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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 31: Dominant; Some families
      • SPG 39: 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
• Complicated FSP: Features associated with spastic paraparesis
  • Early onset
    • SPG 20
    • IAHSP
    • SPG 9
    • SPG 26: Recessive
    • SPG 32: Recessive
    • SPG 35: Recessive
    • SPOAN
    • Myoclonic epilepsy: Recessive
  • Peripheral neuropathy
  • SPG 2
  • SPG 3A
  • SPG 7
  • SPG 11
  • SPG 21
  • SPG 23
  • SPG 25
  • SPG 26
  • SPG 27
  • SPG 30
  • SPOAN
    
  • Adrenomyeloneuropathy
  • Leukoencephalopathy
  • Cavanaugh
  • 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
      
  • Spastic ataxia
  • Thin corpus callosum
    

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

    • SPG1
    • SPG11
    • SPG15
    • SPG21
  • 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
    • Symmetrical spastic cerebral palsy: Occasional
  • Dementia & Mental retardation
    • Often associated with other CNS signs
    • SPG1
    • SPG2
    • SPG4
    • SPG7
    • SPG11
    • SPG14
    • SPG15
    • SPG20
    • SPG21
    • SPG26
    • X-linked SPG
    • Presenilin 1
    • 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
• 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
    • ALS2 & IAHSP: Alsin; ? Vesicle transport
  • Golgi
    • SPG 3A: Atlastin
    • SPG 21: Maspardin
  • Myelination
    • SPG 2: PLP
  • Other
    • SPG39: PNPLA6

• SPG3A (FSP1) ¹⁹
  l Atlastin ; Chromosome 14q11-q21; Dominant
  • Epidemiology: Common cause of dominant, early onset FSP
  • Gene mutations
    • 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
  • 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
  • Comparison to SPG4
    • Onset: Earlier
    • Course: More benign
  • Laboratory
    • Electrodiagnostic: Sensory-motor axonal neuropathy (R495W mutation)
    • Pathology: Predominant loss of large myelinated axons
  
  
• SPG4 (FSP2)
  l Spastin ; Chromosome 2p22-p21; Dominant
  • Epidemiology: Most common form of autosomal dominant hereditary SPG
  • Genetics
    • Mutations
      • > 150 different pathogenic mutations identified⁹
      • Patterns
        • Types: Deletions; Insertions; Base substitutions
        • Functional types: Missense; Nonsense; Splice-site; Deletion & Insertion
      • Location
        • Many exons & splice sites
        • All missense in functional AAA domain
        • Some truncation mutations
      • Commonly private: Specific mutation unique to most individual kindreds
      • 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
    • 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
      • 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
  • Epidemiology
    • Most common dominant FSP: 40% 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
  • 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 15q11.1; 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 12 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
    • Bladder dysfunction (10%)
    • Pes Cavus: Common
    • Progression: May need wheelchair in 40's or 50's
  
  
• SPG8 ⁶¹
  l KIAA0196 (Strumpellin) ; Chromosome 8q23-q24; 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; 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 years; Range infancy to 40 years
    • Gait disorder
  • Clinical: Often pure spastic paraparesis
    • 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
  • Laboratory
    • Electrophysiology: Subclinical sensory-motor neuropathy in all patients
  
  
• SPG12⁸
  l Chromosome 19q13; Dominant
  • Epidemiology: Welsh & Italian families
  • Onset
    • Age: Mean 7 to 14 years
  • Clinical
    • Spinal
      • Spasticity
      • Reflexes
        • Tendon: Legs increased
        • Plantar: Extensor
      • Sensory loss: Vibration (11%)
      • 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%
  
  
• SPG13⁷
  l Heat-shock 60-kD protein 1 (HSPD1; HSP60) ; Chromosome 2q24-q34; 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)
    • Epidemiology: Israeli Bedouin kindred, 23 children
    • Genetics
      • Recessive
      • 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 2p12; Dominant
  • Epidemiology
    • > 16 families, most European
    • Frequency: 3% of hereditary spastic paraparesis, 8% of pure SPG
  • Genetics
    • Mutation types: Varied
      • Most common: 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
    • 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: 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
    • Cerebellar: Normal
    • Scoliosis: Mild; 30% of families
    • Peripheral neuropathy: Unusual
  • 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: Legs
      • Tendon reflexes: Brisk in legs
      • Progression: Slow over decade; Eventual inability to walk
      • Sensation: Normal
  
  
• SPG 36³¹
  l Chromosome 12q23-24; Dominant
  • Onset: Mean 30 years
  • Clinical
    • Spastic paraparesis
    • Amyotrophy: Moderate to severe
  
  
• 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 11p14⁶⁵
  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
    • Proximal weakness: Legs
  
  
• Other syndromes
  • Alzheimer's disease: Presenilin 1 ³⁷
    l Chromosome 14q24.3; Dominant
    • Genetics: Deletion of exon 9
    • 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

• SPG5
  l CYP7B1 ; Chromosome 8q21.3; Recessive³⁹
  • Epidemiology: Tunisian, American, Australian & British families
  • Mutations: Homozygous; Missense or Nonsense
  • CYP7B1 protein
    • Hydroxylases
    • 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
  • Pure spastic pararplegia
  
  
• SPG7 or SPG5C ⁵⁴
  l Paraplegin ; Chromosome 16q24.3; Recessive
  • Epidemiology
    • Frequency: ~5% of SPG families
    • British, Italian & French families
  • Genetics
    • Types
      • Frameshift: Insertion or Deletion
      • Missense: A10S; A572V; G577S; F676L
    • Inheritance
      • Usually recessive
      • Probable dominant: 9 base pair deletion in exon 11
  • Protein¹
    • Cell localization: Mitochondria
    • 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
      • 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 enzymes: Reduced Complex I & II/III activities; Complex IV normal
    • 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 15q13-q15; Recessive
  • Epidemiology
    • Relatively common
    • North America, Europe, Japan, Turkey
  • Genetics
    • Mutations: Nonsense, Deletion & Insertion
    • Mechanism: Loss of function
  • 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
  • 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
      • Mental retardation: 25%
      • Progressive disorder
    • 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
  
  
• 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 14q22-q24; 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, infantile onset (IAHSP)²⁹
  l Alsin ; Chromosome 2q33; Recessive
  • Epidemiology: Families in Algeria, Italy & France
  • Genetics
    • Allelic with
      • ALS2
      • Juvenile PLS
    • Mutations Found in 4 of 10 families Deletions & Splice site
  • 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
  
  
• SPG30: Paraplegia with Mild ataxia & Sensory neuropathy ⁵⁶
    l Chromosome 2q37.3; Recessive
  • Epidemiology: 1 Algerian origin family living in Eastern France
  • Onset
    • Age: Mean 17.5 years; Range 12 to 21 years
  • Clinical
    • 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
  
  
• 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 Chromosome 16q21-q23; Recessive
  • Epidemiology: 1 Omani family
  • Onset
    • Age: 6 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
    • Sensation: Normal
  • Laboratory
    • MRI: Unremarkable
    • Nerve conduction studies: Motor & Sensory normal
  
  
• Spasticity + Systemic Disorders
  • 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
    
    
  • 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
  
  
• Spasticity + PNS
  • SPG17: Silver syndrome; Spastic paraplegia with amyotrophy of hands & feet
    l BSCL2 gene (Seipin) ; Chromosome 11q13; 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 4: Frameshift mutation; with Epilepsy & Cognitive disorder
      • SPG 38
      • Recessive locus
        
        • Onset: 1st decade
        • Spastic paraparesis
        • Wasting & Weakness: Hands & Feet
        • Benign course
    
    
  • SPG20: Troyer syndrome²⁸
    l Spartin ; Chromosome 13q12.3; Recessive
    • Genetics: 1110delA mutation
    • Spartin protein
      • Sequence similarities: Spastin, SNX15, VPS4, Skd1
      • Postulated functions
        • 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
    
    
  • SPG39: Spastic Paraplegia with Distal Arm & Leg Wasting ⁶⁴
      l Patatin-like phospholipase domain-containing protein 6 (PNPLA6; NTE) ; Chromosome 19p13.3; Recessive
    • Epidemiology: Ashkenazi-Jewish & Northern European 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
    • Clinical
      • Onset
        • Age: Childhood
        • Spasticity
      • Paraplegia: Spastic; Progressive
      • Muscle wasting: Distal
    • Laboratory
      • MRI: Spinal cord atrophy, especially thoracic
      • NCV: Motor axonopathy involving arms & legs
    
    
  • 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
  
  
• Spasticity + Ocular disorders
  • 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
  
  
• Spasticity + CNS
  • See: Spastic ataxia syndromes
  • Friedreich ataxia
    • Intermediate number of trinucleotide repeats
    • Spastic ataxia
  • Leukodystrophies: MLD & Krabbe
    • Late onset disorders may present with spasticity & polyneuropathy
  • DRPLA: Homozygotes with intermediate # (40 or 41) of repeats
    
  • Cerebrotendinous xanthomatosis
  • Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH syndrome)
    
    
  • Symmetrical spastic cerebral palsy
    l GAD1 ; Chromosome 2q31; Recessive
    • 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
    
    
  • 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; 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
    
    
  • Phenylketonuria: Adult onset Spastic paraparesis + Dementia ²⁰
    l Phenylalanine hydroxylase; Chromosome 12q24.1; Recessive
    • Onset: 5th & 6th decade
    • Spastic parapaesis
      • 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

• 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; 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 ssyndromes
  • 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: 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
  
  
• Mental retardation with psychosis, pyramidal signs & macroorchidism
  l Chromosome Xq28; Recessive
  • Mental retardation & manic-depressive episodes
  • Increased muscle tone & hyperactive tendon reflexes
  • Tremor; shuffling gait
  • Macroorchidism
  
  
• Spastic diplegia with Mental retardation & Small testes (MRXS3; Sutherland-Haan)
  l ATRX ; Chromosome Xq13; 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
  
  
• Spasticity, Progressive & Mental retardation¹⁴
  l Chromosome Xq28; Recessive
  • Genetics: 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
  l Aristaless-related homeobox (ARX) ; Chromosome Xp22.3-p21.1; 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)
  • 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
  • Genetics
    • Different locus from initial publication
  • Epidemiology: Brazilian family, 12 affected members
  • 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; 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 ; Xp22.2-p22.1; 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 3p21.33; 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%)