) ²³
  l 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
• 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)
  l 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

---

Lipodystrophy with Spastic-Ataxia & Congenital cataracts ²⁵
  l Autosomal Dominant

• Epidemiology: Kentucky family
• Onset
  • Congenital
  • Lipodystrophy
  • Cataracts
• Clinical: Variable neurologic phenotype
  • Lipodystrophy
    • Absence of subcutaneous fat over entire body except buttocks, hips, and thighs
  • Ocular
    • Retinitis pigmentosa
    • Iris deposits
    • Cerebellar:
  • 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
• 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)
  l Chromosome 1p; Dominant

• Genetics
  • Chromosomal region with a cluster of K+ channel genes
• 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
  • EEG: Generalized slowing
  • Treatment: ? Acetazolamide & Phenytoin

---

Hypomyelinating Leukodystrophy 6 (HLD6; HABC)
  l Sporadic, ? Recessive

• Epidemiology: Most Caucasian; > 10 patients
• Clinical
  • Onset age: 8 months to 7 years
  • Extrapyramidal
    • Dystonia
    • Rigidity
    • Choreoathetosis
  • Cerebellum: Ataxia; Nystagmus
  • Spasticity
  • Mental development
    • Poor speech
    • Mental deficiency: Mild to Severe
  • Other: Some patients
    • Short stature
    • Microcephaly
    • Hearing loss
  • Course
    • Progressive
    • Loss of unsupported walking: 2 to 14 years of age
• Brain MRI
  • Hypomyelination: Diffuse; Progressive
  • Putamen: Small or Absent
  • Head of the caudate: Reduced size
  • Cerebellar atrophy: Especially granular layer

---

Leukoencephalopathy with Ataxia, UMN signs & Polyneuropathy⁴⁴
  l Ribose-5-Phosphate Isomerase (RPIA) ; Chromosome 2p11.2; Recessive

• Genetics: Mutations
  • Val61Ala
  • Stop codon (540delG)
• RPIA protein
  • Converts ribulose-5-phosphate to ribose-5-phosphate
  • Deficiency leads to accumulation of pentoses & pentose phosphates
• Epidemiology: Single patient identified
• Onset
  • Early childood
  • Psychomotor retardation: Slow walking & Speech
• Clinical
  • Seizures: Onset 4 years
  • Ataxia
    • Arms & Legs
    • Dysarthria
    • Nystagmus: Lateral gaze
  • Upper motor neuron
    • Hyperactive tendon reflexes: Except at ankles
    • Plantar reflexes: Extensor
  • Cranial nerves: Optic atrophy
  • Peripheral nerve
    • Tendon reflexes at ankles: Reduced
    • Motor: Mild distal atrophy & weakness
    • Sensory loss: Distal
  • Course: Progression after age 7
• Laboratory
  • MRI: Leukoencephalopathy
  • Nerve conduction studies: Axonal neuropathy
  • Proton MRS of brain: Ribitol & D-Arabitol peaks
  • Serum & CSF: High Ribitol & D-Arabitol
  • Lactate & Pyruvate: Normal
  • Nerve conduction testing
    • Motor: Mildly reduced velocities
    • Sensory: Mildly reduced velocities

---

Pelizaeus-Merzbacher–Like Disease (PMLD; HLD2) ⁴⁶
  l Gap Junction Protein α12 (Connexin 46.6; 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
• GJA12 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
• Laboratory
  • Nerve conductions
    • Motor & sensory velocities: Mildly slowed
    • Lower limbs more involved
  • MRI: Leukodystrophy
• Variant syndrome (SPG44 ): Later onset complicated spastic paraplegia⁷³
  • GJA12 (GJC2) Mutation: Ile33Met; Homozygous
  • Mutant protein: Forms gap junction channels with altered functional properties
  • Onset
    • Age: 1st or 2nd decade
    • Gait disorder
    • Hand tremor
  • Clinical
    • 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
  • Laboratory
    • MRI: Hypomyelinating leukoencephalopathy
    • Evoked potentials: Abnormal
    • EMG & NCV: Normal

---

Pelizaeus-Merzbacher–Like Disease 2 ⁷⁹
  l Small inducible cytokine subfamily E, Member 1 (SCYE1) ; Chromosome 4q24; Recessive

• Nosology: Aminoacyl tRNA synthase 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
• Brain MRI
  • Hypomyelination
  • Atrophy: Diffuse

---

Spastic Ataxia with Optic Atrophy (SPAX4) ⁷⁸
  l 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

---

5,10-Methylenetetrahydrofolate Reductase Deficiency
  l MTHFR ; Chromosome 1p36.22; Dominant

• MTHFR protein: Methyl donor for homocysteine re-methylation to methionine
• Clinical: Varied syndromes
  • Common childhood
    • Developmental delay
    • Psychiatric features
    • Polyneuropathy: Some patients
    • Encephalopathy
    • Nitrous oxide sensitivity
    • Plasma methionine: Low or Normal
    • Homocystinuria
  • Spastic paraparesis + CNS⁸⁰
    • Mutation: Homozygous A195V
    • Adult onset
    • 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

---

Hereditary Sensory Ataxia (SNAX1; ADSA) ⁴⁸
  l Ring Finger Protein 170 (RNF170) ; Chromosome 8p11.21; Dominant

• Epidemiology
  • Two Canadian families: From New Brunswick; Anglo-Saxon origin
• Mutation: Missense; R199C
• RNF170 protein
  • Expressed in spinal cord
• Onset
  • Age: Range 3rd to 8th decade
  • Symptoms: Gait disorder; Instability in dark
• Clinical
  • Sensory loss: 100%
    • Legs > Arms
    • Distal
    • Pan-modal
  • Sensory ataxia (66%)
    • Wide based gait
    • Romberg: Positive
  • Reflexes
    • Tendon
      • Legs: Absent
      • Arms: Reduced
    • Plantar: Flexor 70%; Extensor 30%
  • Motor
    • Strength: Usually normal
    • Hypotonia in some patients
  • Ocular: Abnormal saccades
  • Sphincter function: Normal
  • Cognition: Normal
  • Skin: No ulcerations
  • Course: Normal life span
• Laboratory
  • Nerve conduction studies
    • SNAPs: Normal until old age
    • CMAPs: Normal
    • H-reflexes: Absent
  • SSEP: Legs absent; Arms present
  • EMG: Normal
  • MRI: Normal brain & spine
  • CSF: Normal
  • Pathology: Spinal cord
    • Axonal spheroids in dorsal columns of spinal cord
    • Some spheroids contain ubiquitin
• Also see: Sensory ataxia syndromes

---

Spastic dystonia syndromes

• DOPA-responsive dystonia
  l GTP cyclohydrolase I; Chromosome 14q22.2; Dominant
  l Tyrosine hydroxylase; Chromosome 11p15.5; Recessive
  
• Mitochondrial: Hereditary spastic dystonia with Leber's optic atrophy
  l NADH Dehydrogenase, Subunit 4
• SPG
  • SPG 2q24
  • Infantile spasms, Mental retardation & Spasticity
  • SPG 15
  • SPAR
• Neuroaxonal dystrophy
• Ataxias
  • SCA: 3; 12; 17
  • Episodic ataxia
  • Portneuf spastic ataxia with leukoencephalopathy
• Triosephosphate isomerase (TIM) deficiency

---

Mass lesions

• von Hippel-Lindau : Hemangioblastoma
• Neurofibromatosis
  • Type I
    
  • Type II
    
• Meningioma
  
• Multiple hamartoma
  
• Lipoma
  

---

Other familial spinal syndromes

• Hereditary Motor Syndromes
  
  
• Infections: HTLV-1
  
  

---

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

References
1. Neurology 1996;46:1507-1514
2. Am J Med Genet 1997;69:33-43
3. Am J Human Genetics 1999;64
4. Neurology 1999:53:50-56, Nature Genetics 2007; Online February, Neurogenetics 2007;8:301-305, Brain 2010 Online January
5. Human Genetics 1999;104:443-448
6. Am J Human Genetics 1999;65:757-763, J Neurol Neurosurg Psychiatry 2008 Feb 1, Hum Mutat 2008 Oct 13
7. Am J Human Genetics 2000;66:702-707, 2002;70, Am J Hum Genet 2008 Jun 18
8. Am J Human Genetics 2000;66:728-733, J Clin Invest 2012; Online Jan
9. Hum Mol Genetics 2000;9:637-644, Am J Human Genetics 2001;68:, Eur J Hum Genet 2009;17:187-194
10. Am J Human Genetics 2000;67
11. J Neurol Neurosurg Psychiatry 2000;69:150-160
12. Am J Med Genet 2000;94:5-8
13. Am J Med Genet 2000;94:1-4
14. Am J Human Genetics 2000;67
15. Neurology 2001:56:A323&A324
16. Neurology 2001:56:1230-1233, Am J Hum Genet 2008 Online April
17. Brain 2001;124:1426-1437
18. Am J Med Genet 2001;101:135-141, European Journal of Human Genetics 2010; Online June
19. Nature Genet 2001;29:326-331, Arch Neurol 2004;61:1867-1872
20. JNNP 2001;71:795-797
21. Am J Human Genetics 2002;March
22. Hum Mol Genetics 2002;11:153-163
23. Neurology 2002:58:411-416
24. J Neurol Sci 2002:195:71-76
25. Neurology 2002;58:43-47
26. Ann Neurol 2002;51:681-685
27. J Med Genet 2002;39:387–390
28. Nature Genet 2002;31:347-348, J Neurol 2004;251:1105-1110
29. Am J Human Genetics 2002;71:518-527
30. Am J Med Genet 2002;111:152-156, Neurogenetics 2008 May 8
31. Neurogenetics 2001;3:91–97, Neurology 2009 Online April
32. Am J Human Genetics 2002; November
33. Neurology 2002;59:1905–1909
34. Am J Hum Genet 2003;72:February
35. Am J Hum Genet 2003;72:February
36. Am J Medical Genetics 2003;117A:116–121
37. Brain 2003;126:783-791
38. Neurology 2003;60:1529–1532
39. Neurology 2003;61:235-238, AM J Hum Genet 2008; January
40. Am J Hum Genet 2003;73:September
41. Am J Hum Genet 2003;73:September
42. Am J Hum Genet 2003;73:October
43. Nature Genetics March 2004, Brain 2004: Online August
44. Am J Hum Genet 2003;April 2004
45. Nature Genetics April 2004
46. Am J Hum Genet 2004;75:July
47. Neurology 2004;63:710-712
48. J Med Genet 2004;41:634–639, Neurology 2006;67;2239-2242, Brain 2010; Online November
49. Am J Med Genet 2005; Online Jan
50. J Med Genet 2005;42:80–82
51. Ann Neurol 2005;57:567–571
52. Ann Neurol 2005;57:730–737
53. Spine 1999;24:2456-2460
54. Brain 2004;127:973-980, Hum Mutat 2008;29:522-531, Neurology 2008;71:1500–1505
55. Ann Neurol 2005; Online Dec 22
56. Brain 2006; Online January 24, Genome Research 2011;21:658–664
57. Neurogenetics. 2006;7:127-129; Am J Hum Genet 2006; Online May, Brain 2008; Online March
58. Am J Hum Genet 2006; Online June
59. Neurosurgery 2006;58:1027-1039
60. Hum Genet 2006 119:611-616
61. Am J Hum Genet 2007;80:152-161
62. Hum Genet 2007 Feb 2
63. Neurology 2007;68:1837–1840
64. Am J Human Genet 2008; Online March, Muscle Nerve 2011;43:19–25
65. Chin Med J 2008;121:430-434
66. Am J Human Genet 2008; Online May
67. Joint Bone Spine 2008 Apr 28
68. Neurology 2008; On-line May 7, Hum Mutat 2010 Jan 26
69. Neurology 2008; Online Apr 9
70. Mov Disord 2008 Nov 12
71. American Journal of Human Genetics 2008 Online December
72. American Journal of Human Genetics 2008;83:643–648
73. Brain 2008; Online Dec 2008
74. Neurogenetics 2009; Online May
75. Neurogenetics 2009; Online Dec
76. Neurogenetics 2010; Online July
77. PLoS Biol 2010;8:e1000408
78. Am J Human Genet 2010; Online October
79. Am J Human Genet 2010; Online November
80. JNNP 2010; Online December
81. Am J Human Genet 2010; Online December
82. J Med Genet 2011;48:141-144
83. Neurogenetics 2011; Online Aug
84. J Neurol Sci 2011;305:67–70
85. Am J Human Genet 2011; On line November

1/5/2012