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HEREDITARY ATAXIA: RECESSIVE, CONGENITAL & X-LINKED

RECESSIVE ATAXIAS

Friedreich Ataxia ²

Frataxin protein Genetic features Neurological features Pathology Systemic features Variant syndromes

From Bramwell: Atlas of Clinical Medicine Friedreich Ataxia

• Epidemiology
  • Incidence: 1 in 30,000 to 50,000
  • Carrier frequency: 1 in 60 to 110
  • Not found in natives: Far East; sub-Saharan Africans; Australia; Native Americans
  • 75% of hereditary ataxia with onset < 25 years
• Genetic Features
  • FRDA (Frataxin; X25; FXN) (Yeast homolog )
    • FRDA gene contains 7 exons: Exon 6 is non-coding
    • Transcription: Splicing ® 2 major coding sequences
      • Major: Exons 1, 2, 3, 4, 5a
      • Minor: Exons 1, 2, 3, 4, 5b
      • Localization
        • Highest in non-neural tissues: Heart; Skeletal muscle; Liver; Kidney; Pancreas
        • CNS: Spinal cord > Cerebellum > Cerebral cortex
    • Frataxin homologue in yeast plays role in iron metabolism
      • Iron accumulates in mitochondria in yeast mutants
    • Possible disease mechanisms
      • Sequestered iron not available for other iron proteins ® Destabilization
      • Reduced activity of Fe-S cluster-containing subunits
        • Subunits located in mitochondrial complexes I, II, and III & aconitase
      • Accumulation of reactive O₂ species ® Oxidative stress
    • Diseased FRDA (Frataxin) defective, not completely deficient, in function
  • Excess of DNA triplet (GAA) repeats: Usual mutation (> 90%)
    • Friedreich ataxia: Expansion in number of GAA repeats in intron at end of exon 1
    • GAA copy number
      • Normal 6 to 34: Bimodal
        • 6 to 12 repeats (83%)
        • 14 to 34 repeats (17%)
      • Friedreich ataxia
        • Range: 67 to 1,700
        • Most commonly: 800 to 1,000 copies
    • Excess repeats or point mutations in 94% of Italian patients with FA phenotype
    • Intergenerational changes: Unstable
      • Repeat length may expand or contract: Equal likelihood
      • Long GAA repeats unstable during meiosis & mitosis
      • Maternal transmission: Increase or Decrease in length occur with equal frequency
      • Paternal transmission: Decrease in repeat length size
      • Median variation: 150 repeats
    • Expanded GAA repeats suppress FRDA (Frataxin) gene expression
      • Block transcriptional elongation
        • Expanded GAA repeats bind to self: "Sticky" DNA
          • Association of 2 purine-purine-pyrimidine (R-R-Y) triplexes at neutral pH
          • Forms negatively supercoiled plasmids
        • Forms folded, non-B DNA structure
        • GAA repeats lead to
          • Chromatin remodeling & condensation
          • Positional effect variegation (PEV)
          • Post-translational modification of histones
            • Acetylation, Methylation, Phosphorylation, Ubiquitination
            • Changes may be reversed by: Histone deacetylase inhibitors
      • Residual FRDA (Frataxin)
        • Some residual FRDA (Frataxin) probably expressed in all patients
        • Amount: mRNA & FRDA protein inversely proportional to GAA expansion size
        • No homozygous null mutations identified: ? Complete loss of FRDA (Frataxin) is lethal
  • Point mutations
    • Frequency: 4% to 6% of FA patients
    • 17 different point mutations described
    • Occur in residues conserved with the homologous yeast protein
    • Truncating mutations: Usually in exon 1
    • Missense mutations: Usually in last 3 exons coding for FRDA (Frataxin) gene
    • 3 common point mutations: Ile154Phe (Southern Italy); M1I; G130V
    • Missense mutation: Examples & Features
      • Exon 3 Stop
      • Ile154Phe: Exon 4
        • Most common point mutation
        • Southern Italian families
        • Similar disease severity to homozygous GAA repeat
      • Intron 3: Disrupts acceptor splice site at end of intron
      • G130V: Mild disease with slow progression; Same age of onset
    • Mutations on other gene
      • Point mutations usually heterozygous with GAA repeat gene
      • No homozygous point mutations identified yet
  • Genotype-phenotype correlations
    • Clinical features: Correlate with lengths of mutant GAA alleles
      • Length correlates inversely with age of onset
      • Correlation with shorter allele
        • Milder phenotype & later onset with < 500 base pairs in shorter repeat
        • Long shorter repeat
          • Earlier disease onset
          • More cardiomyopathy
          • Reduced Reflexes in arms
          • More rapid disease progression: Earlier age in wheelchair
      • Correlation with length of longer allele: When less than 800 repeats¹⁸
      • Mean GAA allele length higher with: Diabetes; Cardiomyopathy; Scoliosis
      • Other associations with longer repeat length: Optic atrophy; Hearing loss
    • Pseudodominant inheritance may occur: Due to
      • Manifesting carrier fathers: Onset > 40 years, or
      • High carrier rate
    • Intermediate number of GAA repeats (120-156)
      • Spastic ataxia
      • Onset 38 to 45 yrs
      • Acadians
    • Mutations in carboxy half of mature FRDA (Frataxin) (missense or truncating): Severe phenotype
    • Missense mutations in amino-terminal half of FRDA (Frataxin)
      • Atypical & milder disease
      • Early spastic gait
    • Compound heterozygotes
      • Optic atrophy more common
      • 2° Lower residual FRDA levels
    • Heterozygote carriers: Normal
    • Milder disease with mitochondrial haplotype U: Less cardiomyopathy
• FRDA (Frataxin) protein
  • Mitochondrial protein
    • Location: Inner mitochondrial membrane
    • Functions
      • ? Required for maintenance of mitochondrial genome
      • Involved in iron homeostasis
        • Iron chaperone: Fe-S cluster machinery; Heme metabolism
        • Iron transport into mitochondria
        • Iron-sulphur (Fe-S) assembly & transport
      • Respiratory function
      • Reactive oxygen species production control
      • Ferretin-like protein: Minor function
      • Disruption in yeast causes
        • Multiple Fe-S-dependent enzyme deficiencies: Aconitase; Complexes I to III
        • 10x elevated mitochondrial iron content
  • Expression
    • Location: All tissues
    • Mutations
      • GAA expansion: Reduced expression of normal protein; Less with longer repeats
      • Residual levels: Needed for survival
  • Related proteins
    • Mitochondrial intermediate peptidase (MIPEP) : Promotes iron mitochondrial accumulation in absence of Frataxin
    • Mitochondrial processing peptidase (MPP; PMPCB) : Cleaves frataxin into mature form
  • Other disorders of iron metabolism
    • Huntington's disease
    • Aceruloplasminemia
    • Neurodegenerations with brain iron accumulation
      • I : Pantothenate kinase 2
      • II : Ferretin light polypeptide
• Neurological Features: Typical syndrome
  • Onset
    • Age
      • Usually: < 20 years, around puberty; Late 1st decade or Early 2nd decade
      • Range: 2 to > 70 years
      • May vary between siblings
    • Ataxia: Gait instability
    • Scoliosis
    • Allelic with: Late-onset ataxia syndrome
  • Neurological features
    • Cerebellar (100%)
      • Ataxia: Limb & Trunk; Gait (100%)
      • Ocular: Square wave jerks (Common); Nystagmus (20%)
      • Dysarthria (95%): Onset within few years
      • Dysphagia: Late in disease course; Liquids
    • Sensory loss (~80%): Especially vibration & joint position
    • Tendon reflexes: Absent (75%) or reduced
    • Corticospinal tract signs
      • Extensor plantar responses (80%)
      • Spasticity: Intermediate number of repeats
    • Motor
      • Weakness (67% to 88%)
        • Lower extremities
        • May be in "pyramidal" distribution
      • Muscle wasting: Small muscles in hands & feet
    • Optic atrophy (30%): May be no visual impairment
    • Chorea: Occasional patient may have chorea without ataxia
    • Hearing loss: Sensorineural (20%)
    • Autonomic: Cold, cyanotic legs & feet late in course; Sphincters normal
    • Cognitive: Mostly preserved
    • Electrophysiology
      • Sensory nerve potentials: Absent or Reduced
      • Motor: Normal or mildly reduced
      • NCV: Normal or Mildly reduced
      • Spinal somatosensory evoked potentials: Absent
      • VEP: Reduced amplitude
    • CNS MRI
      • Spinal cord atrophy: Cervical
      • Dentate nucleus: Severely abnormal
      • Cerebellum: Mild atrophy late in course
      • Normal: Brainstem, Cerebrum
  • Prognosis

    From Bramwell: Atlas of Clinical Medicine Friedreich Ataxia Spinal cord

    • Course
      • Slow progression
      • Time to wheel chair: Mean 15 years; Range few years to decades
    • Female: Time to wheelchair dependence shorter; Survival same
    • Early onset: Time to wheelchair dependence shorter
    • Death
      • Mean: 38 years
      • Range: 21 to 69 years
      • Cause: Cardiomyopathy
  • Pathology
    • Cellular pathology: Dying back of distal axons
    • Localization
      • Spinal cord
        • Spinocerebellar tracts
        • Dorsal columns
        • Pyramidal tracts
      • Dorsal root ganglia: Loss of neurons
      • Peripheral nerves
        • Loss: Sensory axons, Especially large myelinated
        • Axonal atrophy
      • Cranial nerves: Entering roots involved
      • Cerebellum: Dentate nucleus; Mild neuronal loss in cortex
      • Medulla
      • Cerebral cortex: Mild neuronal loss
    • FA affected tissue features
      • Have similar amounts of frataxin to many unaffected tissues
      • Typically contain non-dividing cells
      • May depend more on aerobic metabolism: CNS; Heart
  • Biochemical abnormalities
    • Mitochondria
      • Aconitase: Reduced
      • Mitochondrial complexes I to III: Reduced activity
      • Iron accumulation
    • Phospholipid levels: Reduced in cerebellar & occipital cortex
  • Treatment: Idebenone for hypertrophic cardiomyopathy
• Systemic Features
  • Skeletal
    • Scoliosis (60% to 80%)
    • Pes cavus or equinovarus (50% to 75%)
  • Cardiac (50% to 75%)
    • Clinical
      • Often asymptomatic
      • More common with: Earlier age of onset
      • Early symptoms: Shortness of breath; Palpitations
    • Hypertrophic cardiomyopathy
      • EKG: T-wave inversions
    • Muscular subaortic stenosis
    • Hypokinetic-dilated left ventricle
      • Q waves; Poor prognosis
    • EKG: Abnormal (65%)
    • Echcardiography: Concentric hypertrophy of ventricles; Asymmetric septal hypertrophy
    • Treatment
      • Idebenone 5-10 mg/kg/day at onset of hypertrophic cardiomyopathy¹³
    • Severity: Variable; May be minimal or cause of death
  • Endocrine
    • Diabetes mellitus (10%): Especially with FA onset < 10 years
    • Carbohydrate intolerance (20%): β-cell dysfunction & Peripheral insulin resistance
  • Sphincter disturbance (~25%)
  • Anesthesia: ? Avoid depolarizing NM blocking agents²⁷
• Friedreich ataxia: Variant neurological syndromes
  • Late onset ataxia syndrome
    • Onset: May be as late as 50 to 70 years
    • Some late onset patients with normal reflexes
    • Fewer skeletal deformities
    • Slower progression
  • Spastic ataxia: 2 molecular associations
    • Intermediate number of GAA repeats (120-156): Onset 38 to 45 yrs; Acadians
    • Missense mutations in amino-terminal half of FRDA (Frataxin) in one allele
  • Friedreich ataxia with retained tendon reflexes
    • Otherwise typical FA clinical syndrome
  • Early onset with rapid progression
    • Mutations
      • One allele with missense mutation in carboxy half of FRDA (Frataxin): Exon 5a; R165P
      • 2nd allele typical GAA expansion
    • Clinical syndrome
      • Early onset: Gait ataxia; 1st decade
      • Cerebellar
        • Gait disorder
        • Dysmetria: Upper limb; Mild
        • Dysarthria: Absent or very mild
      • Upper motor neuron
        • Weakness in lower extremities
        • Upgoing toes
      • Tendon reflexes: Arms normal; Some retained knee jerks
      • Peripheral nerve involvement: Slight to moderate; Sensory potentials present
      • Diabetes
      • Skeletal: Pes cavus
    • Disease progression: Rapid; Wheelchair in 2nd decade
  • Acadian Type (Louisiana Form)
    • Epidemiology: French origin living in North America
    • Frataxin mutations: Intermediate number of repeats
    • Milder course
    • Lower incidence of cardiomyopathy
  • FRDA2
    • Epidemiology: 3 consanguinous families
    • Genetics: 9p23-p11 linkage; Not linked to frataxin gene
    • Clinical features: Similar to FRDA with frataxin gene mutations
      • Onset age: 5 to 14 years
      • Ataxia: Progressive
      • Sensory: Loss, especially vibration & Joint position
      • Tendon reflexes: Absent or Reduced
• External links
  • GeneReviews
  • Friedreich biography

• Mutations: 18 reported
  • Regional distribution
    • North Africa: 744delA
    • Europe: 513insTT, 486delT & arg134 to ter
  • Frame shift deletions common
  • Missense: Milder disease
• ATTP protein: Incorporates α-tocopherol into lipoproteins secreted by liver
• Neurological Features: Phenotype similar to Friedreich ataxia
  • Onset
    • Childhood: Frame shift mutations
    • Middle-age: Point mutation (His101Glu)
    • No clinical signs but low serum vitamin E: Heterozygotes
  • Sensory loss: Large fiber modalities
  • Ataxia
  • Other CNS: Head titubation 28%; Dystonia 13%; Deafness; Bladder dysfunction
  • Tendon reflexes: Absent
• Skin: Xanthelasmata; Tendon xanthomas
• Retinitis pigmentosa: Some patients
  • Ring scotoma
  • Electroretinography: No light-evoked electrical responses
• Laboratory
  • Serum: Very low vitamin E; High cholesterol & triglyceride
  • Electrodiagnostic: Sensory potentials may be normal
• Treatment: Vitamin E supplementation & High fat diet

• Epidemiology: Finnish families
• Genetics
  • Most patients homozygous for Tyr508Cys missense mutation
  • Rare mutation: Silent 1472C->T coding region transition reduces production of Twinkle protein
  • Other mutations cause: Progressive external ophthalmoplegia, Dominant
• Mitochondria
  • Normal enzyme activity
  • mtDNA: No deletions or depletion
• Neurological Features
  • Onset: 1 to 2 years
  • Early
    • Ataxia
    • Athetosis
    • Tendon reflexes: Reduced
  • Later
    • CNS
      • Ophthalmoplegia
      • Hearing loss
      • Seizures
      • Mental capacity: Reduced
    • Polyneuropathy
      • Sensory loss: Large fiber modalities
      • Motor: Distal weakness & Atrophy
      • Progressive
      • Electrophysiology: SNAP amplitudes reduced
      • Nerve pathology: Loss of large myelinated axons; Sensory > Motor
  • Prognosis
    • Wheelchair by teens
    • Early death: Related to seizure disorder
• Systemic
  • Female primary hypogonadism: Hypogonadotrophic
  • No cardiac pathology
• CNS Pathology
  • Atrophy of cerebellum, brainstem & spinal cord
  • mtDNA depletion in brain & liver
  • Respiratory chain complex I & IV deficiency

• Genetic Features
  • Most common mutation: Extra repeats of 12 base pair tandem repeats
    • Repeat sequence: (CCCCGCCCCGCG)n
    • Repeat location: 5' untranslated region
    • Normal number: 2 or 3 repeats
    • Patients: 600 to 900 bp insertion
    • No evidence of intergenerational instability
  • Occasional missense point mutations
  • No null mutations
• Neurological Features
  • Onset 10 to 20 years
  • Myoclonus Eilepsy
  • Ataxia: Late in disease course
  • Death 25 to 35 years
  • Slower course than Lafora disease
• Treatment: Valproic Acid; Clonazepam; Phenobarbital

• Epidemiology: Middle-Eastern families
• Genetics: Homozygous, Missense mutation; R104Q
• PRICKLE1 protein
  • Expression: Multiple brain regions
  • Neuronal
  • Outer nuclear membrane
  • Noncanonical or planar cell polarity (WNT/PCP) signaling pathway
  • Mutant protein: Reduced binding to REST
• Clinical
  • Onset
    • Age: 4 to 5 years
    • Ataxia
  • Ataxia: Gait disorder
  • Myoclonus
  • Seizures: Onset 5 to 10 years
  • Cognitive impairment: Mild or None
  • Eye: Reduced up gaze
  • Sensory neuropathy: Some patients
  • Progressive
• Laboratory
  • Brain imaging: Normal

• Genetics³⁰
  • Mutation types: Loss of function
    • Finnish patients: Homozygous 4-nucleotide duplication; 506_509dupAAGA in exon 6
    • Swedish: Compound heterozygote; 506_509dupAAGA & donor splice site mutation in intron 6 (645+2TtoC)
    • Other mutations
      • Often homozygous; 331CtoT & 212dupA
      • Other: Stop codons; Frame shift; Splice site
  • All patients with mutations have myopathy
• SIL1 protein
  • Nucleotide exchange factor for the heat-shock protein 70 (HSP70) chaperone HSPA5
  • Highest expression in secretory organs
  • Present in muscle
    • Subsarcolemmal crescents often near nuclei
    • Location: Rough endoplasmic reticulum
• Onset: Infancy
• CNS
  • Cerebellar dysfunction
    • Dysarthria; Nystagmus; Ataxia
    • Cerebellar cortical atrophy: Vacuolated or binucleated Purkinje cells
  • Developmental delay: Retarded motor & mental maturation
• Muscle
  • Clinical syndromes
    • Rhabdomyolysis: After viral infections
    • Weakness: Progressive; Some with childhood onset
    • Hypotonia
  • Serum creatine kinase (CK): High; Sustained or episodic elevation
  • Pathology
    • Myopathic changes
      • Fiber size variation
      • Degeneration & Regeneration
      • Internal nuclei
      • Endomysial connective tissue: Increased
    • Rimmed vacuoles
    • Muscle Ultrastructure
      • Autophagic vacuoles with myeloid bodies
      • Nuclei: Pathology most prominent in muscles with rimmed vacuoles
        • Dense nuclear membranous structures
        • Condensed chromatin granules
        • Vacuolation with amorphous inclusions
        • Apoptosis: In scattered myonuclei
    • SIL1 protein in patient muscle
      • Homozygous Finnish patients
        • No definite immunostaining: Compatible with the predicted loss of epitope
      • Compound heterozygotes
        • Staining similar to controls
  • Denervation: Grouped atrophy
• Polyneuropathy
  • Weakness: Mild
  • Areflexia
  • Pathology: Demyelination
• Systemic Features
  • Cataracts: Early childhood or Congenital
  • Skeletal: Short stature; Kypho-scoliosis; Contractures
    • Short metatarsals & metacarpals
    • Bulging sternum
  • Hypogonadism
  • ? Some patients with chylomicron retention disease & vitamin E deficiency
• Progression: Slow
• Variant: CCFDN
  • Similar syndrome with locus on 18qter: CTDP1 mutations
  • Differences from CCFDN syndrome
    • Present in CCFDN: Peripheral neuropathy; Facial dysmorphism; Microcornea; Linkage to 18qter
    • Present in MS: Mental retardation severity; Cerebellar atrophy; Chronic myopathy
• Mouse mutant: woozy

• Genetics
  • Deletions or point mutatons in sacsin gene producing stop codon: Most common
  • Missense mutatins also described
  • Similar locus to Early onset cerebellar ataxia with retained reflexes
    • Tunisian family with milder phenotype³
• Sacsin protein
  • Expressed in fibroblasts, brain, skeletal muscle
  • ? Function in chaperone-mediated protein folding
• Epidemiology
  • Family locations: French-Canadian (Quebec); Tunisia³
• Clinical course
  • Onset: Early
    • Age: Range 1 to 20 years; Mean 4 years
    • More severe & earlier onset in French-Canadian families
    • Never walk normally in French-Canadian families
    • Ataxia: Gait
• Neurologic features
  • Cerebellar
    • Ataxia: Dysarthria; Gait disorder
    • Ocular: Nystagmus (100%); Poor ocular pursuit

      From H Topaloglu Myelinated nerve fibers in the retina

      
      
  • Eye
    • Conjugate gaze defects
    • Retina: Prominent myelinated nerve fibers (Variable frequency)
  • Motor
    • Spasticity
      • Paraparesis with gait disorder: Most patients
      • Extensor plantar responses
      • Progressive
      • No spasticity: Homozygous Phe304Ser mutation
    • Distal wasting & weakness
      • Legs > Arms
      • More apparent in older patients
  • Sensory: Loss of deep sensations
  • Tendon reflexes: Brisk except at ankles
  • Bladder: Urgency in 65%
• Systemic
  • Mitral valve prolapse
  • Pes cavus & Hammer toes: Some patients
• Progression
  • Very slow; Little change after 20 years
  • Variable among family members
  • Some patients in wheelchair at 30 years
• Laboratory
  • Electrophysiology
    • NCV
      • Sensory nerve conduction potentials: Absent
      • CMAPs: Small
      • Conduction velocities: Mildly slow
    • EMG: Denervation of distal muscles
    • Sensory evoked potentials: Abnormal
  • Nerve biopsy
    • Loss of large myelinated axons
    • Regenerating clusters
    • Occasional onion bulbs & thinly myelinated axons
  • Muscle: Neurogeic atrophy
  • Visual evoked responses: Delayed
  • CT scan: Cerebellar atrophy of superior vermis & anterior lobes
  • CNS Pathology
    • Superior vermal & anterior lobe cerebellar atrophy
    • Absent Purkinje cells
• Variant syndromes
  • Ataxia with no spasticity or myelinated retinal axons: Homozygous nonsense mutation, Arg2119X
  • Ataxia with no spasticity

• Mutations
  • Ser301Arg
  • G-T substitution in 3rd base of intron 9
• Caytaxin protein
  • Expressed only in neural tissues: Brain; Dorsal root ganglia; Enteric neurons
  • Contains CRAL-TRIO motif: Commonly binds small lipophilic molecules
  • Other protein with CRAL-TRIO motif: TPPA; Causes vitamin E-responsive ataxia
• Epidemiology: Common in 1 region of Grand Cayman Island
• Onset: Early childhood hypotonia
• Clinical
  • Cerebellar signs: Nonprogressive
    • Intention tremor
    • Dysarthric speech
    • Wide based gait
    • Nystagmus
  • Psychomotor retardation: Marked
• Brain imaging: Cerebellar hypoplasia
• Mouse model: Jittery

• Genetics
  • 13q11-12 locus identified in 1 Tunisian family³
  • Probably heterogeneity
• Onset: First or second decade
• Clinical
  • Ataxia
  • Polyneuropathy
  • Tendon reflexes: Preserved
  • Cognitive & visuospatial abilities: Progressivly impaired
  • Progression
    • Less disability than Friedreich ataxia
    • Confined to wheelchair ~ 5 years after onset
• Imaging
  • MRI: Cerebellar atrophy
  • PET: Cerebellar benzodiazepine receptor binding reduced
• Electrodiagnostic: Axonal neuropathy
• Differential diagnosis
  • 13q11-12 is similar locus to: Charlevoix-Saguenay - Spastic Ataxia
  • Rule out: Friedreich's ataxia (Slower progression)

• Epidemiology: Dutch family
• Onset: Early childhood
• Clinical
  • Cerebellar ataxia
    • Dysarthria
    • Limbs: Dysmetria; Abnormal writing
    • Gait disorder: Eventually severe
    • Eyes: Nystagmus; Saccadic pursuit
  • Pyramidal
    • Legs: Spastic
    • Tendon reflexes: Increased in legs (80%)
    • Plantar responses: Extensor (40%)
  • Fasciculations
  • Sensory loss (60%): Vibration in legs
  • Tremor: Hands, postural (40%)
  • Cognitive impairment: 1 patient
  • Progression: Slow
• MRI
  • Atrophy of cerebellum & pons

• Gene mutations
  • Insertion, Deletion, Missense
  • P206L: Later onset (10 years)
  • Allelic with: Cerebellar ataxia with Muscle coenzyme Q₁₀ deficiency
• Protein
  • Member of histidine triad superfamily
  • Expression: Ubiquitous
  • Subcellular location
    • Nuclear
    • Present in nucleoplasm & nucleolus
  • Role in DNA repair
    • Interacts with repair proteins XRCC1, PARP-1 and p53
    • Co-localizes with XRCC1 along charged particle tracks on chromatin
    • Influences cellular response to genotoxic stress
  • Normally expressed as long & short forms
    • Long form more affected by mutation
  • Mutated protein unstable
• Epidemiology
  • Portuguese & Japanese
  • Most frequent cause of autosomal recesssive ataxia in Japan
• Onset: Mean 4.7 years; Range 1 to 16 years
• Clinical
  • Ataxia (100%)
    • Gait disorder
    • Dysarthria
    • Limb dysmetria: Arms > Legs; Later in course
  • Extrapyramidal (59%): Dystonia (Arms); Masked faces; Occasionally severe
  • Ocular
    • Oculomotor apraxia (100%); Onset after gait ataxia
    • Optic atrophy (14%)
  • Peripheral nervous system (100%)
    • Motor neuropathy
      • Weakness: Often progressive to severe disability
      • Wasting
      • Distribution: Distal; Symmetric
    • Sensory loss
      • Late in course
      • Mild loss of vibration & joint position sense
  • Other CNS: Some patients, especially Japanese, with mental retardation
  • Progression: Slow
• Laboratory
  • Electrophysiology: axonal neuropathy
  • Nerve pathology: Mild loss of large myelinated axons
  • MRI: Cerebellar ± Brainstem atrophy
  • Hypoalbuminemia
  • Coenzyme Q10 levels: May be reduced in muscle
    • Often below normal: No relation to disease duration or severity
    • Especially low levels with homozygous Trp279Ter mutation
    • Secondary defect
    • No effect on levels of mitochondrial oxidative enzymes
    • See: Ataxia with coenzyme Q₁₀ deficiency

• Epidemiology: Single family
• Genetics
  • Mutation: Homozygous Trp279Ter
  • Allelic with: AOA1
• Onset
  • Age related syndromes
    • Birth: Fatal infantile encephalomyopathy with renal involvement
    • Childhood to 16 years: Ataxia syndrome
    • Myopathic + CNS
    • 4th decade: Ataxia + Hypergonadotropic hypogonadism
    • Median onset age: 4 years
  • Hypotonia & Motor delay: Less than 2 years
  • Ataxia: Manifests between 2 and 9 years
  • Seizures: Ages 2 to 6 years
• Clinical
  • Cerebellar ataxia (100%)
    • Onset in all by age 10
    • Distribution: Trunk; Limbs; Speech
  • Seizures (37%)
  • Mental retardation (30%)
  • Pyramidal signs (40%): Variable
    • Tendon reflexes: Brisk
    • Toes: Upgoing
    • Spastic paraparesis: Some patients
  • Weakness (50%)
    • Distal or Proximal
    • Also: Motor delay, developmental
  • Rhabdomyolysis: Some patients
  • Neuropathy (20%)
    • Sensory loss
    • Axonal
  • Other occasional CNS
    • Hemiparesis: Recurrent
    • Ophthalmoplegia
    • Myoclonus
  • Systemic
    • Scoliosis
    • Hypergonadotropic hypogonadism: Late onset cases
  • Course: Slow progression; Wheelchair by 8 years in some
• Laboratory
  • Muscle
    • Morphology: Non-specific abnormalities
      • Denervation changes
    • Coenzyme Q10 levels: 26% to 35% of normal; Less than 15 μmol/g tissue
    • Biochemistry: Only 25% of patients have expected block in transfer of electrons to complex III
  • Systemic testing
    • Lactic acidosis: Inconsistent
    • Normal: Amino acid & Organic acid profiles
    • Adult syndrome: FSH & LH high
  • Electrophysiology
    • NCV: Mildly slowed; CMAPs small
    • SEP: Small amplitude
  • CNS pathology: Cerebellar atrophy, hemispheres & vermis
• Treatment
  • Coenzyme Q₁₀ dietary supplementation: 200 mg to 1,200 mg per day
  • Response to treatment more likely in children than adults
• Also see
  • Coenzyme Q₁₀ deficiency: Myopathy & Rhabdomyolysis

• Epidemiology: Algerian, French & US families
• Genetics: Mutations
  • Type: Missense, Splice site, Frame shift, Deletion
  • Locations: R213W, G272V, G272D, Tyr514Cys, Gly549Ser, E551K,
        Gln167X, Thr584del, c.[1812_1813insG], 1398+2T-C, Asp420X, Lys314_Gln360 del
• CABC1 protein
  • Subcellular location: Mitochondria
  • Required for CoQ biosynthesis
  • Protein kinase: Atypical
  • Expression: Ubiquitous
  • Target of p53 tumor suppressor gene
    • Other p53-interacting protein: RRM2B related myopathy
  • ADCK (aarF-domaincontaining kinases) proteins
    • Share common N-terminal domain: Lys276, Glu278 & Gln279
    • Related to ubiquinone metabolism
• Clinical
  • Onset
    • Age 1.5 to 11 years
    • Gait ataxia
    • Exercise intolerance
  • CNS
    • Ataxia
    • Mental retardation: 50%; Mild to Moderate
    • Seizures: Some patients; Epilepsia partialis continua
  • Exercise intolerance (60%)
  • Tendon reflexes: Reduced to Increased
  • Course: Slow progression (Decades)
  • Treatment: Coenzyme Q10 supplementation has little or no benefit
• Laboratory
  • Lactic acid: High or normal in serum
  • MRI
    • Cerebellar atrophy
    • Stroke-like hyperintensities on T2
  • EMG: Usually normal
  • Muscle biopsy
    • Non-specific
    • Lipid droplets
    • No ragged red fibers
    • Mitochondrial oxidative enzymes: Suggest quinone deficiency
      • High CIV/CII+III & CII+III/CII activity ratios
      • Enzyme activities in muscle mitochondria increased by decylubiquinone
      • Coenzyme Q10: Low

• Nosology: Also called Spinocerebellar ataxia, recessive, non-Friedreich type 1 (SCAR1)
• Epidemiology: Common in French-Canadians
• Genetic
  • Mutations
    • Premature termination in 2/3
    • Missense in some families
    • Often homozygous
  • Missense mustations in
    • ALS4 (Dominant)
    • Distal motor neuropathy with upper motor neuron signs
  • Locus near Joubert congenital ataxia
• Senataxin protein
  • Involved in RNA maturation & termination
  • Helicase: Superfamily 1
  • Expression: Generally ubiquitous
• Clinical
  • Onset: 2 to 22 years; Mean 15 years
  • Ataxia
    • Gait disorder: Severe
    • Limbs & Trunk: Mild
  • Extrapyramidal
    • Choreoathetosis
    • Dystonic posturing with walking
    • Masked faces: with severe disease
  • Ophthalmological
  • Oculomotor apraxia: Variably present (47%)
  • Smooth pursuit: Disordered
  • Optokinetic nystagmus: Absent
  • Saccade palsy
    • Saccades slow: Head turns first, then eyes follow
    • Distribution: Global; Vertical > Horizontal
    • Anatomy of vertical saccades: Originate near rostral interstitial nucleus
  • Peripheral neuropathy (93%)
    • Sensory loss: Vibration (100%); Position (74%); Light touch (57%)
    • Motor: Onset 3rd decade
      • Weakness: Distal
      • Wasting: Distal
    • Electrodiagnostic: Axonal loss
      • SNAPs: Absent or Reduced amplitudes
      • Motor: Mildly reduced CMAP amplitudes
      • EMG: Distal denervation
  • Reflexes
    • Tendon: Absent in legs
    • Plantar: Extensor
  • Cortical: Normal intelligence
  • Neoplasia: No association
  • Progression
    • To early 20's, then stable
    • Disabled from work
  • Differential diagnosis: Ataxia + Saccade failure
    • Ataxia telangectasia
    • Ataxia telangectasia-like syndrome
    • SCA2
    • AOA1
• Laboratory
  • CT: Cerebellar atrophy in some patients, Mild
  • Nerve conduction: Absent sensory potentials
  • a-Fetoprotein: High
  • Serum CK: High in some patients

• Onset: Childhood
• Clinical
  • Cerebellar ataxia
  • Optic atrophy: Visual loss
  • Cochlear degeneration: Deafness

• Onset: 4th & 5th decades
• Pure cerebellar ataxia

• Onset: 4th & 5th decades
• Ataxia; Myoclonus
• Pathology
  • Dentate neuron loss
  • Superior cerebellar peduncle fiber loss

• Nosology: Other names
  • Childhood ataxia with difuse hypomyelination
  • Myelinosclerosis centralis diffusa
• Genetics
  • ? Allelic with Fatal infantile leukodystrophy
  • ~84 mutations identified
  • Most commonly mutated gene: eIF2B5, R113H
  • Mildest phenotype (onset > age 5): Mutations in non-conserved amino acids (R113H in EIF2B5 & E213G in EIF2B2)
  • Severe phenotype: Mutations in highly conserved amino acids (R195H in EIF2B5)
• eIF2B protein function
  • Initiation & regulation of translation of RNA into protein
  • Especially involved with stress or fever
  • Catalyzes exchange of eukaryotic initiation factor 2-bound GDP for GTP
• Onset: Variable
  • Usual: Childhood
  • Occasional: Adult onset
• Course
  • Initial childhood motor & mental development: Normal or mildly delayed
  • Chronic progressive
  • Episodic
    • Deterioration after infections & minor head trauma
    • Periods of coma
  • Death: After years to decades
• Neurologic signs: Spastic ataxia
  • Ataxia
  • Spasticity
  • Occasional
    • Optic atrophy
    • Epilepsy
    • Mental dysfunction
    • Polyneuropathy: Severe patient
      • Pathology: Mild loss of myelinated axons
      • NCV: Mild Slowing
• MRI
  • Diffuse cerebral hemispheric leukoencephalopathy
  • Areas of abnormal white matter have high T2 signal intensity like CSF
• Pathology
  • Cavitating orthochromatic leukodystrophy without atrophy: No plaques
  • Location: Hemispheric white matter
  • Oligodendrocytes: Increased density without mitotic activity
  • Astrocytes: Shrinkage; Reduced number in perivascular regions
• Variants
  • Ovarioleukodystrophy: Mutations in eIF2B2, eIF2B4 & eIF2B5
  • Dominant inheritance²⁸
    • Epidemiology: 1 family; Mother & son
    • Adult onset: 4th decade
    • Somnolence, mental confusion & hemiparesis: After URI with fever

• Epidemiology: Multiple families in US, Europe, Turkey & Russia
• Genetics
  • Heterozygous
  • Type: Missense or Exon-skipping splice site
• Mitochondrial aspartyl-tRNA synthetase protein
  • Class-II aminoacyl-tRNA synthetase family
  • Mutant: Reduced activity
• Clinical
  • Onset: 3 to 15 years
  • Cerebellar ataxia: Slowly progressive; Legs > Arms
  • Spasticity: Legs > Arms; Mild to Severe
  • Sensory: Dorsal column dysfunction; Vibration reduced distally
  • Cognitive: Mild impairment & decline
  • Muscle: No prominent involvement
• Laboratory
  • MRI T2 signal abnormality
    • Cerebral WM: Especially posterior corpus callosum
    • Spinal cord: Dorsal columns; Lateral corticospinal tracts
    • Brainstem tracts: Pyramidal tracts; Medial lemniscus; Cerebellar peduncles
    • In-homogeneous
  • Lactate: High in WM by MRS; Normal in serum
  • Mitochondrial complexes in fibroblasts: Normal
  • NCV: Normal
  • SSEP: Abnormal
  • CSF: Normal protein & lactate
• Also see
  • Myopathy with mitochondrial aspartyl-tRNA mutation
  • Spastic ataxias

• Mutations
  • Finnish: Homozygous Arg39Cys, Milder disease
  • Severe disease: Other deletions, insertions, & missense or nonsense
• Protein: Sialin
  • Homologous to phosphate & glutamate transporters
  • Contains 10 transmembrane helices
  • Mutant protein: Abnormal intracellular trafficking through Golgi
  • Sialic acid storage disease
    • Transport of free sialic acid at lysosomal membrane: Reduced
• Epidemiology: Prevalent in Finland
• Clinical
  • Onset: 12 to 18 months
  • Ataxia
  • Hypotonia
  • Mental retardation
  • Epilepsy (18%): Absence; Later age
  • Hepatosplenomegaly
  • Coarse facial features
  • More severe forms of disease with severe mental retardation, seizures & hypotonia
  • Course: Progressive deterioration in 2nd decade
• Variant syndrome
  • Infantile sialic acid storage disease (ISSD): Caused by deletion mutations
• Laboratory
  • NCV: Demyelinating polyneuropathy (50%)⁶
    • Patients: Severely disabled; Oldest
    • Reduced nerve conduction velocities
    • Prolonged distal latencies
  • Sialuria
  • Lymphocytes: Vacuolated (4% to 15%)
  • Lysosomes: Enlarged
  • MRI
    • Progressive cerebellar atrophy
    • Corpus callosum hypoplasia
    • Delayed myelination

• Epidemiology: One Italian family
• Onset: 5th to 6th decade; Dysphonia
• Clinical
  • Bilateral laryngeal abductor paralysis
    • Hoarseness
    • Laryngeal stridor: Nocturnal
    • Differential diagnosis: Multiple system atrophy; HMSN 2C; Distal SMA
  • Ataxia, Cerebellar
    • Gait unsteadiness
    • EOM: Nystagmus; Abnormal smooth pursuit
    • Limb dysmetria
  • Motor neuropathy
    • Weakness: Distal; Legs > Arms
  • Cognition: Normal
  • Sensory: Normal
• Laboratory
  • MRI: Cerebellar atrophy of vermis & Hemispheres
  • Laryngoscopy: failure to abduct vocal cords
  • EMG: Distal denervation & Fasciculations

• Epidemiology: One Finnish family
• Onset
  • 30 years
  • Gait disorder
  • Normal childhood
• Clinical
  • Cerebellar
    • Ataxia: Limbs & Gait
    • Dysarthria
    • Nystagmus
  • Cranial nerve disorders
    • Dysphagia
    • Upgaze paresis
  • Tendon reflexes: Reduced in legs
  • Sensation: Reduced vibration & joint position sense
  • CNS: Cognitive impairment; Epilepsy in 1 patient
  • Progression: Over 1 to 2 decades
• Laboratory
  • MRI lesions
    • Thalamic (Symmetric)
    • Brainstem gray matter
    • Cerebellar white matter
  • Pathology
    • Vacuolar changes in thalamus
    • Neuronal loss in spinal cord, cerebellum & brainstem
  • Nerve conduction: Axonal sensory neuropathy
    • SNAPs: Absent or reduced in legs
    • Conduction velocities: Slightly reduced

• Epidemiology: Single family; Several members of one generation
• Onset: Gait disorder; Childhood
• Clinical
  • Maculopathy: Atrophic; Bull’s-eye configuration; Reduced visual acuity
  • Cerebellar: Dysarthria; Legs
  • Sensory: Reduced in feet
  • Tendon reflexes: Brisk
  • Cognition: Normal
• Laboratory
  • CT scan: Cerebellar atrophy, midline

• Epidemiology: Single family
• Onset
  • 3rd or 4th decade
  • Gait disorder
  • Difficulty reading
• Clinical
  • Ataxia: Gait; Trunk; Limb; Dysarthria
  • Eye: Macrosaccadic oscillations
    • Horizontal
    • Large saccades have increased speed
    • Induced with each gaze shift
    • Intersaccadic intervals present
    • Similar EOM may occur in Friedreich ataxia
    • Anatomy: Midline cerebellar lesions involving the fastigial nucleus
    • No nystagmus
  • Pyramidal tract (100%)
    • Tendon reflexes increased
    • Plantar responses extensor
  • Myoclonus (100%)
  • Fasciculations (100%)
  • Sensory: Joint position reduced
  • Pes cavus: Mild
• Laboratory
  • Nerve conduction: Axonal sensorimotor neuropathy
  • EMG: Active denervation in distal legs

• Epidemiology: Arab family of Palestinian origin in Kuwait
• Clinical
  • Ataxia: Gait disorder
  • Eye movements: Slow or absent saccades
  • Intellectual impairment
  • Extrapyramidal dysfunction
  • Peripheral neuropathy
  • Skeletal abnormalities
  • Course: Progressive over 1 to 2 decades
• Pathology
  • Midbrain tracts & nuclei

• Epidemiology
  • Geography: Families in Portneuf region South of Quebec City, Canada
  • Variability: Intra- & Inter-familial
• Onset
  • Age: Mean 8 years; Range - Birth to 59 years
  • Motor: Clumsiness; "Cerebral palsy"
• Clinical: Spastic-ataxia
  • Cerebellar
    • Ataxia
    • Dysarthria (74%)
    • Nystagmus(44%): Horizontal
  • Upper motor neuron
    • Spasticity
    • Hyperreflexia
    • Urinary urgency 57%
  • Other features in more severe patients
    • Scoliosis (35%)
    • Dystonia (57%)
    • Cognitive impairment (44%): Mild
    • Eye: Optic atrophy + Cataract (9%): Two older patients
    • Hearing impairment: Mild (13%)
  • Peripheral nerves: Normal
  • Severity: Intrafamilial variability
• MRI
  • Cerebellar atrophy (100%): Vermis & Hemispheres
  • More severe patients
    • Cortical atrophy (40%)
    • Leukoencephalopathy (50%): T2 & FLAIR; Older patients

• Epidemiology: 1 Family; Karak (Southern Jordan)
• Genetics
  • Mutation: Arg632Trp
  • Allelic with: Infantile neuroaxonal dystrophy
• Onset: Early
• Clinical
  • Cerebellar ataxia: Progressive
  • Dystonia
  • Spasticity
  • Intellectual decline
• MRI: "Eye-of-tiger" sign
• Pathology: Iron deposition in CNS

• Epidemiology: Israeli-Arab family
• Onset
  • 3 to 4 years
  • Tremor
  • Gait disorder
• Clinical
  • Ataxia: Limbs; Gait; Stance
  • Dysarthria
  • Seizures: Myoclonic & Generalized tonic-clonic,
  • Eye movements: Upward gaze palsy
  • Reflexes
    • Tendon: Normal or Reduced
    • Plantar: Extensor
  • Neuropathy: Sensory
    • Reduced vibration & joint position sense
    • NCV: Axonal loss
    • Muscle biopsy: Type grouping; No mitochondrial change
  • Cognition: Normal
• Laboratory
  • EEG: Epileptiform discharges
  • MRI: CNS normal

• Epidemiology: French Canadian families
• Mutations
  • Splice site related
    • AG splice acceptor site at junction of exon 85 & intron 84; 310067A-G
    • Intron 81: 306434A-G; Creates new AG cryptic slice acceptor site
  • Premature termination: R2906X; 334338–334342delATTTG; Q7640X
  • Allelic with: Emery-Dreifus MD, Type 3
• Syne-1 protein
  • Widely expressed
  • Size: Very large
  • Subcellular location: Nuclear
  • Contains spectrin domain
    • Other disorders of spectrin domain proteins: Duchenne MD; SPG8; SCA4; SCA5
  • CNS
    • Neuronal selective: High in cerebellar Purkinje cells & Olivary neurons
    • CPG2
      • Brain specific splice variant of SYNE1
      • Localized to postsynaptic endocytotic zone of excitatory synapses
      • Disrupts glutamate receptor internalization
      • May be necessary for rapid cycling of synaptic glutamate receptors
  • Neuromuscular junctions: Anchors specialized myonuclei underneath NMJ
• Onset
  • Age: Mean 30 years; Range 17 to 46 years
  • Signs: Ataxia; Dysarthria
• Clinical
  • Cerebellar
    • Dysarthria (100%)
    • Limb ataxia (98%)
    • Gait ataxia (98%)
    • Ocular: Nystagmus, gaze-evoked (13%); Abnormal saccades (31%); Slow/jerky pursuit (45%)
  • Tendon reflexes: Brisk in 26%
  • Progression: Slow
• Laboratory
  • MRI: Cerebellar atrophy (100%)
  • Muscle: Fewer nuclei beneath neuromuscular junctions; Normal NMJ structure
• Similar syndrome: Holmes ataxia

• Epidemiology: 1 Saudi Arabian family, consanguinous
• Onset
  • Age: 9 to 12 months
  • Epilepsy
• Clinical
  • Epilepsy
    • Type: Generalized, Tonic-clonic
    • Treatment: Valproate; Phenobarbitone; Not helpful in all
  • Ataxia
    • Delayed walking
    • Nystagmus
    • Dysarthria
    • Limbs & Trunk
  • Mental retardation: Talking at 2 to 3 years
  • Tendon reflexes: Reduced
  • No myoclonus or dementia
  • Course: Slowly progressive
• Laboratory
  • MRI: Cerebellar vermis atrophy
  • EMG: Normal
  • Muscle biopsy
    • Muscle fiber size: Varied
    • Vacuoles: Irregular, sarcotubular; ? Artefact
  • EEG: Spikes & slow waves

• Epidemiology: Consanguineous Turkish family of Kurdish origin
• Clinical
  • Cerebellar
    • Dysarthria
    • Dysmetria
    • Dysdiadochokinesia
    • Inability to walk bipedally: Quadrupedal locomotion
  • Mental retardation
    • May be severe
    • Absent speech
  • Skeletal
    • Thoracic kyphosis
    • Short stature
    • Facial features: coarse
  • Other
    • Hirsutism
    • Penis: Small
• Laboratory
  • MRI
    • Cerebellum: Hypogenesis & midline clefting of vermis
    • Brain atrophy
    • Corpus callosum: Mild hypoplasia

• Epidemiology: Iraqi family
• Genetics
  • Mutation: S100P
  • Same gene as mutated in: waddles mouse
• CA8 protein
  • Highly expressed in cerebellar Purkinje cells
  • Influences inositol triphosphate (ITP) binding to its receptor ITPR1 on endoplasmatic reticulum
  • Modulates calcium signaling
• Clinical
  • Onset: Congenital
  • Mental retardation
  • Ataxia
  • Gait: Quadrupedal

• Epidemiology: North Indian family, 2 affected sisters
• Genetics
  • Mutation: 2 base pair deletion
  • Allelic with: Knobloch syndrome
• COL18A1 protein
  • α-chain of type XVIII collagen
  • Multiplexins: Extracellular matrix proteins that contain multiple triple-helix domains
  • Proteolytically produced C-terminal fragment of type XVIII collagen: Endostatin
• Clinical
  • Onset age: 3 to 12 years
  • CNS
    • Ataxia
      • Arms & Legs
      • Gait disorder
      • Nystagmus: Lateral gaze
    • Intellectual delay & Cognitive decline
  • Seizures: Generalized & Myoclonic
  • Eye
    • Glaucoma
    • Lens dislocation
    • Retinal & Corneal dystrophy
• MRI
  • Polymicrogyria: Bilateral, Frontal & Temporal (arrows). There is marked
  • Cerebellar atrophy
  • Other atrophy: Brainstem, Supratentorial, Cervical spinal cord

• Nosology
  • SeSAME: Seizures, Sensorineural deafness, Ataxia, Mental retardation, Electrolyte imbalance
  • EAST: Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy
• Epidemiology: Turkish, British, Canadian & Afghan families
• Genetics: Mutations
  • Loss of function
  • Missense or Termination
  • R65P; G77R; C140R; T164I; A167V; R297C
• KCNJ10 (Kir4.1) protein
  • Inwardly rectifying K⁺ channel
  • Expressed in glia in brain & spinal cord
  • Takes up K⁺ released by neuronal repolarization
  • Several mutations likely to affect channel activity via altered interaction with PIP₂
• Clinical
  • Onset age: ≤ 5 years
  • Seizures: Onset 3 to 4 years; Tonic-Clonic
  • Ataxia: Intention tremor; Gait disorder
  • Developmental delay: Mental retardation
  • Hearing loss: Sensorineural
• Laboratory
  • Electrolyte imbalance: Renal disorder of distal convoluted tubule
    • Hypokalemia
    • Metabolic alkalosis
    • Hypomagnesemia
    • Renin & Aldosterone: Elevated levels
  • MRI
    • Spinal cord: White-matter pathology
    • Cerebellum: Small, some patients
  • Nerve
    • Hypomyelination of large myelinated axons
    • Axonal loss

CONGENITAL ATAXIC DISORDERS

• Cerebellar or vermal aplasia
• Usually Recessive

Type 1: 9q34 Type 2: 11p12 Type 3: AHI1; 6q23 Type 4: NPHP1; 2q13 Type 5: CEP290; 12q21 Type 6: TMEM67; 8q21 Type 7: RPGRIP1L; 16q12 Type 8: ARL13B; 3q11 Type 9: CC2D2A; 4p15 Type 10: OFD1; Xp22 X-linked: CXORF5; Xp22 COACH syndromes   CC2D2A; 4p15   TMEM67; 8q21

From: A Paciorkowski Molar Tooth Sign

• Joubert syndromes: General ⁵²
  • Mutated proteins: Ciliopathies
    • Associated with function of primary cilium/basal body
    • Other ciliopathies
      • Meckel syndrome (MKS)
      • Bardet-Biedl syndrome (BBS)
      • Nephronophthisis
      • Leber congenital amaurosis (LCA)
  • Features
    • Clinical & Lab: All patients
      • Onset: Congenital
      • Motor: Hypotonia & Developmental delay
      • Ataxia
      • Intellectual disability
      • Eye movement disorders: Oculomotor apraxia; Abnormal smooth pursuit; Nystagmus
      • Imaging: Midbrain–hindbrain malformation
        • Cerebellar vermis hypoplasia
        • Superior cerebellar peduncles: Enlarged
        • "Molar tooth" sign
    • Other common features
      • Encephalocele 6%: Especially types 5, 6, 7
      • Retinal disorders: Especially types 3, 5
        • Chorioretinal coloboma 19%
        • Retinal dystrophy 30%
      • Cystic kidney disease 23%: Less common in types 3, 8
      • Liver disease: Portal hypertension or other 18%; Especially types 5, 6, 7
      • Polydactyly 19%: Especially types 6, 7
  • Specific clinical syndromes
    • Cerebellar: Type 1
    • Cerebellar + Cortical: Type 3
    • CNS + Multisystem (Kidney; Retina; Liver): Type 2, variable phenotypes
  • External link: Molar tooth sign
  
  
• Joubert Syndrome, type 1 (Cerebelloparenchymal disorder IV; CPD IV)
  l Chromosome 9q34.3; Recessive
  
  • Type A Joubert syndrome: Involves brain but not kidneys or retina
  • Genetics
    • Middle Eastern families
    • 9q34 Locus near Ataxia with Oculomotor apraxia (AOA)
  • Onset: Infantile
  • Neurologic Features
    • Cerebellar: Ataxia
    • Eye
      • Oculomotor: Nystagmus; Vertical gaze paresis; Oculomotor apraxia
      • Ptosis
      • Retinopathy: Dystrophy; Coloboma; Pigmentary retinopathy
    • Mental Retardation
    • Rhythmic tongue protrusion
    • Respiratory: Episodic hyperpnea or apnea
  • Systemic Features
    • Skin: Dimples at wrist & elbows
    • Skeletal: Telecanthus; Micrognathia
    • Cardiac malformation
  • Pathology
    • Cerebellar vermal aplasia
    • Brainstem malformations: "Molar tooth sign"
      • Deep interpeduncular fossa at isthmus and upper pons
      • Elongated, thick, & maloriented superior cerebellar peduncles
      • Dysplasia of superior cerebellar vermis
      • Absence of decussation of superior cerebellar peduncles
    • NPHP1 mutations: Molar tooth sign is milder
  
  
• Joubert Syndrome, Type 2 (Cerebello-oculo-renal syndrome; CORS2) ¹⁹
  l Chromosome 11p12-q13.3
  • Type B Joubert syndrome: Involves brain, kidney & retina
  • Epidemiology: Families from Pakistan, United Arab Emirates, Europe
  • Onset: Infantile
  • Clinical: Variability among families
    • Neurologic Features
      • Cerebellar: Ataxia
      • Hydrocephalus
      • Respiratory: Episodic hyperpnea or apnea
    • Eye
      • Oculomotor: Oculomotor apraxia
      • Visual impairment
      • Coloboma
    • Renal
      • Multiple small cysts throughout
      • Loss of normal cortico-medullary differentiation, bilateral
    • Facial dysmorphism
      • Depressed nasal bridge
      • Hypertelorism
      • High-arched palate
      • Low-set ears
  • Pathology
    • Cerebellar vermal aplasia
    • Brainstem malformations: "Molar tooth sign"
    • Corpus callosum: Kinked
  
  
• Joubert Syndrome, Type 3
  l AHI1; Chromosome 6q23.2-23.3; Recessive
  • Epidemiology: Turkish & Swiss families
  • Genetics²²
    • Mutations: Stop & Missense
    • R351X; R435X; V443D
  • AHI1 protein
    • Locations: Expressed in brain & kidney
    • High levels in axons that fail to cross midline in Joubert syndrome
  • Onset
    • Age: Neonatal
    • Breathing problems
    • Hypotonia (100%)
  • Clinical
    • Cerebellar: Truncal (100%); Ataxia (50%); Nystagmus (50%)
    • Motor: Late walking or wheelchair bound
    • Cognitive impairment
    • Reduced vision
    • Skeletal: Kyphoscoliosis (30%); Reduced growth (40%)
    • Molar tooth sign (100%)
    • Renal: Normal
  • Laboratory
    • Cerebellar vermis: Hypoplasia
    • Some patients have polymicrogyria
  
  
• Joubert Syndrome, Type 4
  l NPHP1 ; Chromosome 2q13; Recessive
  • Epidemiology: 2 siblings
  • Clinical: Mild form of Joubert syndrome
    • Motor delay: Mild
    • Oculomotor: Apraxia; Head tilt
    • Nephronophthisis
  • MRI
    • Cerebellar vermis: Hypoplasia
    • "Molar tooth sign"
  
  
• Joubert Syndrome, Type 5
  l Centrosomal protein, 290-KD (CEP290) ; Chromosome 12q21.3; Recessive
  • Cerebello-Oculo-Renal JSRD
  • Epidemiology: 8 families
  • Genetics
    • Mutations: Missense & Termination
    • Also mutations in
      • Senior-Loken syndrome 6
      • Meckel syndrome
  • Clinical: Variable form of Joubert syndrome
    • Motor delay: Mild; Hypotonia
    • Ataxia
    • Oculomotor: Apraxia; Head tilt
    • Neonatal breathing abnormalities
    • Nephronophthisis
    • Retinal dystrophy
    • Incomplete phenotypes: Cerebelloretinal & cerebellorenal syndromes
  • MRI
    • Cerebellar vermis: Hypoplasia
    • "Molar tooth sign"
  
  
• Joubert Syndrome, Type 6
  l Transmembrane protein 67 (TMEM67; MKS3; Meckelin) ; Chromosome 8q21.13-q22.1; Recessive
  • Epidemiology: 4 patients
  • Genetics
    • Mutations
      • Missense, Splice site & Termination
      • Heterozygous
    • Also mutations in
      • Meckel-Gruber syndrome
      • COACH syndrome
  • Onset: Gestation or Childhood
  • Clinical
    • Disability: Mild to Severe
    • Hypotonia
    • Motor delay
    • Mental retardation
    • Cerebellar ataxia
    • Stereotypic movements
    • Breathing abnormalities: More severe patients
    • Renal & Hepatic involvement: Some patients
  • MRI
    • Cerebellar vermis: Hypoplasia or Dysplasia
    • "Molar tooth sign"
  
  
• Joubert Syndrome, Type 7 ³⁶
  l RPGRIP1-like protein (RPGRIP1L) ; Chromosome 16q12.2; Recessive
  • Cerebello-Renal JSRD
  • Epidemiology: 7 families
  • Genetics
    • Mutations: Loss of function & missense
    • Mutations also present in Meckel syndrome patients: Complete loss of function
  • RPGRIP1-like protein
    • Expression: Ubiquitous
    • Localization: Basal bodies at base of cilia
    • Interacts with: Nephrocystin-4 (NPHP4)
  • Clinical
    • Ataxia
    • Developmental delay
    • Eye movements: Oculomotor apraxia; Ptosis; Nystagmus
    • Renal failure: Nephronophthisis; Later in childhood
    • Skeletal: Scoliosis; Polydactyly
  • Laboratory
    • MRI: Molar tooth sign
    • No retinal disease by electroretinogram
  
  
  
• Joubert Syndrome, Type 8 ⁴¹
  l ADP-ribosylation factor-like protein 13B (ARL13B; ARL2-like protein 1) ; Chromosome 3q11; Recessive
  • ARL13B protein
    • Ras GTPase family
    • Functions: Ciliogenesis; Body axis formation; Renal function
    • Expressed in developing murine cerebellum
    • Localized to cilia in primary neurons
  • Clinical: Typical Joubert syndrome
    • CNS
      • Hypotonia
      • Ataxia
      • Retardation & Psychomotor delay
      • Oculomotor ataxia
      • Molar tooth sign
    • Retinal: Normal
    • Renal: Normal
  • Mouse: hennin
  
  
• Joubert Syndrome, Type 9 (JBTS9) ⁴⁵
  l Coiled-coil and C2 domains-containing protein 2A (CC2D2A) ; Chromosome 4p15.3; Recessive
  • Genetics: Mutations
    • Loss of function
    • Homozygous: Often
    • Missense & Nonsense: P1122S; R1528C; R950X; L1551P; V1097FfsX1; R1019X/pQ1096H
  • CC2D2A protein
    • Localized at basal body
    • Co-localizes with cep290
    • Expressed in all fetal & adult tissues
  • Clinical
    • Joubert syndrome, uncomplicated
    • Abnormal eye movements: Common
    • Retinal dystrophy: Few patients
    • No polydactyly
    • Renal & Liver disease: Occasional
    • Some patients with
      • COACH phenotype
      • Meckel syndrome (MKS)
  • Laboratory
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome 10, X-linked (JBTS10) ⁵³
  l CXORF5 (OFD1) ; Chromosome Xp22.3-p22.2; Recessive
  • Malaysian family
  • Genetics
    • Frameshift mutation: Exon 21; p.K948NfsX8, p.E923KfsX3
    • Allelic with
      • Orofaciodigital syndrome 1 (OFD1) : X-linked dominant
      • Simpson-Golabi-Behmel Syndrome, Type 2 (SGBS2)
  • Protein
    • Pericentriole
    • Binds to Lebercillin (LCA5)
    • Ciliary formation
  • Clinical
    • Joubert syndrome
    • Mental retardation: Severe
    • Abnormal eye movements: Common
    • Retinitis pigmentosa
    • Polydactyly, postaxial
    • Recurrent infections
    • Central apnea
    • Renal: Normal
    • Course: Death > 20 years
  • Laboratory
    • MRI: Molar tooth sign; Cerebellar vermis hypoplasia

• COACH syndrome
  l Coiled-coil and C2 domains-containing protein 2A (CC2D2A) ; Chromosome 4p15.3; Recessive
  • COACH Nosology: Cerebellar vermis hypoplasia, Oligophrenia, Ataxia, Coloboma, Hepatic fibrosis
  • Genetics
    • CC2D2A mutations also cause: Joubert syndrome 9
  • Neurological Features
    • Ataxia
      • Early-onset
      • Pathology: Vermal aplasia
    • Mental retardation
    • Spasticity
  • Systemic Features
    • Hepatic fibrocirrhosis
    • Ocular: Coloboma, Ptosis
    • Skeletal
      • Hypertelorism
      • Flat round face
      • Polydactyly
      
      
  l Transmembrane protein 67 (TMEM67; MKS3) ; Chromosome 8q21.13-q22.1; Recessive
  • Genetics
    • Compound heterozygotes
    • Frequency of TMEM67 mutations in COACH syndrome: 57%⁴⁷
    • TMEM67 mutations also cause: Joubert syndrome 6
  • Clinical
    • Joubert syndrome CNS
    • Ataxia
    • Abnormal breathing
    • Mental retardation & Developmental delay
    • Oculomotor apraxia
    • Liver
      • Hepatomegaly
      • Congenital hepatic fibrosis
    • Renal: Nephronophthisis
  
  
• Dandy-Walker syndrome
  l ZIC1 & ZIC4 genes; Chromosome 3q24-q25.1; Recessive or Sporadic
  • Genetics: Non-syndromic Dandy-Walker²³
    • Low recurrence rate (1% to 2%)
    • Associated with deletions on chromosome 3q
    • Dandy-Walker: Deletions involving ZIC1 & ZIC4 genes on chromosome 3q
  • ZIC proteins
    • Zinc finger transcription factors of cerebellum
    • Cellular locaization: Nucleus
  • Onset
    • Infancy
    • Slow motor development
  • Neurological Features: Clinical
    

    From: A Paciorkowski Dandy-Walker malformation: 2 day old child

    • Posterior Fossa signs
      • Ataxia
      • Nystagmus
      • Apneic spells
      • Cranial nerve palsies
    • Hydrocephalus: Enlarged head
    • Encephalocele
    • Intellect
      • Learning difficulties
      • Mental retardation
    • Later features
      • Gait ataxia
      • Seizures
  • Pathology
    • Cerebellar vermis: Aplasia or Hypoplasia
    • 4th ventricle: Cystic dilation
    • Other: Some patients
      • ? Agenesis of foramina of Magendie and Luschka
      • Hydrocephalus
      • Absent corpus callosum
  • Heterogeneous features
    • Deletion of neighboring gene
      • Deletions including locus at 3q22.2: Co-deletion of FOXL2 gene
      • Blepharophimosis-Ptosis-Epicanthus inversus syndrome
    • Cardiac (Atrial septal defect)
    • Skeletal: Polydactyly
    • Renal-hepatic-pancreatic dysplasia
    • Craniosynostosis
    • X-linked inheritance
  • External link: Eponym information
  
  
• Dandy-Walker syndrome 2⁵¹
  l FOXC1 ; Chromosome 6p25.3; Familial or Sporadic
  • Genetics
    • Mutations: Deletions & Duplications at chromosome locus 6p25.3
    • Deletions involve FOXC1 plus at least two exons of GMDS
    • More severe syndrome including DWS
      • Large deletions involving at least seven genes (IRF4 to GMDS)
    • Duplications: Milder phenotype; Not complete Dandy-Walker
  • Foxc1 protein
    • Widely expressed in mesenchyme
    • Participates in a broad range of developmental processes
    • Influences proliferation & differentiation by regulating
      • Secreted signaling molecules: Bmp2, Bmp4, Cxcl12, Tgfb1
  • Clinical: See Dandy-Walker 3q24
  • Pathology
    • Cerebellar & Posterior fossa malformations
      • Cerebellar vermis hypoplasia
        • Mutation: Smaller deletions
        • Clinical: Milder syndrome
      • Megacisterna magna
      • Dandy-Walker malformation
        • Mutation: Larger deletions
        • Clinical: More severe syndrome
    • Corpus callosum: Short in some patients
    • Meningeal defects
    • Eye: Axenfeld-Rieger syndrome
  
  
• Carbohydrate deficient glycoprotein syndrome: Type 1a (CDG1A)
  l Type 1a: Phosphomannomutase 2 (PMM2) ; Chromosome 16p13.2-p13.12; Recessive
  • Neurological features: More prominent in older patients
    • Psychomotor retardation
      
    • Hypotonia
      
    • Truncal ataxia
      
    • Polyneuropathy: Demyelinating
  • Systemic features: Present during early onset period
    • Inverted nipples
    • Almond shaped eyes; Strabismus
    • Pigmentary retinal degeneration
    • Fusiform fingers
    • Prominent labia majora
    • Lipodystrophy: Buttocks
    • Cardiac: Hypertrophic cardiomyopathy; Pericardial effusion
    • Hepatic dysfunction
  • Laboratory
    • Serum: Reduced levels of
      • Glycoproteins
      • N-acetylglucosaminyltransferase
    • Glycoproteins: Reduced levels of
      • Sialic acid, galactose & N-acetylgalactosamine
  • Pathology
    • Severe cases with OPCA
    • Cerebellar hypoplasia
  • CDG: Other non-neurologic types
    • Type 1b: Phosphomannose isomerase-1
      • GI disorder with protein-losing enteropathy.
      • Thrombosis & life-threatening bleeding
      • Treatment: Oral mannose
    • Type 4
      • Clinical
        • Microcephaly; Seizures; High arched palate
      • Serum
        • Carbohydrate-deficient transferrin moderately elevated
          
          
• Cerebellar & Pancreatic Agenesis²⁴
  l Pancreas transcription factor 1, α-SUBUNIT (PTF1A) ; Chromosome 10p13-p12.1; Recessive
  • Epidemiology: Pakistani & Northern European families
  • Mutations: Truncation; 705insG, C866T
  • PTF1A protein
    • bHLH transcription factor
    • Expressed in developing pancreas & cerebellum
  • Onset: Congenital
  • Clinical
    • Diabetes: Neonatal
    • Growth retardation: Intrauterine, Severe
    • Dysmorphic face
      • Triangular
      • Small chin
      • Low set ears
    • Contractures: Flexion; Arms & Legs
    • Subcutaneous fat: Reduced
    • Respirations: Irregular
    • Optic nerve: Hypoplasia
    • Course: Early death
  • Laboratory
    • Hyperglycemia
    • Serum insulin & C-peptide: Very low
    • Brain imaging: Agenesis of cerebellum & vermis
    • Pancreas: Absent
  
  
• Cerebral palsy, Ataxic
  l Chromosome 9p12-q12; Recessive
  • Epidemiology: Asian family
  • Clinical
    • Cerebellar ataxia
      • Dysarthria
      • Dysdiadochokinesis
      • Horizontal nystagmus
      • Broad-based gait
    • Cerebral palsy
    • Spasticity: 25%
    • Intelligence: Normal
  
  
• Gillespie syndrome
  l Paired box gene 6 (PAX6); Chromosome 11p13; Sporadic or Dominant
  • Mutations
    • Heterozygous
    • Termination or Splice site
    • Also produce: Aniridia; Optic nerve hypoplasia; Coloboma
  • Clinical
    • Aniridia
      • Fixed dilated pupils
      • Pupil border of iris shows scalloped 'festooned' edge
    • Cerebellar ataxia
    • Hypotonia
    • Mental retardation
    • Face: Asymmetric; High forehead, Ptosis, Strabismus, Hypertelorism, Depressed nasal bridge
    • Course: Non-progressive
  • Pathology: Cerebellar hypoplasia
  
  
  
• Aprosencephaly and cerebellar dysgenesis
  • Aprosencephaly
  • Optic chiasm & Mesencephalon: Absent
  • Metencephalon: Poorly formed
  • Cerebellum: Severely dysplastic
    
    
• Cerebellotrigeminal Dermal Dysplasia (Gomez-Lopez-Hernandez syndrome)
    l Recessive or Sporadic
  • Skeletal
    • Craniosynostosis
    • Midface hypoplasia
    • Short stature
  • Face Corneal opacities Scalp alopecia Low-set ears
  • Neurologic
    • Ataxia
    • Trigeminal anesthesia
    • Mental retardation
  • CNS pathology
    • Brainstem anomaly: Rhombencephalosynapsis
      • Fusion of cerebellar hemispheres
      • Agenesis or hypogenesis of vermis
      • Fusion of dentate nuclei & superior cerebellar peduncles
  
  
• Behr syndrome
  l Autosomal recessive
  • ? Heterogeneous disorder
  • Visual
    • Optic atrophy: Bilateral
    • Visual field defects: Temporal; Incomplete
  • Ataxia
  • Spinal cord
    • Spastic gait
    • Sensory loss: Posterior column
  • Mental retardation
  • Wasting: Distal
  • Tendon reflexes: Reduced in some patients
  • Course: Early progression, then static
  
  
• Cerebellar ataxia 1 (CLA1; Norman; CPD III; SCAR2) : Also see Cerebellar hypoplasia
  l Chromosome 9q34-9qter; Recessive
  • Epidemiology: Lebanese family
  • Cerebellar ataxia: Non-progressive
  • Mental deficiency
  • Short stature
  • ± Albinism
  • 1° Granular cell atrophy of cerebellum
  
  
• Cerebellar ataxia 3 (CLA3; SCAR6)
  l Chromosome 20q11-q13; Recessive
  • Epidemiology: Norwegian family
  • Onset: Infancy
  • Clinical
    • Development
      • Delayed walking
      • Hypotonia
      • Clumsy movements
      • Slow speech development
    • Cerebellar ataxia
      • Non-progressive
      • Gait ataxia
      • Intention tremor
      • Nystagmus
    • Upper motor neuron
      • Tendon reflexes: Brisk
      • Spasticity: Mild; Occasional
    • Intellect: Normal
    • Skeletal
      • Short stature
      • Pes planus
  • Laboratory
    • CNS imaging: Cerebellar vermis atrophy
  
  
• Lissencephaly, familial, with Cleft palate & Cerebellar hypoplasia
  • Clinical
    • Onset: Prenatal growth retardation
    • Course: Death in 1st week
    • Cleft palate
  • Pathology
    • Lissencephaly (Smooth agyric appearance of brain)
    • Cerebral cortex: Thick; Disorganized
    • Cerebellar hypoplasia: Severe
  
  
• Lissencephaly, familial, with Cerebellar hypoplasia ⁷
  l RELN ; Chromosome 7q22; Recessive
  • Nosology: Norman-Roberts
  • Mutations: Splice site; Protein truncation
  • RELN protein
    • Large (338 kD) secreted protein
    • Function: Role in layering of neurons in cerebral cortex & cerebellum
    • Mechanism of action: Ligand for lipoprotein receptors VLDLR & ApoER2
  • Clinical
    • Hypotonia
    • Cognitive delay
    • Seizures
    • Ocular: Nystagmus; Myopia
    • Lymphedema: Congenital; May resolve over 1st 2 years
  • MRI
    • Lissencephaly: Moderate
    • Cerebellar hypoplasia: Severe
  • Mouse model: Reeler
  
  
• Cerebellar Hypoplasia with Cerebral Gyral Simplification
  l Very low density lipoprotein receptor (VLDLR) ; Chromosome 9p24; Recessive
  • Epidemiology: Hutterite population; Turkish family
  • Nosology
    • "Dysequilibrium syndrome"
    • Also see: Quadrupedal locomotion
  • Mutation: Homozygous deletion of 199,163 bp
  • VLDLR protein
    • Receptor for reelin
    • Reelin signaling pathway: Guides neuroblast migration in developing cerebral cortex & cerebellum
  • Clinical
    • Cerebellar ataxia
      • Especially truncal
      • Delayed ambulation
    • Mental retardation: Moderate to profound
    • Strabismus: Most patients
    • Pes planus: Most patients
    • Seizures: 40%
    • Short stature: 15%
    • Course: Nonprogressive
  • Pathology
    • Cerebellum: Inferior hypoplasia
    • Cerebrum: Mild gyral simplification
  
  
• Microcephaly with Polymicrogyria and Corpus callosum agenesis⁴³
  l Eomesodermin, Xenopus, homolog of (EOMES; TBR2) ; Chromosome 3p21.3-p21.2; Recessive
  • Epidemiology: Consanginous Moroccan family
  • Genetics: Mutation
    • Homozygous
    • Balanced translocation between chromosomes 3p and 10q: Silences EOMES transcript
  • EOMES protein
    • Involved in neuronal division and/or migration
    • Transcription factor
    • Member of T-box family
  • Clinical
    • Microcephaly: Prenatal-onset microcephaly
    • Motor delay with hypotonia: Severe
    • Early lethality in most: Death at 15–18 months of age due to respiratory distress after chronic infections
    • Surviving child: Persistent fever & recurrent infections
  • Laboratory: MRI
    • Corpus callosum agenesis
    • Polymicrogyria, bilateral
    • Ventricular dilatation
    • Cerebellum: Small

Ponto-Cerebellar Hypoplasia

• Pontocerebellar hypoplasia with progressive cerebral atrophy (PCH2) ⁴⁴
  • General features of PCH2
    • Progressive microcephaly from birth
    • Extrapyramidal dyskinesia: chorea
    • Epilepsy
  • Specific genetic syndromes
    • PCH2A
      l TSEN54 ; Chromosome 17q25.3; Recessive
      
    • PCH2B
      l TSEN2 ; Chromosome 3p25.2; Recessive
      
    • PCH2C
      l TSEN34 ; Chromosome 19q13.4; Recessive
      
  • Epidemiology
    • Multiple families
  • Genetics
    • Mutations
      • Homozygous or Heterozygous
      • Missense orStop
      • TSEN54: Ala307Ser, Q246X, Q343X & S93P; European
      • TSEN2: Tyr309Cys; Pakistani
      • TSEN34: Arg58Trp; Turkish
    • TSEN2 mutations also in: PCH4
  • TSEN54 protein
    • Part of tRNA splicing endonuclease complex
  • Onset
    • Congenital
    • Restlessnes
    • Poor sucking or swallowing
  • Clinical
    • Microcephaly: Progressive
    • Spastic paresis
    • Extrapyramidal dyskinesia: Severe
    • Failure to acquire voluntary skills
  • Laboratory
    • CNS imaging
      • Pontocerebellar hypoplasia: Pan-cerebellar; Ventral pons
      • Cerebral atrophy: Progressive
    • CNS pathology
      • Loss of neurons in olivopontoneocerebellar system
      • Short cerebellar folia with poor branching ("hypoplasia"): Sparing of the vermis
      • Sharply demarcated areas of full thickness loss of cerebellar cortex
      • Segmental loss of dentate nuclei with preserved islands & reactive changes
      • Segmental loss in the inferior olivary nucleus with reactive changes,
      • Loss of ventral pontine nuclei with near absence of transverse pontine fibers
      • Sparing of spinal anterior horn cells
  
  
• Pontocerebellar hypoplasia with progressive microcephaly (CLAM; PCH3)
  l Chromosome 7q11-q21; Recessive
  • Epidemiology
    • Omani family
  • Onset
    • Congenital
    • Microcephaly
    • Hyoptonia
  • Clinical
    • Craniofacial features
      • Head: Microcephaly; Brachycephaly
      • Prominent eyes
      • Low-set ears
    • CNS
      • Developmental delay: Severe
      • Seizures: 1st year
      • Hypotonia
      • Tendon reflexes: Brisk
      • Optic atrophy: 1 patient
      • No extrapyramidal features
  • Laboratory: CNS imaging
    • Brain stem: Small
    • Cerebellum: Atrophy of hemispheres & vermai, small cerebellar vermis
    • Cerebrum
      • Prominent sulci & lateral ventricles
      • Decreased cerebral white matter volume
  
  
• Pontocerebellar hypoplasia 6 (PCH6) ³⁷
  l Mitochondrial arginyl-tRNA synthetase (RARSL; RARS2) ; Chromosome 6; Recessive
  • Epidemiology: Sephardic-Jewish family
  • Mutation
    • Homozygous
    • Splice site, IVS2+5 a->g
    • Produces frame shift
  • Onset: Congenital
  • Clinical: Encephalopathy; CNS only
    • Hypotonia
    • Poor suck
    • Apneic episodes
    • Seizures
    • Microcephaly
    • Spasticity
  • Laboratory
    • Mitochondrial oxidative enzymes: Variable reduced activity of Complexes
      • I, III & IV, or Complex I or IV only
      • mtDNA levels: High
    • MRI: Progressive atrophy
      • Cerebellum
      • Pons
      • Cerebral cortex
      • White matter
    • EEG: Generalized epileptic activity
    • Lactate: High in serum or CSF
  • Other defect in mitochondrial tRNA(Arg)
    • mtDNA mutation: a->g mutation at position 10438
    • Onset: Childhood; 8 years
    • Progressive encephalopathy
      • Mental retardation: Moderate
      • Nystagmus
      • Delayed dysarthric speech
      • Clumsiness
  
  
• Pontocerebellar hypoplasia (PCH): Other recessive syndromes
  • PCH4 : Fatal infantile with relative preservation of vermis & cerebellar foliation abnormalities
    l TSEN2 ; Chromosome 3p25.2; Recessive
    
    • Epidemiology: 1 Hispanic family, 3 siblings
    • Allelic with: PCH2B
    • Clinical
      • Onset: Neonatal
      • Microcephaly
      • Myoclonus
      • Hypertonia
    • Pathology: Neuronal loss in inferior olives & pontine nuclei
  • PCH5 : Hypocellular vermis & fetal seizures
    • Epidemiology: 1 family, 3 siblings
    • Clinical
      • Onset: Fetal
      • Fetal seizures
      • Death: Before birth, 3rd trimester
    • Pathology: Diffuse CNS volume loss, Most prominent in cerebellum & brain stem
  • PCH associated with other syndromes
    • Congenital muscular dystrophies
    • Lissencephaly
    • Chromosomal abnormalities
    • Defects in glycosylation of proteins

• Congenital X-linked ataxia
  l Chromosome Xq23
  • Clinical
    • Ataxia: Walking at ages 1 to 7
    • Dysarthria & delayed speech
    • External Ophthalmoplegia
    • Tendon reflexes: Brisk
    • No mental retardation, spasticity or sensory loss
  • Course: Non-progressive beyond childhood
  • Pathology: Hypoplasia of cerebellar hemispheres & vermis
  
  
• Congenital X-linked ataxia (SCAX1)⁴
  l Chromosome Xp11.21-q21.3; Recessive
  • Clinical
    • Onset: Birth
    • Hypotonia
    • Motor delay
    • Ocular: Slow eye movements
    • Cerebellar ataxia: Non-progressive
    • Cognitive: Normal or Mild delay
  • MRI: Normal early; Cerebellar atrophy by age 3
  
  
• Congenital ataxia with extrapyramidal involvement (SCAX2)
  l Chromosome X; Recessive
  • Epidemiology: Single family
  • Early onset
  • Clinical
    • Ataxia
    • Spasticity
    • Rigidity
    • Early death
  • Cerebellar atrophy: Purkinje cells absent
  
  
• Ataxia-Deafness syndrome (SCAX3)
  l Chromosome X; Recessive
  • Clinical
    • Onset: Infancy
    • Hypotonia
    • Ataxia
    • Deafness: Sensorineural
    • Developmental delay
    • Ocular: Esotropia; Optic atrophy
    • Course: Progressive; Death in childhood
  • Heterozygous females: May have episodes of ataxia
  • Pathology
    • Neuron loss & gliosis of the dentate nucleus & inferior olive
    • Red nucleus, Dorsal motor nucleus of the vagus & Central auditory pathways severely affected
  
  
• Congenital ataxia with severe mental retardation⁵
  l Chromosome Xq24-q27.3; Recessive
  • Mental retardation
  • Epilepsy
  • Ophthalmoplegia
  • Craniofacial dysmorphology
  • Cerebellar atrophy
  
  
• Hoyeraal-Hreidarsson Syndrome
  l Dyskerin (DKC1); Chromosome Xq28; Recessive
  • Neural
    • Cerebellar hypoplasia: Reduced cellularity of molecular and granular layers
    • Microcephaly
  • Pancytopenia: Onset 5 months; Progressive for years
  • Dyskeratosis congenita
  • Growth retardation
  
  
• Mental retardation with epilepsy, rostral ventricular enlargement¹⁷
  l Oligophrenin 1 (OPHN1) ; Chromosome Xq12; Recessive
  • Epidemiology
    • Mental retardation + Cerebellar anomalies: 12% of families
    • X-linked mental retardation: 1% of families
  • Genetics: Loss of function mutations
    • Chromosomal rearrangement: Females
    • Deletions: Large or Small; Frameshift
    • Some deletions possibly Alu-repeat mediated
  • Oligophrenin protein
    • Rho-GTPase activating protein
    • Expressed in neuronal & glial cells
    • Directly interacts with F-actin filaments
    • Regulates cytoskeletal dynamics through Rho-GTPase modulation
    • Specifically involved in dendritic spine morphogenesis
  • Clinical
    • Variability: Intrafamilial & Interfamilial
    • Mental retardation
      • Moderate to Severe
      • May be only feature with some oligophrenin 1 mutations
    • Epilepsy: Generalized
      • Myoclonic jerks & absences in 1st year
      • 6 years: Generalized tonic-clonic seizures
    • Motor
      • Hypotonia (Neonatal)
      • Delay
    • Cerebellar
      • Dysmetria
      • Adiadocokinesia
      • Oculomotor: Nystagmus, Strabismus, External ophthalmoplegia
      • Gait ataxia: Uncommon
      • Intention tremor
    • Eye
      • Strabismus
      • Reduced acuity due to refractive errors
      • Deep set
    • Skeletal
      • Facial dysmorphism
        • Prominent chin
        • Hypotelorism
        • Deep-set eyes
        • Prominent supraorbital ridges
        • Long tubular nose
        • Short philtrum
        • Thin upper lip
      • Macrocephaly
      • Large stature
    • Male hypogenitalism: Hypoplastic scrotum; Microphallus
  • CNS pathology
    • Ventriculomegaly: Lateral
    • Cerebellar hypoplasia: Vermian; Lacking folia; Asymmetric
    • Caudate nucleus head: Hypoplasia
    • No progression
  • Laboratory
    • EMG & NCV: Normal
    • Blood chemistries: Normal
  • Female cariers: Strabismus; Learning difficulties
  
  
• Cataracts, ataxia, short stature & mental retardation (CASM) ³¹
    l Chromosome Xpter-q13.1; Semi-Dominant
  
  • Epidemiology: Chinese family
  • Onset: Birth
  • Clinical
    • Cataracts
      • Whole lens opacities
      • Congenital
    • Short stature: Less than 5th percentile
    • Mental retardation: Mild to Moderate
    • Hypotonia
    • Ataxia
      • Distribution: Limbs & Trunk
      • Dysarthria
      • Gait ataxia: Limited or no walking
  • Female heterozygotes: Congenital cataracts
  
  
• X-linked congenital ataxia (SCAX5) ³⁸
    l Chromosome Xq25-q27.1; Recessive
  
  • Epidemiology: American family of Norwegian descent
  • Onset: Neonatal
  • Clinical
    • Hypotonia: Severe neonatal
    • Motor development: Delayed early
    • Eye movements: Slow
    • Ataxia
      • Tremor
      • Nystagmus
      • Dysarthria: 1st year of life
      • Non-progressive: Symptoms improve wtih age
      • Walking without support
    • Intelligence: Normal/Borderline
  • Laboratory
    • MRI: Cerebellar hypoplasia, global
  
  
• X-linked mental retardation with short stature, small testes, muscle wasting & tremor
    l Cullin 4B (CUL4B) ; Chromosome Xq23; Recessive
  
  • Nosology: Cabezas syndrome
  • Mutations: Missense, Truncating & Stop
  • CUL4B protein
    • Ubiquitin ligase (E3) subunit
    • Restricts DNA replication licensing: Prevents aberrant reinitiation of DNA replication
    • Facilitates degradation of CDT1
    • Pathway in which fat-soluble ligands regulate target protein-selective degradation
    • Cullin proteins: Function
      • Scaffold proteins for series of ubiquitin-protein ligase complexes that regulate protein degradation
  • Clinical
    • Birth weight: Low
    • CNS
      • Low IQ (range 29–54)
      • Speech: Impaired or absent
      • Attention span: Decreased
      • Hyperactivity
      • Mood swings
      • Aggressive behaviour
      • Seizures
    • Skeletal
      • Short stature (<10%)
      • Head circumference: Large
      • High palate
      • Feet: Small; Pes cavus
      • Hyperextensible joints
      • Kyphosis
    • Morphology
      • Obesity: Truncal
      • Lower lip: Prominent
      • Gap between 1 & 2 toes
    • Motor
      • Fine tremor: Increased with motor activity
      • Muscle wasting: Lower leg
      • Gait: Wide based
      • Fine motor coordination: Decreased
    • Endocrine
      • Hypogonadism: Testes (<10%)
      • Gynecomastia
      • Pituitary: Normal
• X-linked brain malformation phenotype with microcephaly ⁴²
    l Calcium/calmodulin-dependent serine protein kinase (CASK) ; Chromosome Xp11.4; Recessive
  
  • Genetics: Mutations
    • Heterozygous
    • Loss of function
  • CASK protein
    • Membrane-associated guanylate kinase (MAGUK) family
    • Family properties
      • Target to neuronal synapses
      • Regulate trafficking, targeting & signaling of ion channels
    • CASK
      • ‘Pseudokinase’
      • Functions as part of large signaling complexes in both pre- & postsynaptic sites
      • Translocates to nucleus
        • Interacts with brainspecific T-box family member TBR1
        • Regulates gene expression
  • Clinical
    • Microcephaly: Congenital; Severe
    • Mental retardation
    • Hearing loss: Sensorineural
  • Laboratory
    • Brain MRI: Reduced number & complexity of gyri; Thin brainstem; Cerebellar hypoplasia
    • Pathology: Abnormal cerebellar & cortical layering

• Also see: Congenital ataxia
  
  
• Sideroblastic anemia & Spinocerebellar ataxia (XLSA/A)
    l ATP-binding cassette 7 (ABCB7; ABC7) transporter ; Chromosome Xq13
  • ABC7 transporter
    • ABC family: Mediate ATP-dependent transfer of solutes
    • Structure
      • 2 Transmembrane domains: Form pore in membrane & Determine substrate specificity
      • 2 Cytosolic ATP-binding domains: Couple ATP binding to solute movement
    • Localization: Mitochondrial inner membrane
    • Function: Iron homeostasis; Export from matrix to the intermembrane space
    • Other ABC genes mutated in adrenoleukodystrophy, cystic fibrosis,
    • Friedreich's ataxia also related to disordered iron homeostasis
  • Neurologic features
    • Ataxia: Onset @ 1 year; Non-progressive
    • Long-tract signs: Hyperreflexia, Babinski
  • Hematologic features
    • Anemia: Mild not requiring transfusion
    • Elevated free erythrocyte protoporphyrin levels
    • No excessive parenchymal iron deposition
    • Ring sideroblasts in bone marrow
  • Heterozygous females: May have mild anemia, but not ataxia
  
  
• Arts syndrome
    l Phosphoribosylpyrophosphate synthetase 1 (PRPS1) ; Chromosome Xq22.3
  
  • Genetics
    • Mutations: Missense; Gln133Pro, Leu152Pro
    • Allelic with
      • CMT X5
      • Hyperuricemia, Mental retardation & Sensorineural deafness with PRPS1 superactivity
  • PRPS1 protein: Mutations
    • Loss of function
    • May cause impaired purine biosynthesis
  • Onset: Early childhood
  • Clinical
    • Motor
      • Hypotonia: Early-onset
      • Flaccid tetraplegia & Areflexia: Late
    • Ataxia
    • Liability to infections: Especially URI
    • Deafness
    • Prognosis: Most with death < 5 years
  • Laboratory
    • Hypoxanthine: Undetectable in urine
    • Pathology: Loss of myelinated axons in spinal cord posterior columns
  • Female carriers: Hearing impairment in early adulthood
  
  
• Ataxia with Tremor & Cognitive decline (FXTAS) ¹⁴
    l Fragile X mental retardation gene (FMR1) ; Chromosome Xq27.3
  
  • Genetics: Mutations in FMR1 gene
    • CGG expansions: Mean 84; Range 69 to 135 repeats
    • "Premutation allele"
    • Frequency in population: 1 in 259 females; 1 in 813 males
    • FMR1 mRNA: Elevated 4x; ? Gain of function mutation from elevated message levels
    • Allelic with: Fragile X mental retardation syndrome with > 200 CGG repeats
  • FMR1 protein
    • Location: Dendrites
    • Disease
      • Levels: Low-normal or mildly decreased
      • Result: Reduced AMPA receptor levels (Increased internalization)
  • Family history
    • Positive for adult CNS syndrome in 40%
    • Commonly postive for fragile X syndrome
    • Penetrance: Probably higher with increasing age
  • Onset
    • Males > 50 years
    • Tremor: Most common
    • Executive function defects
  • Clinical
    • CNS
      • Cerebellar
        • Intention tremor: Action (70%) > Rest (10%); 3 to 5 Hz; May be asymmetric; Progressive
        • Ataxia: Dysarthria; Legs; Postural & Gait disorder; Dysmetria
        • Nystagmus
      • Cognitive: Decline; Reduced short-term memory
      • Psychiatric: Mood lability; Anxiety; Reclusive behavior
      • Parkinsonism: Mild; Bradykinesia & Rigidity
      • Pyramidal signs: Brisk tendon reflexes; Upgoing toes
    • PNS: Polyneuropathy (60%)⁴⁰
      • Genetics: More prominent with longer mutation repeat length
      • Onset age: Late adulthood; 6th & 7th decade
      • Clinical
        • Sensory Loss: Vibration & Pin; Feet
        • Autonomic: Impotence (80%); Urinary (55%); Bowel incontinence (30%); Syncope
        • Tendon reflexes: Reduced distally
      • NCV
        • CMAP amplitudes: Small
        • Velocity: Mildly slowed
        • Sensory: SNAP amplitudes small
      • Pathology: Intranuclear inclusions
        • Location: Sensory & Autonomic ganglion cells
        • Similar to: Neuronal intranuclear hyaline inclusion disease (NIHID)
        • May contain: Lamin A/C; Expanded-repeat FMR1 mRNA
    • Weakness (30%): Proximal legs
    • Other: Heart disease (50%)
    • Course
      • Progressive over decades
      • May be more rapid after general anesthesia
      • Death: Related to age at onset; Congestive heart failure
  • Laboratory
    • Nerve conduction velocities: Mildly reduced
    • MRI
      • T2 signal intensity increased in middle cerebellar peduncles & adjacent cerebellar white matter
      • Symmetrical
  • CNS pathology¹⁴
    • Brain atrophy: Generalized
    • Cerebellum: Purkinje cell loss & torpedoes
    • Inclusions
      • Eosinophilic
      • Intranuclear
      • Neurons & Astrocytes: Especially in hippocampus
      • Stain for ubiquitin
  • Differential diagnosis: Multiple system atrophy
  • Female carriers: Premature menopause in 20% of carriers of premutation expansions
  
  
• Ataxia-Dementia (SCAX4)
  • Epidemiology: One family
  • Onset
    • Age: 2 to 3 years
    • Delayed walking
    • Tremor
  • Clinical
    • Ataxia: Progressive
    • Pyramidal tract signs
    • Dementia: Adult onset; Memory problems
    • Death: 6th decade
  
  
• Mental Retardation, Microcephaly, Epilepsy & Ataxia (Angelman-like Syndrome)
    l Solute carrier family 9, isoform A6 (SLC9A6) ; Chromosome Xq24-q27.3
  
  • Genetics
    • Mutations: Deletion; Stop; Splice site
  • SLC9A6 protein
    • Na⁺/H⁺ exchanger NHE6
    • Wide tissue expression
  • Clinical
    • Neonatal period: Normal
    • Head
      • Microcephaly
      • Slow growth
    • Epilepsy
      • Onset age: 9 to 26 months
      • Multiple types
    • Ataxia: Unsteady gait
    • Mental retardation
      • Severe
      • Delayed development
      • Absent speech
      • Episodes of unprovoked laughter
    • Pyramidal signs: Some patients
      • Tendon reflexes: Brisk
      • Plantar reflex: Extensor
    • Hyperkinetic movements
    • Gastrointestinal
      • Mouth: Open; Profuse drooling
      • Swallowing difficulties
      • Frequent regurgitation: Due to gastroesophageal reflux
    • Morphology: Thin
  • Laboratory
    • EEG: Epileptiform activity; Fast background rhythm
    • MRI: Cerebellar atrophy, progressive
  
  
• Pyruvate dehydrogenase: Episodic ataxia
  
  
• Pelizaeus-Merzbacher allelic variant: PLP null syndrome
  
  
• X-linked congenital ataxia

• Enzyme defects
  • Cerebrotendinous xanthomatosis
  • Copper enzyme disorders
    • Wilson's disease
    • Menkes syndrome : Cu⁺⁺-transporting ATPase, α polypeptide
      • Mental retardation; Spastic diplegia; Ataxia; Short stature; Kinky hair
    • Aceruloplasminemia
  • Hexosaminidase deficiency
  • Hypoxanthine guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome)
    • Partial enzyme deficiency
    • Also see: Atlanto-axial dislocation
  • Metachromatic Leukodystrophy
  • Pyruvate metabolic disorders
  • ? Carnitine Acetyltransferase: Episodic ataxia in 1 child
  
  
• Mitochondrial syndromes
  • NARP
  • Leber's
  
  
• Ataxia + Hypogonadism
  • Hypogonadotropic hypogonadism¹⁵
    • Onset: Childhood to 4th decade
    • Ataxia
      • Dysarthria
      • Gait imbalance
      • Appendicular ataxia
    • Dementia: May be severe
    • Other CNS: Occasional
      • Mental retardation
      • Reduced smell
      • Sensorineural deafness
    • Hypogonadotrophic hypogonadism
      • Small testes
      • Laboratory: Low sex steroid levels; Inappropriately low gonadotropin levels
      • Primary pituitary or hypothalamic defects in different families
      • Treatment: Hormonal replacement
    • Chorioretinal dystrophy: Boucher-Neuhauser
    • Brain MRI: Brain atrophy, especially cerebellar hemipheres
    
    
  • Cerebellar ataxia & Hypergonadotropic hypogonadism ³⁵
    l Recessive
    • Onset: Adult (3rd decade)
    • Clincial: Progressive
      • Ataxia: Dysarthria; Wide-based gait; Nystagmus or mild saccade disorders
      • ENT
        • Deafness: Sensorineural hearing loss
        • Vestibular hypofunction
      • Intellectual impairment
      • Neuropathy: Pansensory loss, Distal, Symmetric
      • Hypogonadism: Primary amenorrhoea in females
    • Laboratory
      • MRI: Cerebellar atrophy, Hemispheres & Vermis
      • Gonadotropins: Post-menopausal range
      • Muscle: Coenzyme Q10 deficiency
    
    
  • Cerebellar ataxia & Hypergonadotropic hypogonadism: Childhood onset
    • ? Several syndromes
      • Partial deficiency of cytochrome c oxidase in 1 family
    • Ataxia
    • Mental retardation
    • Abnormal puberty
  • Marinesco-Sjögren
  • Ataxia with muscle CoQ10 deficiency
  • Mitochondrial, multiple mtDNA deletions: With choroidal dystrophy & Complex I deficiency
  
  
• Multisystem disorders: Other
  • Hypomyelinating leukodystrophy (HLD7) with ataxia and hypodontia
    • Epidemiology: > 10 sporadic patients identified
    • Clinical
      • Onset age: < 5 years
      • Ataxia
        • Tremor
        • Dysarthria
        • Hypometric saccades
        • Course: Progressive
      • Pyramidal signs: Spasticity; Variable
      • Cognitive dysfunction: Mild
      • Teeth
        • Delayed dentition
        • Abnormal order of tooth eruption
    • MRI
      • Hypomyelination: Supratentorial white matter; Thin corpus callosum
      • Cerebellar atrophy
    • Sural nerve biopsy
      • Granular debris-lined clefts
      • Expanded abaxonal space
      • Vacuolar disruption & loss of normal myelin periodicity
  • Absence of tibia, Polydactyly, Retrocerebellar arachnoid cyst (congenital)
  • Cerebello-trigeminal-dermal dysplasia :
    • Craniosynostosis; Midface hypoplasia; Low-set ears; Short stature
    • Ataxia
    • Other CNS: Trigeminal anesthesia: Mental retardation
    • Scalp alopecia; Corneal opacities
  • Giant axonal neuropathy
  • Posterior column ataxia & Retinitis pigmentosa (AXPC1)
    
  
  
• Storage disorders
  • Ceroid lipofuscinosis : Palmitoyl-protein thioesterase
  • Refsum
  • Sialidosis : Sialidase
  • Sphingomyelin storage

• Reeler