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HEREDITARY ATAXIA: RECESSIVE, CONGENITAL & X-LINKED ¹⁰⁶

RECESSIVE ATAXIAS

Friedreich Ataxia ²

Frataxin protein Genetic features Neurological features Pathology Systemic features Variant syndromes

From Bramwell: Atlas of Clinical Medicine Friedreich Ataxia

From Wikipedia

• Epidemiology
  • Western Europeans
    • Incidence: 1 in 20,000 to 125,000
    • Carrier frequency: 1 in 60 to 110
    • 75% of hereditary ataxia with onset < 25 years
    • GAA expansion appears only in: European, North African, Middle-Eastern or Indian individuals
  • Male = Female
  • Not found in: Far East; Sub-Saharan Africans; Native Americans & Australians
• 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 repeat numbers & variations
      • Usual character: Perfect repeats
      • Normal 6 to 33: Bimodal
        • < 12 repeats (80% to 85%)
        • 12 to 33 repeats (17%)
      • Mutable alleles: 34-65 GAA repeats
        • Premutation
        • Unstable
        • Frequency: < 1%
        • Clinical
          • 34 to 43 repeats: Normal
          • 44 to 66 repeats: Possible clinical disease
      • Friedreich ataxia
        • Range: 66 to 1,700
        • Penetrance: Usual
        • Most commonly: 600 to 1,200 repeats
      • Other variant: "Interrupted FXN alleles"
        • GAA repeats not in perfect tandem order
        • Repeats interrupted by other nucleotides
        • Location: Usually close to 3’ end of GAA repeats
        • May be pathogenic & associated with clinical disease
    • 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
      • No return to normal size of repeat
    • Expanded GAA repeats: Suppress FRDA (Frataxin) gene expression
      • Block or inhibit 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
        • Increased 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
          • Increased formation of RNA/DNA hybrids (R-loops): Impairs gene transcription
      • Residual FRDA (Frataxin)
        • Amount
          • mRNA & FRDA protein levels inversely proportional to GAA expansion size ⁸⁸
          • Some residual FRDA (Frataxin) probably expressed in all patients
        • No homozygous null mutations identified: ? Complete loss of FRDA (Frataxin) is lethal
  • Point mutations
    • Frequency: 4% to 6% of FA patients
    • > 20 different point mutations described
    • Truncating mutations: Usually in exon 1
    • Missense mutations
      • Locations
        • Residues conserved with homologous yeast protein
        • Usually in last 3 exons coding for FRDA (Frataxin) gene
      • Common point missense mutations: Ile154Phe (Southern Italy); M1I; G130V
      • Missense mutation: Examples & Features
        • Exon 3 Stop
        • G130V: Mild disease with slow progression; Same age of onset
        • 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
      • Mutations on 2nd gene
        • Point mutations usually heterozygous with GAA repeat gene
        • Homozygous point mutations
          • Rare
          • Arg165Cys: Normal frataxin levels in skin
  • 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
          • No relation to diabetes
      • Correlation with length of longer allele: When less than 800 repeats ¹⁸
      • Mean GAA allele length higher with: Diabetes; Cardiomyopathy; Scoliosis
      • Other associations with longer repeat length: Optic atrophy; Hearing loss
      • Acadians: Milder phenotype
    • 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
    • GAA expansion + FXN exon deletion ⁶⁷
      • Frequency: 1% of FA patients
      • Disease onset: Earlier; Mean 7 years; Range 3 to 12 years
      • Wheelchair: Time to connfinement shorter (9 years); Age lower (20 years)
      • Probably more common: Cardiomyopathy; Scoliosis; Diabetes mellitus; Ileus
    • Heterozygous carriers
      • Produce reduced amounts of frataxin
      • Clinical: Unaffected
    • Pseudo-dominant inheritance in families with ¹³⁸
      • Regions with high frequency of carriers
      • Consanguinity
    • Milder disease with mitochondrial haplotype U: Less cardiomyopathy
  • Allelic disorders: Late-onset ataxia syndrome
• 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
      • Ferritin-like protein: Minor function
      • Disruption in yeast causes
        • Multiple Fe-S-dependent enzyme deficiencies
          • Aconitase
          • Complexes I to III
        • 10x elevated mitochondrial iron content
      • Chaperone
  • Expression
    • Location: All tissues
    • Mutations
      • GAA expansion in intron
        • Reduced expression of normal protein: Less with longer repeats
      • Residual levels: Needed for survival
    • Dyclonine: May increase tissue FRDA expression when mutation present
  • 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
• Neurological Features: Typical syndrome
  • Onset
    • Age
      • Range: 2 to > 70 years
      • Usually: < 20 years, around puberty; Late 1st decade or Early 2nd decade
      • May vary among siblings
      • Early onset with rapid progression
      • Late-onset FA (LOFA): > 25 years
      • Very LOFA (vLOFA): > 40 years
    • Ataxia: Gait instability
    • Scoliosis
  • 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 Course: Progressive with increasing age Sensory loss (~80%) Vibration & Joint position: Prominent loss Light touch & Pin: Also reduced Autonomic Cold, cyanotic uncomfortable legs & feet: Late in course Sphincters normal Motor Weakness (67% to 88%) Lower extremities May be in "pyramidal" distribution Muscle wasting: Small muscles in hands & feet Tendon reflexes: Absent (75%) or reduced Corticospinal tract signs Extensor plantar responses (80%) Spasticity: Intermediate number of repeats Optic atrophy (30%) May be no visual impairment Visual acuity reduced in 13% Visual evoked potentials: Often abnormal Chorea: Occasional patient may have chorea without ataxia Hearing loss: Sensorineural (13% to 20%) 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

    Course Slow progression Time to wheel chair: Mean 10 to 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 Total number of axons: Near normal; Preserved small axons Axonal atrophy Schwann cells S100α: Few immunoreactive cells Laminin-2: Abnormal distribution 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

    From Bramwell: Atlas of Clinical Medicine Friedreich Ataxia Spinal cord

  • 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%) Echocardiography Concentric hypertrophy of ventricles Asymmetric septal hypertrophy Treatment Idebenone 5-10 mg/kg/day at onset of hypertrophic cardiomyopathy 13 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 Symptoms: Up to 80% Clinically significant: 22% Anesthesia: ? Avoid depolarizing NM blocking agents 27

  Gowers

• Friedreich ataxia: Variant neurological syndromes
  • Late onset Friedreich ataxia syndrome (LOFA) ⁹⁰
    • Genetics
      • Frataxin: Shorter GAA expansion on smaller allele
    • Clinical
      • Onset: May be as late as 50 to 70 years
      • All patients
        • Ataxia: Gait & Limb
      • Some late onset patients
        • Normal reflexes
        • Predominantly spastic paraparesis or tetraparesis
      • Less frequent
        • Dysarthria
        • Skeletal deformities
        • Absent reflexes
        • Scoliosis
        • Cardiomyopathy
      • Course: Slower progression
    • MRI: Cerebellar atrophy in 50%
  • 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
        • Missense mutation in carboxy half of FRDA: 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

• Epidemiology: > 100 patients
• Mutations: > 20 reported
  • Regional distribution
    • North Africa & Mediterranean: 744delA
    • Europe: 513insTT, 486delT & arg134 to ter
  • Frame shift deletions common
  • Missense: Milder disease; T303G in Japan
• ATTP protein
  • Carrier of RRR-α-tocopherol (primary vitamin E isomer in plasma)
  • Incorporates α-tocopherol into lipoproteins secreted by liver
  • TTPA mutatioins: Impair hepatic incorporation of α-tocopherol in very low density lipoprotein
• Clinical
  • Neurologic: Phenotype similar to Friedreich ataxia
    • Onset
      • Age
        • Childhood
          • Mutations: Frame shift
          • Mean 13 years
          • Range 2 to 37 years
        • Middle-age: Missense mutation (His101Glu; T303G); Up to 59 years
      • Gait disorder
    • Sensory loss (67%): Large fiber modalities
    • Ataxia: Progressive
      • Gait
      • Limb: Legs > Arms
      • Dysarthria
      • Nystagmus (10%)
    • Pyramidal syndrome
      • Extensor plantar response
      • Gait: Spastic
    • Other CNS
      • Head titubation 28%
      • Dystonia 13%
      • Deafness
      • Bladder dysfunction: Urgency
      • Visual loss: Retinitis pigmentosa (especially Japanese)
    • PNS
      • Polyneuropathy (50%): Sensory-Motor
      • Leg amyotrophy (10%): Distal
      • Tendon reflexes: Absent at ankle & knee
    • Course: Wheelchair age 22 to 32 yers
  • Skin: Xanthelasmata; Tendon xanthomas
  • Skeletal (50%)
    • Pes cavus
    • Hammer toes
    • Kyphoscoliosis
  • Retinitis pigmentosa: Some patients
    • Ring scotoma
    • Electroretinography: No light-evoked electrical responses
  • Treatment: Vitamin E supplementation (800mg/day) & High fat diet
• Laboratory
  • Vitamin E, Serum: Very low (<2.5 mg/ml) with normal serum vitamin A
  • Cholesterol & triglycerides: High
  • Electrodiagnostic
    • SNAPs & CMAPs: Some reduced amplitudes; May be only sensory or motor
    • NCV normal in few patients (9%)
  • Muscle biopsy: Fiber type grouping
  • Nerve biopsy: Mild loss of myelinated axons
  • Brain MRI: Often normal; Occasional atrophy
• Heterozygotes: No clinical signs but low serum vitamin E

• Epidemiology: Finnish families higher frequency, Korean, English, Turkish
• Genetics
  • Finnish patients: Homozygous for Tyr508Cys missense mutation
  • Other mutations: Varied locations
    • P83S/R463W; Y508C/A318T; Y508C/R29X; T451I/T451I; c.1460C>T (T487I)/c.1485-1G>A (Splice)
    • Silent 1472C->T coding region transition reduces production of Twinkle protein
  • Allelic disorders
• Clinical
  • Neurologic
    • Onset age: 8 months to 2 years
    • Early
      • Ataxia
      • Athetosis
      • Tendon reflexes: Reduced
    • Later
      • CNS
        • Ophthalmoplegia: Some patients
        • Hearing loss
        • Seizures
        • Mental capacity: Reduced
      • Polyneuropathy
        • Sensory loss: Large fiber modalities
        • Motor: Distal weakness & Atrophy
        • Progressive
        • Electrophysiology: SNAP amplitudes reduced
        • Nerve pathology
          • Axon loss: Large myelinated, Sensory > Motor
          • Axon regeneration
          • Onion bulbs: Occasional
    • Prognosis
      • Course: Progressive
      • Wheelchair by teens
      • Early death: Related to seizure disorder
  • Systemic
    • Female primary hypogonadism: Hypogonadotrophic
    • No cardiac pathology
• Laboratory
  • Blood lactate: May be mildly high or normal
  • Serum CK: Normal
  • Mitochondria
    • Normal enzyme activity
    • mtDNA: No deletions or depletion
  • Muscle
    • Fiber size: Varied, Small angular
    • Fiber type grouping
    • SDH & COX staining: Normal
    • Ultrastructure: Mitochondrial morphology abnormal
  • MRI
    • Middle cerebellar peduncles: High-signal lesions in more severe disease
  • CNS Pathology
    • Atrophy of cerebellum, brainstem & spinal cord
    • mtDNA depletion in brain & liver
    • Respiratory chain complex I & IV deficiency

• Epidemiology: Pakistani & Egyptian families
• Genetics
  • Mutations: Truncating; Thr955Serfs*120, Cys627Ter
  • Allelic with: SCA5, Dominant
• SPTBN2 protein
  • Spectrins & Spectrin disorders
• Clinical
  • Onset age: Early childhood
  • Cognition
    • Psychomotor delay
    • Impairment
  • Cerebellar
    • Gait: Wide based
    • Dysmetria & Tremor
    • Eye: Saccades, Hypometric; Nystagmus
  • Upper motor neuron
    • Tendon reflexes: Increased
    • Plantar response: Extensor
    • Muscle tone: Spastic
  • Sensation: Normal
  • Course: Non-progressive
• Laboratory
  • Brain MRI: Cerebellar atrophy; Corpus callosum hypoplasia (1 patient)
• Also see: Spastic ataxias

• Epidemiology: Common in Finland
• Genetics
  • 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
  • Missense & nonsense point mutations: Occasional
• CSTB protein: Cysteine protease inhibitor
• Clinical
  • Onset age: 6 to 20 years
  • Myoclonus: Epilepsy; Action
  • Ataxia: Late in disease course
  • Seizures: Absence
  • Course
    • Death 25 to 35 years
    • Slower than Lafora disease
  • Treatment: Valproic Acid; Clonazepam; Phenobarbital
• Laboratory
  • EEG: Polyspike on photic stimulation

• Epidemiology: 1 patient
• Genetics
  • Mutations: R84W missense & Exon deletion
  • Allelic disorder: Progressive Myoclonic Epilepsy 3 (EPM3)
• KCTD7 protein
• Clinical
  • Onset age: 5 months
  • Ataxia: Gait disorder; Dysmetria
  • Opsoclonus
  • Myoclonus: Multifocal; Minipolymyoclonus
  • Tendon reflexes: Brisk
  • Motor: Strength normal; Tone reduced
  • Seizures: Myoclonic
  • Cognitive: Speech delay
  • Symptoms may show partial improvement with corticosteroid treatment
• Laboratory
  • CSF: Increased B- & atypical T-cells
  • EEG: Spike & Wave

• Epidemiology: Middle-Eastern families
• Genetics
  • Mutations: 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

• Genetics ³⁰
  • 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
    • Other endoplasmic reticulum disorders
• Clinical
  • Onset: Infancy
  • CNS
    • Cerebellar dysfunction
      • Dysarthria
      • Nystagmus
      • Ataxia
      • Cerebellar cortical atrophy: Vacuolated or binucleated Purkinje cells
    • Developmental delay: Retarded motor & mental maturation
  • Muscle
    • Rhabdomyolysis: After viral infections
    • Weakness: Progressive; Some with childhood onset
    • Hypotonia
  • 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
• Muscle
  • 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
• 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

Charlevoix-Saguenay - Spastic Ataxia (ARSACS; SPAX 6) 152   ● Sacsin (SACS; DNAJC29) ; Chromosome 13q12.12; Recessive Epidemiology Family locations: French-Canadian (Quebec); Tunisia 3 Worldwide: Frequent recessive ataxia Genetics Mutations > 200 Loss of function Common location: Exon 10 (80%) Deletions or point mutations in sacsin gene Produce stop codon Most common French-Canadian: c.6594delT (94%) Missense mutations & large deletions also described Similar locus to Early onset cerebellar ataxia + retained reflexes Tunisian family with milder phenotype 3 Variant syndromes Sacsin protein Expressed in fibroblasts, brain, skeletal muscle Subcellular Most: Cytoplasmic Also: Mitochondria; Nuclear Cellular: Large neurons Interacts with: Dynamin-related protein 1; HSP70; Proteasome Function: Chaperone-mediated protein folding Clinical 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; Falling Neurologic Cerebellar Ataxia: Dysarthria; Gait disorder; Appendicular Ocular: Nystagmus (100%); Poor ocular pursuit Eye EOM Conjugate gaze defects Supranuclear upgaze paresis Saccadic pursuit Retina Nerve fiber layer & Macula: Thick Peripapillary, striated Spasticity Paraparesis with gait disorder: Most patients Early in disease course Extensor plantar responses Progressive No spasticity: Homozygous Phe304Ser mutation Polyneuropathy Wasting & Weakness (Amyotrophy) Distal Legs > Arms More apparent in older patients Sensory: Loss of deep sensations Tendon reflexes: Brisk except at ankles Bladder: Urgency in 65% Dystonia: Mild; Occasional Intellectual disability (50%): Adults Epilepsy (9%) Hearing loss: With macrodeletion 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 Distal latencies: May be prolonged EMG: Denervation of distal muscles Sensory evoked potentials: Abnormal Nerve pathology Large myelinated axons: Reduced Regenerating clusters Occasional onion bulbs & thinly myelinated axons Muscle: Neurogenic atrophy Visual evoked responses: Delayed CT scan: Cerebellar atrophy of superior vermis & anterior lobes MRI Cerebellum: Vermian atrophy Brainstem (Pons & middle cerebellar peduncles) Linear hypointensities (T2) Muscle Fatty change Distal legs; Medial gastrocnemius & foot muscles Symmetric Relatively preserved: Thighs; Lateral gastrocnemius CNS Pathology Superior vermal & anterior lobe cerebellar atrophy Absent Purkinje cells SACS Variant syndromes Ataxia with no spasticity or myelinated retinal axons Homozygous nonsense mutation: Arg2119X Ataxia with no spasticity SACS: Axonal neuropathy, early onset, Recessive (HMSN) 112 Epidemiology: 9 families Genetics Inheritance: Recessive SACS Mutations Type: Misense or Stop May be same as seen in full SACS syndrome Clinical Onset age: 1 to 15 years Weakness: Distal; Legs & Arms Sensory loss: Distal; Large fiber modalities; Ataxia DTRs: Reduced or Normal Pes cavus Nystagmus (60%) Spasticity: None Disease course: Slow progression Laboratory Brain MRI Pons: Linear hypointensities Cerebellum: Superior vermis atrophy NCV: Motor & Sensory axon loss CMAPs: Absent or Reduced amplitude in legs SNAPs: Absent or Reduced amplitude NCV: 20 to 44 m/s Nerve biopsy Axon loss: Large & Small Myelin: Increased folding

From H Topaloglu Retina: Myelinated Axons ARSACS Cerebellum: Vermis Atrophy Pons: Linear T2 hypointensities (Arrow) From: R Bucelli, W Zhao & B Trikamji

• Epidemiology
  • Common in 1 region of Grand Cayman Island
  • Pakistan family
• Genetics
  • Mutations
    • Cayman: Ser301Arg; IVS9, G-T
    • Pakistan: 7-BP DEL, NT599
• Caytaxin protein
  • Expressed only in neural tissues: Brain; Dorsal root ganglia; Enteric neurons
  • Contains CRAL-TRIO motif: Commonly binds small lipophilic molecules
  • Recruits cholinergic machinery to neurite terminals
  • Other protein with CRAL-TRIO motif: ATTP; Causes vitamin E-responsive ataxia
• Clinical
  • Onset
    • Age: Infancy to Early childhood
    • Hypotonia
  • Cerebellar signs: Nonprogressive
    • Intention tremor
    • Dysarthric speech
    • Wide based gait
    • Eyes: Nystagmus; Ocular apraxia
  • Atrophy: Distal legs
  • Extrapyramidal: Dystonia, Bradykinesia
  • Psychomotor retardation: Marked
• Brain imaging: Cerebellar hypoplasia
• Mouse model: Jittery

• Genetics
  • 13q11-12 locus identified in 1 Tunisian family ³
  • Probably heterogeneity
• Clinical
  • Onset age: First or second decade
  • 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 & American patients
• Genetics
  • Mutations: IVS5AS,G-C,-1; Splice, c.509-1G>C & c.1029G>C, p. Glu343Asp
  • Allelic with
    • Ceroid lipofuscinosis, neuronal, 2 (CLN2)
    • Spastic paraparesis +
• TPP1 protein
  • Lysosomal exopeptidase
  • Sequentially removes tripeptides from N termini of proteins
  • Mutant TPP1 enzyme activity: 3% to 15% of control
• Clinical
  • Onset age: Early childhood
  • Cerebellar ataxia
    • Dysarthria
    • Limbs: Dysmetria; Abnormal writing
    • Gait disorder: Wide based; 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: 3 patients
  • Progression: Slow
• MRI
  • Cerebellum & Pons: Atrophy
• TPP1 variant: Spastic paraparesis ¹¹⁰
  • Epidemiology: 1 family
  • Genetics
    • Inheritance: Recessive
    • Mutations: c.1525C>T, p.Q509*; c.1340G>A, p.R447H
  • Clinical
    • Onset age: Juvenile
    • Spastic paraplegia, progressive
      • Gait disorder
      • Bulbar palsy
    • Intellectual function: Reduced
    • Seizures: Occasional
    • Dystonia: Neck
    • Treatment: Temporary response to L-DOPA
  • Laboratory
    • Brain MRI: Cerebral atrophy; Corpus callosum thin

• Epidemiology: 2 Somali families
• Genetics
  • Mutations: Arg399His; G149V
  • Allelic with: Ceroid lipofuscinosis, neuronal, 10
• Cathepsin D protein
  • Lysosomal proteinase
  • Functions: Proteolytic degradation, Cell invasion, Apoptosis
  • Ubiquitously expressed
• Clinical
  • Onset age: 8 to 15 years
  • Ataxia
  • Retinopathy: Pigmentary
  • Cognitive decline: Progressive
• Laboratory
  • Muscle
    • Angular small fibers with granulovacuolar material: Gomori trichrome+ & Acid phosphatase+
    • Ultrastructure: Granular osmiophilic deposits
  • NCV: Normal or Sensory axonal neuropathy
  • Brain MRI: Cerebellar atrophy
  • Cathepsin D activity: 11% of controls

• Epidemiology: 29 patients
• Genetics
  • Mutations: Missense & Nonsense
  • Allelic disorder: MRT69
• ZBTB11 protein
  • Transcriptional regulation
• Clinical
  • Onset age: Early childhood
  • Developmental delay/Intellectual disability
  • Cataracts
  • Ataxia
  • Spasticity
  • Movements: Dystonia, Myoclonus, Tremor, Chorea
  • Seizures
  • Course: Progressive
• Laboratory
  • Combined Malonic & Methylmalonic aciduria (CMAMMA)
  • Brain imaging: Cerebellar atrophy; Corpus callosum aplastic

• Epidemiology
  • Portuguese & Japanese
  • Most frequent cause of autosomal recesssive ataxia in Japan
• 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 of nucleotide hydrolases & transferases
  • Expression: Ubiquitous
  • Subcellular location
    • Nuclear & Mitochondrial
    • 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
  • APTX depletion: Mitochondrial dysfunction: Reduced citrate synthase activity & mtDNA copy number
• Clinical
  • Onset age: Mean 4.7 years; Range 1 to 16 years
  • 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

Cerebellar ataxia with Muscle coenzyme Q₁₀ deficiency (EAOH)

• Epidemiology: Single family
• Genetics
  • Mutation: Homozygous Trp279Ter
  • Allelic with: AOA1
• APTX protein
• Clinical
  • 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
  • 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
  • Allelic with: Myopathy, Myoglobinuria + CNS disorder
• CABC1 protein
  • Subcellular location: Mitochondria
  • Required for CoQ biosynthesis
  • Protein kinase: Atypical
  • Expression: Ubiquitous
  • Chaperone
  • 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: Epilepsia partialis continua
    • Some patients; Stroke-like episodes
  • 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

• Epidemiology: Japanese family
• Genetics
  • Homozygous missense mutation; Gly484Asp
  • Another patient reported with chromosomal deletion & more severe CNS syndrome
• SYT14 protein
  • Membrane trafficking proteins
  • Secretory vesicle exocytosis
  • Expressed in human adult & fetal brain: Purkinje cells
  • Phospholipid binding activity
  • Location: Perinuclear & Sub membrane
  • Mutant protein: Endoplasmic reticulum
• Clinical
  • Mental retardation: From childhood
  • Ataxia
    • Onset age: 6th decade
    • Truncal > Limb
    • Bulbar: Dysarthria; Dysphagia
    • Ocular: Nystagmus; Abnormal smooth pursuit
    • Course: Slowly progressive
  • No pyramidal or extrapyramial signs
• Laboratory
  • MRI: Cerebellar atrophy
  • Normal: Serum albumin, Vitamin E & α-fetoprotein
  • Nerve conduction: Normal

• 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 mutations in
    • ALS4 (Dominant)
    • Distal motor neuropathy with upper motor neuron signs
    • Neurodegeneration, early onset + Axonal polyneuropathy (Dominant; Thr8Met) ¹³¹
  • Locus near Joubert congenital ataxia
• Senataxin protein
  • Involved in RNA maturation & termination
  • Helicase: Superfamily 1
  • Expression: Ubiquitous; Peripheral nerve axons & myelin
  • NMJ plasticity: via TGF-β pathway
• 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: Axon loss
      • SNAPs: Absent or Reduced amplitudes
      • Motor: Mildly reduced CMAP amplitudes
      • EMG: Distal denervation
  • Reflexes
    • Tendon: Absent in legs
    • Plantar: Extensor
  • Cortical: Normal intelligence
  • Systemic
    • Neoplasia: No association
    • Ovarian failure: Few patients
  • 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
  • α-Fetoprotein: High
  • Serum CK: High in some patients
• SETX variant: Neurodegeneration, early onset + Axonal polyneuropathy ¹³¹
  • Epidemiology: 2 patients
  • Genetics
    • Inheritance: de novo Dominant
    • Mutations: Missense; c.23C>T (p.Thr8Met)
  • Clinical
    • Onset age: childhood; Failure to thrive
    • Motor
      • Delay
      • Non-ambulatory
      • Weakness: Face; Distal limbs
    • Tongue fasciculations
    • Sensory loss: Distal
    • Tendon reflexes: Reduced or Absent
    • Contractures: Distal; Arms & Legs
    • Tone: Axial hypotonia; limb spasticity
    • Polyneuropathy
  • Laboratory
    • Brain MRI: Non-diagnostic
    • NCV: SNAPs absent; CMAPs reduced amplitude; Velocities slow
    • Nerve biopsy: Myelinated axon loss; Büngner Bands

• Epidemiology: Saudi Arabian family; 4 patients
• Genetics: Homozygous, Missense mutatio; P629S
• PIK3R5 protein
  • Receptor-regulated class I phosphoinositide 3-kinase
  • Phosphorylates the membrane phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to PtdIns(3,4,5)P3
  • PIK3R5: PI3K regulatory subunit
  • Highly expressed in cerebellum
  • PtdIns/PIP kinase
• Clinical
  • Onset age: 12 to 18 years
  • Cerebellar
    • Gait disorder
    • Dysmetria
    • Slurred speech
  • Ocular
    • Saccades: Slow; Hypometric; Associated with head thrust
    • Pursuit: Normal
    • Nystagmus
    • Oculomotor apraxia
  • Weakness
    • Distal
    • Legs > Arms
    • Distal atrophy
  • Sensory loss
    • Legs > Arms
    • Pan-modal: Especially posterior column
  • Tendon reflexes: Absent or Reduced
  • Course: Progression to wheelchair in 3rd decade
  • Cognition: Normal
• Laboratory
  • α-Fetoprotein levels: High
  • MRI: Cerebellar hemisphere & vermis atrophy
  • NCV: Axonal sensory neuropathy
    • SNAPs: Absent in legs
    • CMAPs: Amplitude reduced
    • NCV: Normal

• Epidemiology: 8 Portuguese & 1 Norwegian families
• Genetics
  • Mutations
    • Truncation; Homozygous or Compound heterozygous
    • Portuguese: c.1123G>T (p.Gly375Trp)
    • Norwegian: c.1196T>C (p.Leu399Pro); c.1393_1396del, (p.Glu465*)
  • Allelic disorders
    • Microcephaly; Seizures, early-onset, intractable; Developmental delay (MCSZ; EIEE10)
    • CMT2B2 ⁹²
    • AOA4
• PNKP protein
  • Dual-function enzyme: Catalyzes
    • 5-prime phosphorylation of nucleic acids
    • 3-prime phosphatase activity
  • Pathways of DNA-damage repair
    • Single-strand & Double-strand breaks
    • After ionizing radiation or oxidative damage
• Clinical
  • Onset age: 1 to 9 years; Mean 4.3 years
  • Dystonia
  • Ataxia
  • Oculomotor apraxia
  • Polyneuropathy: Sensory loss, Vibration, Distal
  • Motor deficit
  • Cognitive impairment (50%)
  • Obesity (40%)
  • Course: Progressive to wheelchair in 2nd or 3rd decade
• Laboratory
  • Brain MRI: Cerebellar ± brainstem atrophy
  • Hypoalbuminemia
• CMT2B2 (ARCMT2)

• Epidemiology: Arab-Israeli & Turkish families
• Genetics
  • Mutations: Pro134Leu; Gly306Arg
  • Allelic disorder: BVVL2
  • SCABD1: PEX6
• Clinical
  • Onset age: Childhood
  • Cerebellar ataxia
  • Optic atrophy: Visual loss
  • Cochlear degeneration: Deafness
  • Weakness: Distal
  • Tendon reflexes: Absent
  • Contractures: Hands & Feet
  • Course: Progressive
• Laboratory
  • NCV: Sensory neuropathy
  • Brain MRI: Anterior superior cerebellar vermis atrophy

• Onset age: 4th & 5th decades
• Cerebellar ataxia: Pure

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

Leukoencephalopathies with Vanishing White Matter (VWM) 151 VWM1   ● Translocation initiation factor eIF2B1, α subunit ; Chromosome 12q24.31; Recessive VWM2   ● Translocation initiation factor eIF2B2, β subunit ; Chromosome 14q24.3; Recessive VWM3   ● Translocation initiation factor eIF2B3, γ subunit ; Chromosome 1p34.1; Recessive VWM4   ● Translocation initiation factor eIF2B4, δ subunit ; Chromosome 2p23.3; Recessive VWM5   ● Translocation initiation factor eIF2B5, ε subunit ; Chromosome 3q27.1; Recessive VWM (MC1DN10)   ● MYC-induced mitochondrial protein (B17.2L; Mimitin) ; Chromosome 5q12.1; Recessive Other   ● Dominant VWM Nosology: Other names Childhood ataxia with difuse hypomyelination Myelinosclerosis centralis diffusa VWM5: Cree leukoencephalopathy Epidemiology > 100 patients Asia & Europe: eIF2B5 common India: eIF2B3 common Female prodominance Genetics ~84 mutations identified Most commonly mutated gene: eIF2B5, R113H Phenotype relation Milder (Onset > 5 yrs): Mutations Non-conserved amino acids: R113H (EIF2B5) & E213G (EIF2B2) Severe: Mutations Highly conserved amino acids (R195H in EIF2B5) Allelic disorders Ovarioleukodystrophy ? Fatal infantile leukodystrophy eIF2B complex Eukaryotic translation initiation factor eIF2B 5 Subunits: α, β, γ, δ, ε Functions 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 eIF2B mutation effects Mitochondrial dysfunction Astrocyte disorder Clinical Onset age: 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 Variant: Ovarioleukodystrophy 28 Epidemiology: 1 family; Mother & son Genetics Mutations in eIF2B2, eIF2B4 & eIF2B5 Inheritance: Dominant Clinical Adult onset: 4th decade Somnolence, mental confusion & hemiparesis: After URI with fever

Leukoencephalopathy with Vanishing WM eIF2B2 mutation T2 Flair T2 T1

• Epidemiology: Multiple families in US, Europe, Turkey & Russia
• Genetics
  • Heterozygous
  • Type: Missense or Exon-skipping splice site
• DARS2 protein: Mitochondrial aspartyl-tRNA synthetase
  • Class-II aminoacyl-tRNA synthetase family
  • Mutant: Reduced activity
• Clinical
  • Onset: 3 to 15 years
  • Cerebellar ataxia
    • Slowly progressive
    • Legs > Arms
    • May be
      • Episodic: Post exercise
      • Acetazolamide responsive
  • 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
  • Leukoencephalopathy with DARS mutation

• Epidemiology: 20 patients
• Genetics
  • Mutations: Multiple types; Loss of function
• Chloride channel 2 protein
  • Brain ion & water homeostasis
• Clinical
  • Onset age: Childhood or Adult
  • Childhood onset
    • Cerebellar ataxia
    • Other: Variable
      • Spasticity, mild
      • Visual field defects
      • Learning disabilities
      • Headaches
      • Male infertility
      • Seizures
  • Adult onset
    • Cerebellar ataxia
    • Other: Variable
      • Eye: Chorioretinopathy; Visual field defects, Optic neuropathy
      • Headaches
• MRI: White matter abnormal
  • Middle cerebellar peduncles, Cerebral peduncles, Pyramidal tract, Internal capsule, posterior

• Nosology
  • 4H syndromes: Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism
  • Genes: POLR3A, POLR3B, POLR1C, POLR3K
  • Hypomyelinating Leukodystrophy 11
• Epidemiology: > 30 patients
• Genetics
  • Mutations: Frameshift & Missense
  • Allelic disorder: Treacher-Collins 3 (TCS3)
• POLR1C protein
  • Subunit of POLR1 & POLR3
  • POLR3: Synthetizes small noncoding RNAs with roles in transcription & RNA processing and translation
• Clinical
  • Onset age: Childhood; 0 to 6 years
  • CNS
    • Psychomotor development: Delayed; Cognition abnormal
    • Ambulation: Loss
    • Cerebellar: Ataxia; Tremor; Dysarthria
    • Spasticity
  • Myopia
  • Endocrine
    • Hypogonadotrophic hypogonadism
    • Puberty: Delayed
  • Short stature
  • Disease course: Progressive
• Laboratory
  • Brain imaging: Hypomyelination; Corpus callosum & Cerebellum small

• Epidemiology: 12 families, including French-Canadian
• Genetics
  • Mutations
    • Types: Missense; Nonsense; Splice site
    • No patient with 2 nonsense mutations
  • Allelic with
    • Leukodystrophy with oligodontia
    • HLD7 (4H syndrome)
    • Spastic ataxia + Dental
    • Wiedemann-Rautenstrauch (Progeroid, Neonatal)
  • Also see: POLR1C & POLR3B mutations
    • Phenotype more severe than POLR3B mutations
• POLR3A protein
  • Largest subunit of RNA polymerase III
  • Mutations: Reduced POLR3A protein levels
  • POLR3: Synthetizes small noncoding RNAs
• Clinical
  • Onset age: 1 to 5 years
  • Spasticity
  • Ataxia
  • Tremor: Postural
• Laboratory
  • Leukodystrophy
• POLR3A variant syndrome: Hypomyelinating leukodystrophy (HLD7) with Ataxia & Hypodontia
  • Nosology: 4H syndromes
    • Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism
    • Genes: POLR3A, POLR3B, POLR1C, POLR3K
  • 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
    • Hypogonadotropic hypogonadism
    • Puberty: Delayed
    • Short stature
  • 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
• POLR3A variant syndrome: Spastic ataxia + Dental disorders ⁹⁸
  • Epidemiology: 3% of spastic ataxia
  • Genetics
    • Inheritance: Recessive
    • Common mutation: Deep-intronic; Splice; c.1909 + 22G>A
    • Other mutations: Missense & Stop
  • Clinical
    • Onset age: 12 to 51 years
    • Spastic
      • Legs > Arms
      • Plantar response: Extensor
    • Ataxia
    • Tremor, involvement of the
    • Sensory
      • Central tract involvement
      • Vibration: Reduced
    • Urinary urgency: Some patients
    • Dental: Hypodontia; periodontal disease, early onset
  • Laboratory
    • Brain MRI: Hyperintensities (FLAIR) in superior cerebellar peduncles; Myelination normal
    • NCV: Usually normal
    • Sensory evoked potentials: Abnormal

• Nosology: 4H syndromes
  • Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism
  • Genes: POLR3A, POLR3B, POLR1C, POLR3K
• Genetics
  • Mutations
    • Leukodystrophy: Stop; Splice + Missense
    • Polyneuropathy: Usually Missense, Dominant, de novo
  • Allelic disorders
    • de novo Dominant: Missense mutations
      • Ataxia, Spasticity, & Demyelinating neuropathy
      • CMT1I: Demyelinating polyneuropathy ± CNS features (CMT1I)
      • CMT2: Axonal Polyneuropathy
      • Infantile Myoclonic/Atonic Seizures ± Ataxia ¹⁴⁹
    • HLD8: Recessive
• POLR3B protein
  • Pol III subunit
  • Polymerase III (Pol III)
    • Transcribes small untranslated RNAs
    • Regulates transcription, RNA processing, translation
• Clinical
  • Onset age: Mean 3.4 years; Range 1 to > 10 years
  • CNS
    • Delayed development: After 1 year
    • Intellectual disability: Mild
    • Ataxia
      • Speech
      • Gait: Wide based
      • Dysdiadochokinesis
      • Dysmetria
      • Tremor
      • Nystagmus
    • Hypotonia
    • Pyramidal
      • Hyperreflexia: Mild
      • Spasticity: Some patients
    • Extrapyramidal: Dystonia
  • Endocrine
    • Hypogonadotropic hypogonadism
    • Delayed puberty
  • Tooth disorders (Some patients): Hypodontia; Delayed dentition
  • Eye
    • Myopia
    • Smooth-pursuit eye movements: Slow
    • Vertical gaze: Limited
  • Osteosclerosis: Some patients
  • Course: Slowly progressive
  • Less severe disease than POLR3A mutations
• Laboratory
  • MRI
    • Hypomyelination, leukodystrophy
    • Corpus callosum: Hypoplastic in Adults
    • Cerebellar atrophy
    • Posterior limb of internal capsule: Hypointense dot
• POLR3B variant: CMT1I
  • Epidemiology: 9 patients
  • Genetics
    • Inheritance: Dominant, de novo
    • Mutations: Missense
  • Clinical
    • Onset
      • Age: 18 months to 5 years
      • Motor milestones: Delayed
    • Weakness
      • Legs > Arms
      • Distal > Proximal
    • Sensory loss: Distal
    • Tendon reflexes: Absent
    • Skeletal: Pes cavus; Claw hands
    • CNS: Some patients
      • Spasticity
      • Developmental delay
      • Seizures
  • Laboratory
    • NCV
      • Demyelination (20 to 26 M/s)
      • Axon loss: Especially large myelinated
      • Motor & Sensory
    • Nerve pathology: Loss of myelinated axons
    • CNS: Normal, Cerebellar or White matter pathology
• POLR3B variant: CMT2, Axonal polyneuropathy ¹⁴²
  • Epidemiology: 1 patient
  • Genetics
    • Inheritance: Dominant, de novo
    • Mutation: Missense; Arg1064Cys; Partial loss of function
  • Clinical
    • Onset age: Adolescence, early
    • Weakness
      • Distal
      • Legs > Arms
      • Gait disorder
    • Sensory loss: Panmodal
    • Tendon reflexes
      • Absent in legs
      • Reduced in arms
    • Contracture: Ankle
  • Laboratory
    • Brain MRI: Normal
    • NCV
      • CMAPs & SNAPs: Absent in legs
      • Velocities
        • Arms: 25 to 45 M/s
        • Proximal: Normal
    • Sudomotor function: Impaired
    • Skin biopsy: Axon loss, length dependent
    • Sural nerve pathology
      • Myelinated axons: Severe loss
      • Remaining myelinated axons: Small; Thin myelin

• Nosology: 4H syndromes
  • Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism
  • Genes: POLR3A, POLR3B, POLR1C, POLR3K
• Epidemiology: 2 patients
• Genetics
  • Mutation: Homozygous; c.121C>T/p.Arg41Trp
• POLR3K protein
  • Pol-III subunit
  • Transcription of short genes
  • Mutations: Reduced expression of 5S & 7S ribosomal RNAs
• Clinical
  • Onset age: < 1 year
  • CNS
    • Cognitive: Poor or no language
    • Motor: Delay: Little or no walking
    • Cerebellar disorders: Nystagmus; Ataxia
    • Extrapyramidal: Dystonia; Athetosis
    • Pyramidal signs
  • Endocrine
    • Hypogonadism: Cryptorchid
    • Short stature
  • GI disorders: Gastrostomia needed
  • Hypodontia
  • No myopia
  • Course: Progressive; Episodes
• Laboratory
  • Brain MRI: Cerebellar & Corpus callosum atrophy

• Epidemiology: 7 families
• Genetics
  • Mutations: Missense; Recurrent; R363Q, R365Q
• RNF220 protein
  • Ubiquitin E3 ligase
  • Expression: Developing nervous system
  • Sub cellular
    • Most neurons: Cytoplasmic; Perinuclear
    • Cerebellum: Nucleus
  • Binds to: Lamin B1
  • Functions
    • Nuclear morphology:
    • Rgulation of neural stem cell proliferation & differentiation
    • Development of noradrenergic neurons
    • Mutations: Lamin B1 binding reduced
• Clinical
  • Onset
    • 3 to 8 years
    • Developmental delay: Walking or Speech
  • Ataxia
  • Spastic paraplegia: Hyperreflexia; Dysarthria
  • Deafness: Sensorineural
  • Cardiomyopathy: Fibrotic; Dilated
  • Hepatopathy
  • Course
    • Progressive
    • Wheelchair: 9 to 16 years
    • Death: 10 to 21 years; Cardiomyopathy
• Laboratory
  • Brain imaging
    • Leukodystrophy, Hypomyelinating: Brain, not cerebellum
    • Cerebellar atrophy (50%)
  • Brain pathology: Neuropil microvacuolar changes; Hypomyelination
  • AST & ALT: High
  • Polyneuropathy, axonal (50%)

• Nosology: Free Sialic Acid Storage Disorder (FSASD)
• Epidemiology
  • Prevalent in Finland (> 160 patients)
  • 200 patients worldwide
• Genetics
  • Mutations
    • Finnish: Homozygous Arg39Cys, Milder disease
    • Severe disease: Other deletions, insertions, & missense or nonsense
    Allelic disorder: ISSD
• Protein: Sialin
  • Homologous to phosphate & glutamate transporters
  • Contains 12 membrane domains
  • Sialic acid transporter
  • Lysosomal
  • Mutant protein
    • Abnormal intracellular trafficking through Golgi
    • Sialic acid accumulates in lysosomes
  • Sialic acid storage disease
    • Transport of free sialic acid at lysosomal membrane: Reduced
• Clinical
  • Onset age: 12 to 18 months
  • Ataxia
  • Hypotonia
  • Mental retardation
  • Epilepsy (18%): Absence; Later age
  • Hepatosplenomegaly
  • Coarse facial features
  • More severe disease: Mental retardation, Seizures, Hypotonia
  • Course: Progressive deterioration in 2nd decade
• 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
    • Cerebellar atrophy: Progressive
    • Corpus callosum: Hypoplasia
    • Myelination: Delayed; Reduced
  • Muscle
• SLC17A5 Variant syndrome: Infantile sialic acid storage disease (ISSD)
  • Genetics
    • Mutations: Deletion
    • Inheritance
  • Clinical
    • Hypotonia
    • Cerebellar ataxia
    • Mental retardation
    • Visceromegaly
    • Coarse features
  • Laboratory
    • Brain MRI: Cerebellar atrophy; Dysmyelination
    • Pathology: Enlarged lysosomes

• Epidemiology: One Italian family
• Clinical
  • Onset age: 5th to 6th decade; Dysphonia
  • Laryngeal abductor paralysis, Bilateral
    • 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

• See: SANDO
• Epidemiology: One Finnish family
• Clinical
  • Onset
    • 30 years
    • Gait disorder
    • Normal childhood
  • 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
• Clinical
  • Onset
    • Age: Childhood
    • Gait disorder
  • 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: > 10 families
• Genetics
  • Mutations: Nonsense, Missense & splicing
  • Allelic disorders
    • Movement disorder & Spastic Ataxia, Childhood onset
    • Leigh Syndrome
• VPS13D protein
  • Mitochondrial metabolism: Viability, Fission; Autophagy, Clearance
  • Mutations: Increased mitochondrial unfolded protein response
  • VPS13 disorders
• Clinical: Spastic ataxia
  • Onset
    • Age: 3rd & 4th decade
    • Gait disorder
    • Difficulty reading
  • 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
  • Brain MRI: Cerebellar atrophy (50%)

• 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
• Genetics
  • Mutations
    • MARS2 duplications
    • Common association: Large deletion (681Δ268bpfs236X) or Large insertion
    • More severe, earlier onset phenotype: Homozygous, common duplication
  • Allelic disorder: COXPD25
• MARS2 protein
  • Location: Mitochondrial matrix
  • Mutation: Reduced MARS2 protein levels
  • Function: Aminoacyl-tRNA synthetase (ARS)
• Clinical: Spastic-ataxia
  • Onset
    • Age: Mean 8 years; Range - Birth to 59 years
    • Motor: Clumsiness; "Cerebral palsy"
  • 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
  • Course: Progressive; Wheelchair 14 to 72 years
• Laboratory
  • MRI
    • Cerebellar atrophy (90%): Vermis & Hemispheres
    • More severe patients
      • Cortical atrophy (40%)
      • Leukoencephalopathy (40%): T2 & FLAIR; Older patients
  • Mitochondrial respiratory chain: Complex I deficiency
• MARS2 variant: COXPD25
  • Epidemiology: 1 family, 2 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations: Gln184Ter; Arg142Trp
  • Clinical
    • Onset: Congenital; Premature birth
    • GI: Weight gain, poor; Constipation; GE reflux
    • Psychomotor development: Delayed
    • Dysmorphic face: Forehead midline ridge; Ears low-set; Abnormal nose
    • Hearing loss: Sensorineural
    • Hypotonia
    • Pectus carinatum
  • Laboratory
    • Growth hormone: Deficiency
    • Brain MRI: Ventricles large; Cerebral & Cerebellar atrophy; White matter abnormal
    • Fibroblasts: Complex I & IV activity low

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

• Epidemiology: Israeli-Arab family
• Clinical
  • Onset
    • 3 to 4 years
    • Tremor
    • Gait disorder
  • 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 Canada, Japan & Brazil 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-Dreifuss MD, Type 4
• 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
• Clinical
  • Onset
    • Age: Mean 30 years; Range 17 to 46 years
    • Signs: Ataxia; Dysarthria
  • 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: Saudi Arabian & Israeli Palestinian families, consanguinous
• Genetics
  • Mutation: Pro47Thr; Gly372Arg
  • Allelic disorder: Infantile epileptic encephalopathy (IEE; EIEE28), Recessive
  • Somatic mutations: Esophageal squamous cell carcinoma
• WWOX protein
  • Cytoplasmic
  • WW domains
    • Protein-protein interaction domains
    • Recognize proline-rich sequences
  • Interacting proteins: p73, RUNX2, ERBB4, Dvl2, SIMPLE/LITAF
  • Mediator of tumor necrosis factor-α-induced apoptosis
  • Tumor suppressor
  • Mutations, somatic: Esophageal squamous cell carcinoma
• Clinical
  • Onset
    • Age: 9 to 24 months
    • Epilepsy
  • 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 or Increased
  • Spasticity: 1 family
    • Legs > Arms
  • 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
• Animal model: Ide rats

• Epidemiology: US, Irish & Egyptian families, 6 patients
• Genetics
  • Mutations: Splice-donor (c.425+1G>A); Truncating (c.413_414delinsAA)
• TDP2 protein
  • Nosology: Tyrosyl DNA phosphodiesterase-2
  • Expression: High in brain & heart
  • Repairs Topoisomerase II (TOP2) induced DNA double-strand breaks
  • Mutations: Inactivating
• Clinical
  • Onset ages: 2 months to 12 years
  • Epileptic encephalopathy
    • Symptomatic, Generalized epilepsy
    • Seizures: Frequent (1 to 4 per day); Refractory to anti epileptic drugs
  • Ataxia: Progressive; Wheelchair
  • Intellectual disability: IQ 30 to 40
  • Microcephaly
  • Systemic: Cardiac arrhythmia; GI dysmotility
• Laboratory
  • EEG: Epileptiform activity

• Epidemiology: 2 Saudi Arabian families
• Genetics
  • KIAA0226 mutation: Frameshift; c.2624delC; p.Ala875ValfsX146
• RUBCN (KIAA0226; Rubicon) protein
  • Colocalizes with: Late endosome marker Rab7; Lamp I at lysosomes
  • Contains: N-terminal RUN domain; Cystein-rich diacylglycerol (DAG) binding-like C-terminal domain
  • Component of autophagy-related complex with: beclin-1 , Vps34 (PIK3C3) , Vps15 (PIK3R4) , UVRAG
  • Involved in: Vesicular tracking; Endosome maturation
  • Mutation: Diffuse cytosol location
• Clinical
  • Onset
    • Age: 7 months to 3 years
    • Epilepsy or Gait disorder
  • Epilepsy
    • Type: Generalized, Tonic-clonic
    • Treatment: Usually effective; No recurrence after age 3
  • Ataxia
    • Limbs: Legs > Arms
    • Trunk & Gait
    • Walking: Delayed (2 to 3.5 years); Always limited; Inability to run
    • Eyes: Nystagmus or Saccadic pursuit
    • Dysarthria
  • Mental retardation: From early childhood
  • Tendon reflexes: Reduced in arms
  • Normal: Strength; Sensation; Pyramidal function
  • Course: Slow progression
• Laboratory
  • MRI: Cerebellar vermis atrophy with increasing age
  • EEG: Multifocal spikes & Spike + Slow wave foci
  • NCV: Normal

• Epidemiology
  • > 38 patients
  • Common: Turkish, Portuguese & British
• Genetics
  • Mutations
    • > 28 described
    • Loss of function or Truncation
    • Stop, Splice or Deletion (c.2596C>T; c.1108+1181_2108.2342del; c.1894+1G>A)
  • Animal variant: Hungarian Vizsla dog
• SNX14 protein
  • Sorting nexin protein
  • Expressed at high levels in brain: Co-expression with Islet-1
  • Neuronally imprinted gene
  • RGS-PX protein family: Contains PX domain
  • Binds to phosphoinositides (PtdIns3P) on cytoplasmic leaflets of organelles
  • Defines subcellular localization & function of PX domain-containing proteins: Endosomal sorting & trafficking
  • Roles
    • Synaptic transmission: Promotion
    • Neuronal excitability: Regulation
    • Lipid biogenesis
  • Mutations
    • Affect endoplasmic reticulum associated neutral lipid metabolism
    • Alter autophagic flux
  • Lipid droplet (LD)-ER contact site: Proteins & Disorders ¹¹⁸
    • Seipin: Lipid droplet (LD) biogenesis (Early)
    • PLIN4: Lipid droplet regulation
    • FITM2: Diacylglycerol (DAG) binding; LD biogenesis
    • SNX14: LD biogenesis; LD-ER tether
    • VPS13: LD-ER tether; Interorganellar lipid transfer
    • Rab18 : LD biogenesis; LD-ER contact formation
    • FATP1-DGAT2: LD growth; DAG transport
    • ORP2 (OSBPL2)-VAP : LD-ER tether
    • VMP1 : Autophagy
    • Lipin-1 (Pah1): LD biogenesis
• Clinical
  • Onset
    • Age: 1st year
    • Motor delay
  • Intellectual disability: Moderate-severe; Delayed speech
  • Motor delay: Hypotonia; Sitting & Walking late
  • Cerebellar ataxia
  • Hearing loss (50%): Sensorineural
  • Skeletal
    • Facial features
      • Progressive coarsening
      • Short palpebral fissures
      • Upper eyelids: Full
      • Nose: Broad/bulbous
      • Philtrum: Broad deep long
      • Lip vermilions: Thick
    • Macrocephaly
    • Digits
      • Brachycamptodactyly: 5th fingers
      • Fingers & Toes: Broad
  • No seizures
• Laboratory
  • Brain MRI: Cerebellar atrophy, global (Thin folia & Enlarged fissures)
  • Skin & Fibroblast cells
    • Vacuoles & Inclusions
    • Differential diagnosis: Marinesco-Sjögren
  • Serum CK: Normal

• Epidemiology: 1 Japanese family
• Genetics
  • Mutation: Homozygous; c.1865A>C, p.K622T
• VWA3B protein
  • Expression: Ubiquitous
  • Probably intracellular
  • Mutant protein: Cell prone to apoptosis
  • VWA-containing proteins
    • Extracellular or Intracellular
    • Many bind metal ions
    • Function in multiprotein complexes
• Clinical
  • Onset age: Childhood
  • Intellectual disability
  • Ataxia
    • Adult onset
    • Dysarthria
    • Gait instability
    • Truncal
    • Dysmetria
    • Intention tremor
    • Nystagmus
  • Pyramidal tract signs
    • Spasticity: Legs
    • Tendon reflexes: Increased
• Laboratory
  • Brain MRI
    • Superior cerebellar vermis & cerebellar hemispheres: Atrophy
    • Corpus callosum: Thin
  • NCV: Normal; F-waves persistent

• Epidemiology: 4 families
• Genetics
  • Mutation types: Splice (IVS9DS, G-A, +1 (c.964+1G>A)), Missense (Asp13His, Asp132Gly), Stop
• CWF19L1 protein
  • Cell localization: Nuclei
  • Expression: Brain & Spinal cord
  • Possible role in mRNA, cell cycle or endsomal trafficking
• Clinical
  • Onset: Congenital
  • Hypotonia: Extremities
  • Walking: Delayed (1.5 to 2 years); Unsteady with falls
  • Ataxia: Dysarthria; Dysmetria; Trunk; Limbs
  • Tendon reflexes: Increased in legs
  • Cognition: IQ low
  • Progression: Slow or None
• Laboratory
  • Brain MRI: Cerebellar vermis & hemisphere atrophy

• Epidemiology: Consanguineous Turkish family of Kurdish origin
• Mutations: Pro856Leu
• WDR81 protein
  • High expression in cerebellum & corpus callosum
  • ? Role in development
• 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: > 20 families
• Genetics
  • Mutations: Missense common, Nonsense & Splice; Ser100Pro
  • 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: Motor & Speech delay
  • Ataxia
  • Spasticity (30%)
  • Axial hypotonia
  • Gait: Quadrupedal
  • Eyes: Strabismus; Nystagmus; Abnormal pursuit & saccades
• Laboratory
  • Brain MRI: Normal or Cerebellar atrophy
  • PET: Glucose metabolism reduced in cerebellum & temporal lobes

• Epidemiology: > 10 patients
• Mutation: Missense
• ATP8A2
  • P₄-Type ATPase
  • Complex with: CDC50A (TMEM30A)
  • Phosphatidylserine translocase
  • Expression: Brain (Cerebellum); Retina; Development
  • Transport of aminophospholipids toward cytoplasmic leaflet
    • Phosphatidylserine & Phosphatidylethanolamine
    • From outer membrane layer to Inner cytoplasmic layer
    • Maintains asymmetry of lipid bilayer
• Clinical
  • Onset: Congenital or Childhood
  • Hypotonia
  • Ataxia: Truncal; Quadrupedal gait in some; Dysarthria; Dysmetria
  • Optic atrophy
  • Mental retardation: Severe; Speech delay
  • Tendon reflexes: Increased or Decreased
  • Strabismus
  • Ambulation: None or Support dependent
• MRI
  • Cerebellar & Cerebral atrophy
  • Cortical gyri simplified
  • Corpus callosum: Thin
• Mouse mutant: wabbler-lethal (wl)
  • Ataxia
  • Body tremor
  • Polyneuropathy
    • Axonopathy
    • Modulated by Wld^s & Bax mutations
  • Death at 4 weeks

• 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: Epilepsy, progressive myoclonic 6 (EPM6)
• Epidemiology: Family origins around North Sea; > 10 Families
• Genetics
  • Mutation: Gly144Trp
  • Allelic disorder: Congenital Muscular Dystrophy ± Seizures (MYOS)
• GOSR2 protein
  • Qb-SNARE family of vesicle docking proteins
  • Location: cis-Golgi
  • Mutation: Prevents interaction between SNARE domains
• Clinical
  • Onset
    • Age: 1 to 3 years
    • Ataxia: Gait disorder
  • Ataxia
  • Tremor
  • Myoclonus: Action; Onset age 6 years
  • Seizures: Absence; Drop attacks; Tonic-clonic
  • Tendon reflexes: Absent
  • Skeletal: Scoliosis; Pes cavus; Syndactyly
  • Cognition: Normal
  • Course
    • Progressive
    • Disability: Wheelchair by age 13 to 24
• Laboratory
  • EEG: Spike-Wave, Photosensitive, Posterior predominant; Focal
  • Serum CK: 140 to 2,100; Usual ~700
  • EMG: Normal
  • NCV: Axon loss in some patients
  • Muscle histology: Normal
  • CNS MRI: Normal
• GOSR2 variant syndrome: Congenital Muscular Dystrophy ± Seizures (MYOS) ¹²⁰
  • Epidemiology: 6 families
  • Genetics
    • Inheritance: Recessive
    • Mutations: Compound Heterozygous; Missense & Stop; c.430G>T (Gly144Trp), Common; c.2T>G
  • Clinical
    • Onset age: < 6 months to 4 years
    • Hypotonia
    • Weakness: Diffuse; Proximal > Distal; Respiratory
    • Muscle size: Small
    • Tendon reflexes: Reduced or Absent
    • Seizures
    • Cerebellar: Nystagmus; Ataxia
    • Cognitive decline: Older patients
    • Course: Progressive
  • Laboratory
    • Serum CK: High; Up to 5,000
    • Muscle pathology
      • Dystrophic
        • Fiber sizes: Varied
        • Internal nuclei
        • Necrosis & Regeneration
      • Mitochondrial morphology: Abnormal
      • α-Dystroglycan reduced or Mosaic (VIA4-1)
      • GOSR2: More reduced on type 2 fibers
    • Muscle MRI: Fat replacement Proximal > Distal
    • Brain MRI: Atrophy or Normal
    • EEG: May be abnormal

• Epidemiology: 7 patients
• Genetics
  • Mutations: Nonsense (More severe) & Missense (Less severe)
• IRF2BPL protein
  • Expression: Broad, including nervous system
  • Cell localization: Nuclei
  • Transcriptional regulator
• Clinical
  • Onset age: 1st decade
  • Ataxia
  • Developmental delay & Mental retardation
  • Seizures
  • Dysphagia
  • Spasticity: Some patients
  • Extrapyramidal: Dystonia; Athetosis
• Laboratory
  • Brain MRI: Cerebral atrophy

• Epidemiology: 5 children
• Genetics
  • Mutations: Missense; Splice site; Frameshift
  • Allelic disorders
    • Rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL)
    • Cerebellar ataxia, nonprogressive
• BRAT1 protein
  • DNA damage & repair
• Clinical
  • Onset age: Infancy
  • Delayed psychomotor development: No, or Reduced, language; Abnormal behavior
  • Eyes: Poor fixation, Optic atrophy, Nystagmus
  • Motor: Siffness, Spasticity, Hand fisting
  • Staring spells
  • Cerebellar: Ataxic gait, Truncal titubation, Tremor, Dysmetria
  • Face: Dysmorphic features
• Laboratory
  • Brain MRI: Cerebellar atrophy; Dysmyelination
• BRAT1 variant: Cerebellar ataxia, nonprogressive ¹¹⁵
  • Epidemiology: Pakistani sibling pair
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous; Missense, Val62Glu
  • Clinical
    • Onset age: 1 to 2 years
    • Cerebellar
      • Ataxia
      • Dysarthria
      • Oculomotor apraxia
      • Nystagmus, gaze evoked
    • Intellectual disability, mild
  • Laboratory
    • Brain MRI: Cerebellar atrophy

• Epidemiology: 2 families, 3 patients
• Genetics
  • Mutations: Nonsense & Large deletion
• DOCK3 protein
  • Transcript in brain
• Clinical
  • Onset age: Infancy
  • Developmental delay, global
  • Hypotonia
  • Ataxia: Gait
  • Dysmorphic: Face
• Laboratory
  • Brain image: Normal

• Epidemiology: 22 families, 30 patients
• Genetics
  • Mutations: Missense & Stop
• GEMIN5 protein
  • snRNP complex assembly
  • Location: Nucleus > Cytoplasm
  • Binds to snRNA via AU_5–6 sequence
  • Controls expression of SMN by regulating translation of its mRNA
• Clinical
  • Onset age: < 2 years
  • Developmental delay
  • Hypotonia
  • Motor dysfunction
  • Spasticity (40%)
    • Tendon reflexes: Brisk
  • Ataxia
  • Course: Stable or Slow progression
  • Severe disease: PCH-like
• Laboratory
  • Brain imaging: Cerebellar atrophy
  • NCV: Motor neuropathy

• Epidemiology: 1 family, 2 patients
• Genetics
  • Mutations: Truncation; Splice
  • Allelic disorder: Intellectual developmental disorder, autosomal recessive 79 (MRT79)
• TPR protein
  • Nuclear pore complex
  • Scafolding element of nuclear facing interior
• Clinical
  • Onset: Infancy
  • Intellectual disability
  • Ataxia: Gait
  • Muscle tone: Increased in arms
  • Microcephaly
• Laboratory
  • NCV: Normal
  • Brain MRI: White matter pathology
  • Serum CK: Mildly high

• 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
  • Allelic disorders
    • Gitelman-like syndrome
    • Enlarged vestibular aqueduct, digenic
• 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

• Epidemiology: 2 patients
• Genetics
  • Mutations
    • Heterozygous: 1 severe & 1 mild
    • Missense & Insertion
  • Allelic disorders
    • Neonatal adrenoleukodystrophy (NALD)
    • Zellweger syndromes (Peroxisome biogenesis disorders): PBD6A ; PBD6B
    • External link: DBPEX
• PEX10 protein
  • Function: Peroxisome synthesis
• Clinical
  • Onset
    • 5 to 6 years
    • Gait disorder
  • Ataxia
    • Gait unsteady
    • Limb ataxia
    • Dysarthria, mild
    • Smooth pursuit: Impaired
    • Slowly progressive
  • Motor: Distal atrophy
  • Sensory: Reduced vibration, mild
  • Tendon reflexes:
  • Intelligence: Normal
  • Possible treatment
    • Bile acid supplements
    • Dietary restriction of phytanic acid
• Laboratory
  • MRI: Cerebellar atrophy
  • EMG: Axonal motor neuropathy
  • SSEP: Posterior column dysfunction
  • Phytanic & Pristanic acid levels: Increased
  • Bile acid intermediates & Pipecolic acid: Increased
  • Fibroblasts: Peroxisomal mosaicism, Mixed population of fibroblasts with & without peroxisomes

• Epidemiology
  • > 20 families
  • Common recessive ataxia: Also see SYNE1
• Genetics
  • Mutations: Missense, Splice site, Deletion (2 bp)
  • Variant syndrome: Ataxia + CoenzymeQ10 deficiency
• Anoctamin 10 protein
  • ? Calcium-activated chloride channel
  • Membrane protein
  • Expression: Brain > Retina & Heart
• Clinical: Spastic-Ataxia
  • Onset age: 13 to 53 years
  • Ataxia
    • Appendicular
    • Gait
    • Dysarthria
    • Hypermetric saccades
    • Nystagmus: Downbeat & Other
  • Motor
    • Atrophy, Proximal legs
    • Lower motor neuron Δ (50%)
  • Reflexes
    • Tendon: Increased in Arms & Legs
    • Plantar: Usually flexor
  • Extrapyramidal: Bradykinesia
  • Cognitive defects (50%)
  • Eyes: Upgaze paresis
  • Conjunctival vessels: Tortuous (50%)
  • Pes cavus
  • Course: Progressive
• Laboratory
  • EMG: Denervation
  • MRI: Cerebellar atrophy; Normal supratentorial structures
  • Sensory evoked potentials: Large
• Variant syndrome: Ataxia + CoenzymeQ10 deficiency ⁸²
• Epidemiology: 2 patients
• ANO10 genetics
• Mutations: Asp615Asn; c.132_133insT; c.1315G>T, p.Glu382*
• Clinical
  • Onset age: 7 to 30 years
  • Ataxia: Gait; Dysarthria; Dysmetria; Intention tremor
  • Eye: Oscillopsia; Nystagmus, downbeat
  • Pyramidal: Spasticity; Tendon reflexes brisk
  • Treatment: Possible improvement with CoQ10
• Laboratory
  • Muscle: Type 2 atrophy; Respiratory chain normal; CoQ10 levels borderline
  • MRI: Cerebellar atrophy

• Epidemiology: 1 Moroccan family, 2 patients
• Genetics
  • Mutation: 3-bp deletion (p.K19del); Homozygous
• CHP1 protein
  • Cofactor of NHE1 (Regulator of intracellular ions & pH homeostasis)
• Clinical
  • Onset age: 1 to 5 years
  • Motor neuropathy
    • Weakness: Distal
    • Muscle atrophy: Distal
  • Cerebellar
    • Gait ataxia
    • Dysmetria: Limbs; Ocular
  • Spastic paraparesis
    • Gait disorder
    • Tendon reflexes: Increased
    • Plantar reflex: Extensor
  • Intellectual disability: Mild
  • Eye: Slow saccades
  • Skeletal
    • Pes cavus
    • Growth retardation
• Laboratory
  • Brain MRI: Cerebellar vermis atrophy

• Epidemiology: 5 families
• Genetics
  • Mutations: Deletions, Missense, Stop & Duplications
  • Homozygous nonsense mutations: May be more severe disease
  • Allelic disorders
    • SPG, complicated
    • Ataxia, Semi-Dominant
    • Schizophrenia association: GRID2 deletion
    • Mouse allelic disorders: Lurcher; Hotfoot
• GRID2 protein
  • GluD2 protein
  • High expression: Cerebellum
  • Ionotropic glutamate receptor
  • Synapse organization
  • Cerebellar & CNS development
    • Purkinje cells: Dendritic arborizations
    • Motor learning
  • Autoantibodies: Associated with childhood acute cereballar ataxia
• Clinical
  • Onset age: Early infancy
  • Hypotonia
  • Development delay: Marked; Gross motor skills; Inability to walk
  • Encephalopathy: Static
  • Cerebellar ataxia
    • Dysarthria
    • Dysdiadochokinesis
    • Dysmetria
    • Nystagmus
    • Truncal ataxia
  • Cranial nerves
    • Oculomotor apraxia
    • Optic nerve: Pallor
    • Hearing loss
  • Pyramidal tract (UMN signs)
    • Tendon reflexes: Brisk
    • Plantar response: Extensor
  • Kyphoscolosis
• Laboratory
  • MRI: Cerebellar atrophy, Progressive
• GRID2 Variant syndrome: Spastic paraplegia, complicated ⁷⁶
  • Epidemiology: 1 patient
  • Genetics
    • GRID2 mutation: 276 kb deletion spanning exon 1
    • Inheritance: Sporadic
  • Clinical
    • Onset age: 10 years
    • Spastic paraplegia
      • Gait
      • Tendon reflexes: Increased in legs
    • Ataxia: Dysarthria; Dysmetria
    • Dementia: Frontotemporal
    • Lower motor neuron: Hand muscle wasting
  • Laboratory
    • NCV: CMAP amplitudes reduced; Sensory normal
    • EMG: Chronic distal denervation
    • MRI: Cerebellar & Mesencephalic atrophy
• GRID2 Variant syndrome: Ataxia, Semi-Dominant ¹⁵⁰
  • Epidemiology: 4 patients
  • Genetics
    • Inheritance: Semi-Dominant or de novo
    • Mutations: Missense (Leu652Ile, Ala654, Leu656Val) & Deletions
    • lurcher mouse: Ala654Thr
    • Mutation effect: Constitutively active receptors
  • Clinical
    • Onset age: Childhood to 46 years
    • Ataxia: Gait disorder; Limbs; Dysarthria
    • Eyes
      • Oculomotor apraxia
      • Saccadic pursuit
    • Cognitive decline: Some patients
    • Gross motor delay
    • Course: Very slow progression
  • Laboratory
    • Brain MRI: Cerebellar or Vermian atrophy; Some normal
    • α-Fetoprotein: High

SCAR19: Ataxia-Deafness (Lichtenstein-Knorr syndrome )

• Epidemiology: Turkish siblings
• Genetics
  • Mutation: G305R
• SLC9A1 protein
  • Na-H transporter
  • Interacts with: CHP1
• Clinical
  • Onset: < 2 years; Walking delayed
  • Ataxia: Gait; Limbs
  • Tendon reflexes: Absent
  • Hearing loss: Sensorineural
• Laboratory
  • Brain MRI: Normal or Vermis atrophy
  • EEG: Normal

• Nosology: CALFAN (Low γ-glutamyl-transferase Cholestasis, Acute Liver FAilure, Neurodegeneration)
• Epidemiology: 8 families, 11 patients
• Genetics
  • Mutations: Stop, Splice site, Missense; c.937delG, c.1230+1G>A, c.1509_1510delTG, c.1636C>T
• SCYL1 protein
  • Golgi-Endoplasmic reticulum pathway
  • Nuclear-cytoplasmic tRNA transport
  • Disease: Absent SCYL1; Enlarged Golgi
• Clinical
  • Onset age: Infancy to 3 years
  • Hepatic
    • Liver failure: Acute
    • Jaundice: Neonatal
    • Episodic dysfunction: With fever
    • Hepatosplenomegaly
  • Cerebellar
    • Gait ataxia
    • Tremor, Intention
    • Oculomotor disturbance
  • Polyneuropathy
    • Weakness: Distal; Legs > Arms
    • Sensory: Pin loss; Paresthesias
  • Tendon reflexes: Reduced or Increased
  • Weakness: Proximal
  • Cortical
    • Intellectual disability: Mild
    • Neurogenic stutter
    • Seizures: Few patients
  • Spasticity: 1 patient
  • Skeletal: Short stature, Hip dysplasia, Rib anomalies, Scoliosis
  • Course: Episodes + Slow progression
• Laboratory
  • Brain MRI: Cerebellar vermis atrophy; Optic nerves thin
  • NCV: Axon loss
  • Liver pathology: Microvesicular steatosis; Focal bridging fibrosis

• Epidemiology: 1 Shanxi Chinese family, 2 patients
• Genetics
  • Mutations: Heterozygous; K310E & R246X
  • Allelic disorders
    • Epileptic encephalopathy, early infantile, 44 (EIEE44)
      • Intellectual disability, Hypotonia & Movement disorders
    • Congenital neuropathy, fatal ¹¹⁶
• UBA5 protein
  • Location: Cytoplasm
  • Co-localized with: GM130 (Golgi marker)
  • Ubiquitin-activating protein family
  • E1 enzyme in UFM1 cascade
• Clinical
  • Onset ages: 5 & 8 years
  • Cerebellar: Gait, Limb & Speech disorders; Nystagmus
  • Cataract
  • Growth: Delayed in childhood; Normal later
  • Cognition: Normal
  • Course: Slow progression; Live to adulathood
• Laboratory
  • Brain MRI: Cerebellar atrophy
  • NCV: Polyneuropathy in 1 patient
• UBA5 variant: Congenital Neuropathy
  • Epidemiology: 1 Lebanese-Australian family, 5 patients
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous; p.Arg11Trp
  • Clinical
    • Fetal: Movements reduced; Polyhydramnios
    • Irritability
    • Weakness: Severe; Face, Limbs (Proximal & Distal), Respiratory, Feeding, Soft cry
    • Hypotonia
    • Contractures: Foot or Ankle
    • Fasciculations: Tongue
    • Course: Progressive weakness; Early death at 19 days to 16 weeks
  • Laboratory
    • EMG: High amplitude motor unit potentials
    • NCV: Mildly slow (19 to 21 M/s); Progressive to absent SNAPs & CMAPs
    • Nerve pathology: Axon numbers normal, or mildly reduced, in sural nerve
    • Brain MRI: Normal
    • Serum CK: Normal

• Epidemiology: 1 Turkish family, 2 patients
• Genetics
  • Mutation: Glu122Asp; Homozygous
• ATG5 protein: Autophagy related
• Clinical
  • Onset age: Congenital
  • Psychomotor development
    • Walking: Delayed (2.5 to 4 years) & Unsteady
    • Low IQ, ~70
    • Inability to read or write
  • Cerebellar
    • Ataxia: Truncal
    • Dysmetria: Legs > Arms
    • Nystagmus: Horizontal ± Vertical
  • Tendon reflexes: Increased in legs
  • Course: Non-progressive; some functional improvement
• Laboratory
  • Brain MRI: Cerebellar hypoplasia, especially vermis

• Epidemiology: East Indian female
• Genetics
  • Mutations: Lys431Asn; Gln465X
• XRCC1 protein
  • Interacts with
    • Human polynucleotide kinase (PNK)
    • DNA polymerase-beta (POLB)
    • DNA ligase III (LIG3)
    • Aprataxin
  • Repair single-strand DNA breaks: Due to reactive oxygen species & ionizing radiation
• Clinical
  • Onset age: 28 years
  • Ataxia: Gait disorder; Limb dysmetria; Dysphagia
  • Eyes: Oculomotor apraxia; Nystagmus; Hypermetric saccades
  • Polyneuropathy: Distal; Weakness & Sensory loss
  • Tendon reflexes: Reduced
  • Course: Progressive to loss of ambulation
• Laboratory
  • Nerve conduction studies: Axon loss, Motor & Sensory
  • Brain imaging: Cerebellar atrophy, progressive

• Epidemiology: 3 patients
• Genetics
  • Mutation type: Loss of function
  • Mutations: c.946C4T; p.(Gln316*); c.1305dup; p.(Ser436fs*36); c.1198_1199insG; p.(His400fs*15); c.134del (Pro45Leufs*22)
• GDAP2 protein
  • Brain expression: High
  • Lysosomal membrane
  • Upregulated during neurite sprouting
• Clinical
  • Onset age: 4th decade
  • Ataxia: Dysarthria; Dysmetria, arms & legs; Gait
  • Eyes: Gaze-evoked nystagmus, Jerky pursuit, Hypermetric saccades;
  • Spasticity: Legs > Arms; Tendon reflexes brisk
  • Dementia
  • Strength: Normal
  • Sensation: Normal
  • Course: Progressive disability
• Laboratory
  • Brain MRI: Cerebellar atrophy
  • Pathology: Brain
    • Degenerative changes: Cerebellum, Inferior olive, Thalamus, Substantia nigra, Pyramidal tracts
    • tau pathology: Hippocampus, Amygdala
  • EMG & NCV: Normal

• Epidemiology: 6 patients
• Genetics
  • Mutations: Missense; Deletion; Splice site
• COA7 protein ¹³²
  • Location: Mitochondrial matrix or intermembrane space
  • Disulfide reductase activity
  • Heme-binding
  • Schwann cell cytoplasm
  • Respiratory complex synthesis
    • IV: Early stages
    • Regenerates copper relay system
    • COA7 depletion: Most affects Complexes I & IV
• Clinical
  • Onset age: Infancy to 4th decade
  • Peripheral neuropathy
    • Weakness: Distal legs
    • Sensory loss: Romberg +
    • Tendon reflexes: Reduced
  • Ataxia
    • Dysarthria
    • Gait disorder
  • Cognitive impairment (40%)
  • Encephalopathy: Younger onset patients
  • Course: Progressive
• Laboratory
  • Brain MRI: Cerebellar ± Spinal cord atrophy; Leukoencephalopathy (60%)
  • Serum CK: Mildly high
  • NCV
    • SNAPs: Absent
    • CMAPs: Absent in legs
    • NCV: 49 to 52 M/s
  • Nerve biopsy: Loss of large & medium myelinated axons; Thinly myelinated small axons
  • Muscle: Fiber size varied; Some fibers SDH+ or COX-
  • Mitochondrial oxidative enzymes: Complex IV reduced in 2 patients

• Epidemiology: 1 Turkish family, 2 siblings
• Genetics
  • Mutation: Ala912Val
  • Allelic disorders
    • Zellweger 4A
    • PDB 4B
    • Heimler syndrome 2
• PEX6 protein: Peroxisomal
• Clinical
  • Onset age: 3 years
  • Ataxia: Dysmetria, Adiadochokinesia, Intention tremor, Dysarthria
  • Retinitis pigmentosa
  • Spasticity: 1 patient
• Laboratory
  • Brain MRI: Cerebellar white matter changes
  • NCV: Slow velocities

• Epidemiology: Italian & Mexican families, 5 patients
• Clinical
  • Onset
    • Age: 18 to 30 years
    • Cough
  • Cough: Paroxysmal; Alleviated by water
  • Cerebellar ataxia
    • Onset age: 4th or 5th decade
    • Gait
    • Limbs
    • Tremor
  • Sensory loss: Vibration
  • Restless legs
  • Chorea
  • Tendon reflexes: Absent in legs
  • Muscle atrophy: Distal limbs; Face
  • Oculomotor: Nystagmus; Saccadic hypometria
  • Cognitive dysfunction
• Laboratory
  • MRI: Cerebellar atrophy
  • NCV
    • SNAPs: Amplitudes reduced; Prolonged latencies
    • Motor: Normal
  • BAER: Abnormal

• Epidemiology: 3 families, 6 patients
• Genetics
  • Mutations: Missense & Trunction
• EMC1 protein
  • Tissues: Ubiquitous
  • Endoplasmic reticulum (ER) protein complex
  • ER-mitochondria crosstalk
  • Protein folding
  • Elimination of misfolded membrane proteins
• Clinical
  • Onset age: Early childhood
  • Eyes
    • Visual impairment: Optic atrophy
    • Strabismus
    • Myopia
    • Deep set
  • Developmental delay
    • Global
    • Psychomotor retardation
    • Speech delay
  • Hypotonia: Trunk
  • Dystonia & Increased tone: Extremities
  • Scoliosis
  • Tendon reflexes: Reduced
• Laboratory
  • Brain imaging: Progressive changes
    • Cerebellar atrophy
    • Corpus callosum short
    • cortical atrophy
  • Visual evoked potentials & ERG: Abnormal

• Epidemiology: 14 patients
• Genetics
  • Mutations: Homozygous; Missense; Val55Ala, Leu294Pro, Cys51Trp
• THG1L protein
  • Forms complex with: MFN1; MFN2
  • Mitochondrial fusion
  • Guanylyltransferase: Adds additional G nucleotide to 5' end of mtRNA^His
• Clinical: Spastic ataxia
  • Onset age: 9 to 30 months
  • Ataxia
  • Dysarthria
  • Developmental delay: Motor or Language
  • Cognitive disorder (67%)
  • Pyramidal signs
    • Tendon reflexes: Increased
    • Plantar response: Extensor
• Laboratory
  • Brain MRI: Cerebellar vermis hypoplasia

• Epidemiology: 15 patients; 11 families
• Genetics
  • Mutations: Frameshift, Nonsense, Missense
• AGTPBP1 protein
  • Catalyze deglutamylation of polyglutamylated proteins
  • Upregulated after axotomy
• Clinical
• Onset: Infancy
• Failure to thrive
• Hypotonia
• Eye movements: Strabismus; Nystagmus
• Cortical (100%): Global developmental delay; Intellectual impairment
• Feeding difficulties
• Course: Progressive
• Microcephaly
• Lower motor neuron
  • Muscle: Weakness (Generalized) & Atrophy
  • Motor delay
  • Neurogenic defect
  • Tongue: Fasciculations
  • Respiratory (40%)
• Tendon reflexes: Absent in 60%
• Ataxia
• Pyramidal: Tetraparesis, Spasticity
• Dystonia (30%)
• Hearing loss
• Laboratory
  • Brain: Cerebellar atrophy; Dysplastic (thin) corpus callosum
  • NCV: Axonal motor neuropathy
  • EMG: Denervation
  • Muscle: Accumulation of polyglutamylated tubulin

• Epidemiology: 47 patients
• Genetics
  • Mutations: Nonsense, Frameshift & Missense; Recurrent V335G
• ADPRHL2 protein (ARH3)
  • Locations: Mitochondrial matrix; Cytoplasm; Nuclear
  • ADP-ribosylation (ADPr)
    • Transfer of single or poly-ADP-ribose unit(s) from nicotinamide adenine dinucleotide(NAD) onto target proteins
    • ADPRHL2
      • ADP-ribosylhydrolase
      • Removes posttranslational addition of poly-ADP riboses (PAR) from proteins
    • Stress
      • Poly-ADP ribosyl synthesis increases rapidly by up to 500-fold
      • After stress: ADPRHL2 (ARH3) hydrolytic activity vs ADP ribose polymers modified by ADPr
  • Related actions
    • Cellular stress response pathway
    • DNA damage response/repair
• Clinical
  • Onset age: 1 to 13 years
  • CNS
    • Development: Delay or Regression (90%)
    • Seizures (60%): Infection-related
    • Ataxia
      • Gait disorder; Tremor; Dysmetria
      • Episodic
    • Spasticity
    • Extrapyramidal: Dyskinesias; dystonia
  • Polyneuropathy (85%): Motor > Sensory
    • May be early feature
    • Weakness: Distal; Legs > Arms
    • Sensory loss: Vibration
    • Axon loss: Motor > Sensory
  • Eye: Nystagmus (30%); Hypometric saccades; Ophthalmoplegis (Few patients)
  • Microcephaly (30%)
  • Skeletal: Scoliosis; Pes cavus
  • Respiratory insufficiency (50%)
  • Cardiac (14%): conduction; Hypertrophy
  • Course
    • Progressive
    • Triggering factors: Infection, Stress, Exercise, cold water
    • Sudden death: Some; Child or Adult
• Laboratory
  • Brain MRI pathology: Cerebellar (80%); Other (Basal ganglia; Cortex; corpus callosum)
  • NCV: Axon loss; Motor or Sensory-Motor
  • Nerve biopsy: Axon loss
  • Muscle biopsy: Type 2 atrophy
  • Mitochondrial oxidative enzymes: Normal

• Epidemiology: 4 patients
• Genetics
  • Mutations: Missense, Deletion, Duplication
• POU4F1 protein
  • Nuclear
  • Multifunctional transcription factor
  • Regulates expression of genes involved in differentiation & survival
  • Somatosensory neurons & Brainstem motor nuclei
  • Regulates dorsal root ganglion sensory neuron specification & axonal projection into spinal cord
• Clinical
  • Onset: Childhood
  • Hypotonia
  • Developmental delay
  • Delayed walking (2 to 8 years)
  • Ataxia: Intention tremor, Gait, Dysarthria
  • Eyes: Strabismus; Tonic upgaze
• Laboratory
  • Brain imaging: Cerebellar atrophy & Olive enlargement with age

• Epidemiology: 5 families, 9 patients
• Genetics
  • Mutations: Thr114Ile (Common); Other missense, nonsense, or large deletion
• EXOSC5 protein
  • Exosome
  • Structural subunit of ring-like component of RNA exosome
  • Processing & degradation of RNAs in nucleus & cytoplasm
• Clinical
  • Onset: Infancy
  • Hypotonia
  • Global developmental delay: Most
  • Motor development: Poor, Feeding abnormal
  • Overall growth: Reduced
  • Cerebellar: Gait ataxia; Dysarthria, Nystagmus
  • Ocular anomalies: Varied
  • Pyramidal: Spasticity, Hyperreflexia,
  • Dysmorphic features: Non-specific
  • Cardiac conduction defects
    • Onset: Childhood or Adolescence
    • Often require pacemaker
• Laboratory
  • Brain imaging: Cerebellar ± Brainstem hypoplasia, Ventricles large, Myelination delayed, Corpus callosum thin

• Nosology: Birk-Landau-Perez syndrome
• Epidemiology: 1 Bedouin family; 6 patients
• Genetics
  • Mutation: Homozygous; c.1047_1049delGCA, p.(A350del)
• SLC30A9 protein
  • Tissue expression: Ubiquitous
  • Cytosol: Endoplasmic reticulum
  • Zinc transporter
  • Wnt signalling
• Clinical
  • Psychomotor retardation/regression
  • Speech delay
  • Ataxia: Limbs
  • Tone
    • Hypotonia: Axial
    • Increased: Limbs
  • Camptocormia
  • Dystonia/choreoathetosis
  • Eyes: Oculomotor apraxia; Ptosis; Strabismus
  • Renal (66%): Nephropathy, Early-onset
    • Tubulo-interstitial nephritis
    • Hypertension
    • Hyperkalemia, tendency
    • Course: Stable
• Laboratory
  • Brain MRI: Normal
  • Hyperkalemia: Maximum 5 to 7

• Epidemiology: Common in Japan
• Genetics
  • Mutations: Missense & Deletions
• CTSA protein
  • Ubiquitously expressed
  • Multifunctional enzyme
    • Deamidase
    • Esterase
    • Carboxypeptidase
    • Preference for substrates with hydrophobic amino acid residues at the P1-prime position
  • Lysosomal multienzyme complex
  • Stabilizes lysosomal beta-galactosidase (GLB1 )
  • Activation of lysosomal neuraminidase (NEU1 )
• Clinical
  • Coarse facies
  • Eyse: Cherry red spots; Visual loss
  • Bone: Vertebral changes; Dysostosis
  • Hearing loss
  • Subtypes
    • Early infantile: Fetal hydrops, Edema, Ascites, Visceromegaly, Skeletal dysplasia, Early death
    • Late infantile: Hepatosplenomegaly, Growth retardation, Cardiac, Rare neurologic signs
    • Juvenile/adult: Myoclonus, Ataxia, Angiokeratoma, Mental retardation, Neurologic deterioration, Long survival
  • Neuropathy: Rare; Adolescent onset
    • Sensory axonal: Neuropathic pain & Hyperalgesia attacks
    • ?? Motor axonal: Distal weakness in hands & feet; Anterior horn cell abnormalities
• Laboratory
  • Lysosomal storage disorder: Combined deficiency
    • β-Galactosidase (GLB1 )
    • Neuraminidase (NEU1 )

• Epidemiology
• Genetics
  • Mutations: Missense, Splice & Stop
  • Common mutation in Europe: Arg750Trp
• MAN2B1 protein
  • Cleaves α-linked mannose residues from nonreducing end of N-linked glycoproteins
• Clinical: Continuum of features with 3 general categories
  • Type 1: Mild
    • Onset age: > 10 years
    • CNS: Intellectual disability
    • No skeletal or muscle features
    • Course: Slow progression
  • Type 2: Moderate
    • Onset age: < 10 years
    • Skeletal: Coarse face features;' Bone disease
    • Myopathy: Hypotonia; Macroglossia
    • Hearing: Impaired
    • CNS
      • Developmental delay
      • Mental retardation
      • Psychiatric symptoms
      • Ataxia
    • Eyes: Lens, Cornea
    • Course: Slow progression
  • Type 3: Severe
    • Onset age: Prenatal or Neonatal
    • CNS
    • Course: Early death
• Laboratory
  • Vacuoles: Lymphocytes & Muscle fibers
  • CNS: Storage material
  • Brain MRI: Cerebellar atrophy
  • Immunodeficiency: Frequent infections
  • Urine: Increased mannose-rich oligosaccharides

• Epidemiology: 1 family
• Genetics
  • Mutations: Missense
  • Allelic disorder: Developmental and epileptic encephalopathy 38 (DEE38)
• ARV1 protein
  • Sterols: Trafficking into plasma membrane
  • Sphingolipid metabolism
  • May transport ceramides between endoplasmic reticulum & Golgi apparatus
• Clincal
  • Ataxia
  • Seizures
  • Eyes: Roving movements: Nystagmus
• Laboratory
  • α-fetoprotein: Increased
  • Differential diagnosis: AOA2; AOA4; AT

CONGENITAL ATAXIC DISORDERS

• Cerebellar or vermal aplasia
• Usually Recessive

CONGENITAL ATAXIAS: AUTOSOMAL RECESSIVE or SPORADIC

Joubert syndromes ^{26, 61}

Joubert: General features Types: Usually recessive 1: INPP5E; 9q34 2: TMEM216; 11q12 3: AHI1; 6q23 4: NPHP1; 2q13 5: CEP290; 12q21 6: TMEM67; 8q22 7: RPGRIP1L; 16q12 8: ARL13B; 3q11 9: CC2D2A; 4p15 10: OFD1 (CXORF5); Xp22 11: TTC21B; 2q24; Dominant 12: KIF7; 15q26 13: TCTN1; 12q24 14: TMEM237; 2q33 15: CEP41; 7q32 16: TMEM138; 11q12 17: CPLANE1; 5p13 18: TCTN3; 10q24 19: ZNF423; 16q12 20: TMEM231; 16q23 21: CSPP1; 8q13 22: PDE6D; 2q37 23: KIAA0586; 14q23 24: TCTN2; 12q24 25: CEP104; 1p36 26: KIAA0556; 16p12 27: B9D1; 17p11 28: MKS1; 17q22 29: TMEM107; 17p13 30: ARMC9; 2q37 31: CEP120; 5q23 32: SUFU; 10q24 33: PIBF1; 13q21 34: B9D2; 19q13 35: ARL3; 10q24 36: FAM149B1; 10q22 37: TOGARAM1; 14q21 38: KIAA0753; 17p13 39: TMEM218; 11q24 40: IFT74; 9p21 Joubert: EXOC8; 1q42 Joubert: C2CD3; 11q13 Joubert: SLC30A7; 1p21 COACH syndromes   CC2D2A; 4p15   TMEM67; 8q22 Nephronophthisis   ATXN10; 22q13.31

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)
      • Also see: ALS
        • c21orf2 mutations
        • ALS 24: NEK1
  • Features
    • Clinical & Lab
      • Onset: Congenital
      • Motor
        • Hypotonia
        • Developmental delay
        • Breathing pattern: Episodic hyperpnea or panting
      • Ataxia: Impaired coordination; Dysarthria
      • Intellectual disability
      • Eye movement disorders
        • Oculomotor apraxia
        • Smooth pursuit: Abnormal
        • Nystagmus
      • MRI imaging: Molar tooth sign; Midbrain–hindbrain malformation
        • Interpeduncular fossa: Deep
        • Superior cerebellar peduncles: Elongated & Enlarged
        • Cerebellar vermis: Hypoplasia
        • External link
    • Other associated anatomic disorders
      • Encephalocele 6%: Especially types 5, 6, 7
      • Retina: Especially types 3, 5, 22
        • Chorioretinal coloboma 19%
        • Retinal dystrophy 30%
      • Renal (Cystic) 23%: Less common in types 3, 8
      • Hepatic: Portal hypertension or other 18%; Especially types 5, 6, 7
      • Skeletal: Polydactyly 19%; Especially types 6, 7
  • General clinical syndromes
    • Cerebellar: Type 1
    • Cerebellar + Cortical: Type 3
    • CNS + Multisystem (Kidney; Retina; Liver): Type 2, variable phenotypes
  
  
• Joubert Syndrome, type 1 (JBTS1; Cerebelloparenchymal disorder IV; CPD IV)
  ● Inositol polyphosphate-5-phosphatase, 72-kD (INPP5E) ; Chromosome 9q34.3; Recessive
  
  • Type A Joubert syndrome: Involves brain but not kidneys or retina
  • Epidemiology: Middle Eastern families
  • Genetics
    • Mutations
      • Type: Missense & Stop
      • Location: Catalytic domain
    • Allelic with: Mental retardation, truncal obesity, retinal dystrophy, and micropenis (MORM)
  • INPP5E: PIP phosphatase
  • Neurologic Features
    • Onset age: Congenital; Infantile
    • 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 (JBTS2; Cerebello-oculo-renal syndrome; CORS2) ¹⁹
  ● TMEM216 ; Chromosome 11q12.2; Recessive
  • Type B Joubert syndrome: Involves brain, kidney & retina
  • Epidemiology: Families from Pakistan, United Arab Emirates, Europe
  • Genetics ⁵⁴
    • Mutation in Ashkenazi Jews: R12L
    • Allelic with: Meckel syndrome 2 (MKS2)
      • Occipital encephalocele & Posterior fossa defects
      • Cystic dysplastic kidneys
      • Hepatic bile duct proliferation
      • Polydactyly
  • TMEM216 protein
    • Localized to base of primary cilia
    • Loss of TMEM216: Defective ciliogenesis & centrosomal docking
    • Forms complex with Meckelin
  • Clinical: Variability among families
    • Onset: Infantile
    • Neurologic Features
      • Cerebellar: Ataxia
      • Hydrocephalus
      • Respiratory: Episodic hyperpnea or apnea
    • Eye
      • 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
    • Similar to: Joubert syndrome 16
  • Pathology
    • Cerebellar vermal aplasia
    • Brainstem malformations: "Molar tooth sign"
    • Corpus callosum: Kinked
  
  
• Joubert Syndrome, Type 3 (JBTS3)
  ● Abelson helper integration site 1 (AHI1; Jouberin) ; Chromosome 6q23.3; Recessive
  • Epidemiology: Turkish & Swiss families
  • Genetics ²²
    • 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
  • Clinical
    • Onset
      • Age: Neonatal
      • Breathing problems
      • Hypotonia (100%)
    • Cerebellar: Truncal (100%); Ataxia (50%); Nystagmus (50%)
    • Motor: Late walking or wheelchair bound
    • Cognitive impairment
    • Reduced vision
    • Skeletal: Kyphoscoliosis (30%); Reduced growth (40%)
    • Renal: Normal
  • Laboratory
    • Molar tooth sign (100%)
    • Cerebellar vermis: Hypoplasia
    • Some patients have polymicrogyria
  
  
• Joubert Syndrome, Type 4 (JBTS4)
  ● Nephrocystin 1 (NPHP1) ; Chromosome 2q13; Recessive
  • Epidemiology: 2 siblings
  • Genetics
    • Mutation: Homozygous 290 kb deletion of NPHP1 gene
    • Allelic with
      • Nephronophthisis 1, juvenile
      • Senior-Loken syndrome-1
      • Bardet-Biedl
  • 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 (JBTS5)
  ● Centrosomal protein, 290-KD (CEP290) ; Chromosome 12q21.32; Recessive
  • Cerebello-Oculo-Renal JSRD
  • Epidemiology
    • Multiple families
    • More common in: Japan; Saudi Arabia
  • Genetics
    • Mutations: Missense & Termination
    • Allelic disorders
      • Senior-Loken syndrome 6
      • Meckel syndrome 4
      • Episodic ataxia, Recessive
      • Leber congenital amaurosis 10
      • Bardet-Biedl syndrome 14
  • cep290 protein
    • Localization: Basal body
    • Colocalizes with CC2D2A
  • 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 (JBTS6)
  ● Transmembrane protein 67 (TMEM67; MKS3; Meckelin) ; Chromosome 8q22.1; Recessive
  • Epidemiology: 4 patients
  • Genetics
    • Mutations
      • Missense, Splice site & Termination
      • Heterozygous
      • Iranian families: Asn242Ser
    • Also mutations in
      • Meckel-Gruber syndrome
      • COACH syndrome
  • TMEM67 protein
    • Colocalized with α-tubulin at primary cilia
  • Clinical
    • Onset age: Gestation or Childhood
    • 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 (JBTS7) ³⁶
  ● RPGRIP1-like protein (RPGRIP1L; NPHP8) ; Chromosome 16q12.2; Recessive
  • Cerebello-Renal JSRD
  • Epidemiology: 7 families
  • Genetics
    • Mutations: Loss of function & missense
    • Allelic with
      • Meckel syndrome 5 : Complete loss of function mutations
      • COACH syndrome 3
  • 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 (JBTS8) ⁴¹
  ● ADP-ribosylation factor-like protein 13B (ARL13B; ARL2-like protein 1) ; Chromosome 3q11.1; Recessive
  • Epidemiology: 5 families
  • Genetics
    • Mutations: Missense & Stop
  • ARL13B protein
    • Ras GTPase family
    • Functions: Ciliogenesis; Body axis formation; Renal function
    • Expressed in developing murine cerebellum
    • Localized to cilia in primary neurons
    • Interaction: KIAA0556
  • Clinical: Typical Joubert syndrome
    • CNS
      • Hypotonia
      • Ataxia
      • Retardation & Psychomotor delay
      • Oculomotor ataxia
    • Obesity: 1 patient
    • Retinal: Normal or Optic atrophy
    • Renal: Normal
  • Laboratory
    • Brain MRI: Molar tooth sign
    • ERG: May be absent
  • Mouse: hennin
  
  
• Joubert Syndrome, Type 9 (JBTS9) ⁴⁵
  ● Coiled-coil and C2 domains-containing protein 2A (CC2D2A) ; Chromosome 4p15.32; Recessive
  • Epidemiology: > 20 families
  • Genetics: Mutations
    • Loss of function
    • Homozygous: Often
    • Missense, Splice & Nonsense: P1122S; R1528C; R950X; L1551P; V1097FfsX1; R1019X/pQ1096H
    • Joubert syndrome: Often with at least 1 missense mutation
    • Allelic disorders
      • COACH 2
      • Meckel syndrome 6 (MKS6)
      • Retinitis pigmentosa 93
  • CC2D2A protein
    • Localization: Basal body complex
    • Co-localizes with: cep290
    • Expressed in all fetal & adult tissues
  • Clinical
    • Joubert syndrome, uncomplicated
    • Abnormal eye movements: Common
    • Seizures
    • Retinal dystrophy: Few patients
    • No polydactyly
    • Renal & Liver disease: Occasional
  • Laboratory
    • MRI: Molar tooth sign; Ventriculomegaly
  
  
• Joubert Syndrome 10, X-linked (JBTS10) ⁵³
  ● CXORF5 (OFD1) ; Chromosome Xp22.2; 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
  
  
• Joubert Syndrome 11 (JBTS11) ⁵⁸
  ● Tetratricopeptide repeat domain 21B (TTC21B) ; Chromosome 2q24.3; Dominant
  • Epidemiology: Turkish & European familes
  • Genetics
    • Mutations: Missense
    • Allelic with
      • Meckel syndrome (MKS)
      • Bardet-Biedl syndrome (BBS)
      • Nephronophthisis
      • Jeune asphyxiating thoracic dystrophy
    • Syndromes may be Dominant or Recessive
    • Mutations may modify other ciliopathy syndromes
  • Protein: IFT139
    • Retrograde intraflagellar transport protein
    • Negatively modulates sonic hedgehog transduction
  • Clinical
    • Joubert syndrome
  • Mouse: 'alien' (aln)
  
  
• Joubert Syndrome 12 (JBTS12)
  ● Kinesin family member 7 (KIF7) ; Chromosome 15q26.1; Recessive
  • Epidemiology: 4 familes
  • Genetics
    • Mutations: Nonsense & Frameshift
    • Allelic disorders
      • Acrocallosal syndrome (ACLS)
      • Hydrolethalus-2 (HLS2)
    • Patients with possible digenic inheritance: Mutations in TMEM67 + Heterozygous KIF7
  • KIF7 protein
    • Cilia-associated protein
    • Belongs to kinesin family: Role in hedgehog signaling pathway via regulation of GLI transcription factors
    • Role in regulation of microtubule acetylation & stabilization
    • Co-precipitates with NPHP1
  • Clinical
    • CNS: Mental retardation
    • Skeletal: Polydactyly (Especially hallux); Hypertelorism; Macrocephaly
    • Other (Some patients): Hypotonia; Ataxia; Optic atrophy; Ventricular septal defect
  • Laboratory
    • Brain MRI: Corpus callosum, absent
  
  
• Joubert Syndrome 13 (JBTS13)
  ● Tectonic family, member 1 (TCTN1) ; Chromosome 12q24.11; Recessive
  • Epidemiology: Bangladeshi family
  • Mutation: Splice-acceptor; Homozygous
  • Clinical
    • Onset: Congenital
    • Joubert syndrome
    • Eye & Renal: Normal
  • Brain MRI: Cerebellar vermis hypoplasia; Molar tooth sign
  
  
• Joubert Syndrome 14 (JBTS14) ⁶³
  ● Transmembrane protein 237 (TMEM237; ALS2CR4) ; Chromosome 2q33.1; Recessive
  • Epidemiology: Canadian Hutterite, Jordanian, Hispanic & Austrian
  • Genetics: Stop, frameshift & splice site mutations
  • TMEM237 protein
    • Localization: Ciliary transition zone
    • Tetraspan membrane protein
    • Control: Basal body-transition zone anchoring to membrane; Ciliogenesis
    • Interacts with nphp-4
    • Mutation: Defective ciliogenesis; Deregulation of Wnt signaling
  • Clinical
    • Severe Joubert syndrome (MKS)
    • Cystic kidney
    • Eye
      • Optic atrophy
      • Morning glory disc anomaly
      • Nystagmus
      • Strabismus
    • Death: 2 days to 28 years
  • Laboratory
    • MRI: Molar tooth sign; Dandy-Walker; Cerebellar vermis hypoplasia
    • Cystic kidney
  
  
• Joubert Syndrome 15 (JBTS15) ⁶⁴
  ● Testis-specific protein 14 (TSGA14; CEP41) ; Chromosome 7q32; Recessive
  • Epidemiology: Egyptian & Portuguese families
  • Mutations
    • Splice site: Premature stop
    • Homozygous
  • CEP41 protein
    • Centrosomal
    • Cilia & Centrioles
    • Tubulin glutamylation: Mediates transport of TTLL6 between basal body and cilium
    • Mutation: Disabled ciliary motility
  • Clinical
    • Joubert syndrome
    • Hypotonia
    • Psychomotor delay & Mental retardation
    • Oculomotor apraxia (50%)
    • Renal: Normal
  • Laboratory
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome 16 (JBTS16)
  ● Transmembrane protein 138 (TMEM138) ; Chromosome 11q12.2; Recessive
  • Epidemiology: Arab families, consanguinous
  • Genetics: Missense or Splice site mutations
  • TMEM138 protein function: Assembly & function of cilia
  • Clinical: Similar to Joubert syndrome 2
    • Oculomotor apraxia
    • Coloboma: Variable
    • Renal: Rare
  • MRI: Molar tooth sign
  
  
• Joubert Syndrome 17 (JBTS 17) ⁶⁶
  ● Ciliogenesis and planar polarity effector 1 (CPLANE1; c5orf42) ; Chromosome 5p13.2; Recessive
  • Epidemiology: French-Canadian families, Lower St. Lawrence region; Chinese families
  • Genetics
    • Mutations: Missense, Splice site & Truncating
    • Allelic disorder: Orofaciodigital syndrome VI
  • CPLANE1 protein
    • Cilium assembly
    • Nuclear envelope
  • Clinical
    • Developmental delay: Global
      • Walking: Onset 2.5 to 8 years
      • Cognitive: Borderline intelligence to Mild intellectual disability
    • Oculomotor apraxia
    • Breathing abnormality: Hyperventilation episodes
  • Laboratory
    • MRI: Molar tooth sign
    • No retinal or renal pathology
  
  
• Joubert Syndrome 18 (JBTS 18)
  ● Tectonic family, member 3 (TCTN3) ; Chromosome 10q24.1; Recessive
  • Epidemiology: Turkish family, 2 patients
  • Genetics
    • Mutation: Homozygous; Missense; Gly314Arg
    • Allelic with: Mohr-Majewski Syndrome; Orofaciodigital syndrome IV
  • TCTN3 protein
    • Ciliary related functions
    • Necessary for transduction of sonic hedgehog (SHH) signaling pathway
  • Clinical
    • Onset age: Congenital
    • Skeletal: Kyphoscoliosis
    • Mental retardation: 1 patient
    • Eye movements: Abnormal in 1 patient
    • Renal: Horseshoe kidney in 1 patient
  • MRI
    • Molar tooth sign
    • Cerebellar vermis agenesis
  
  
• Joubert Syndrome 19 (JBTS 19)
  ● Zinc Finger Protein 423 (ZNF423) ; Chromosome 16q12.1; Recessive or Dominant
  
  • Epidemiology: 3 patients
  • Genetics
    • Missense & Frameshift mutations
  • Clinical
    • Cerebellar vermis hypoplasia
    • Leber congenital amaurosis
    • Renal: Polycystic kidney disease; Nephronophthisis
  
  
• Joubert Syndrome 20 (JBTS 20)
  ● Transmembrane protein 231 (TMEM231) ; Chromosome 16q23.1; Recessive
  • Epidemiology: 2 French-Canadian families
  • TMEM231 protein
    • Component of ciliary complex
  • Clinical
    • Developmental delay: Nonverbal; Nonambulatory
    • Aggressive behavior
    • Oculomotor apraxia
    • Breathing abnormalities
    • Postaxial polydactyly
    • Retinal involvement
  • Laboratory
    • Renal cysts: Normal renal function.
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome 21 (JBTS21)
  ● Centrosome and spindle pole associated protein 1 (CSPP1) ; Chromosome 8q13.2; Recessive
  • Epidemiology: > 25 families
  • Genetics
    • Mutations: Truncating
  • CSPP1 protein
    • Core Centrosomal
    • Ciliogenesis
    • Interacts with Myo-GEF; RPGRIP1L (NPHP8)
    • Location: Base & Transition zone of primary cilium
  • Clinical: Multiple phenotypes
    • Hypotonia
    • Developmental delay
    • Intellectual disability
    • Ataxia
    • Eye: Oculomotor apraxia; Nystagmus; Ptosis
    • Respiratory: Neonatal Hyperpnea & Apnea
    • Hearing loss
    • Syndromes
      • Joubert
      • Meckel-Gruber
      • Jeune Asphyxiating Thoracic Dystrophy
  • Laboratory
    • MRI: Variable
      • Molar tooth sign
      • Cerebellar vermis dysgenesis
      • Heterotopias
      • Corpus callosum: Hypopolasia
      • Brainstem hypoplasia (50%)
      • Encephalocele: Few patients
  
  
• Joubert Syndrome 22 (JBTS22)
  ● Phosphodiesterase 6D, cGMP-specific, rod, delta (PDE6D) ; Chromosome 2q37.1; Recessive
  • Epidemiology: 1 family, 3 siblings
  • Genetics
    • Mutation: IVS3AS, G-A, -1; Exon 3 skip & Premature termination
  • PDE6D protein
    • Component of phosphodiesterase cGMP-PDE: Stabilizes catalytic dimer
    • Modulates cGMP degradation
    • Protein network targeting phospholipid phosphatase INPP5E to ciliary membranes
    • PDE-delta binds to farnesylated small G proteins
    • Localization: Endoplasmic reticulum & Golgi
  • Clinical
    • Intrauterine growth retardation
    • Facial dysmorphism
    • Postaxial polydactyly: Feet, syndactyly
    • Renal hypoplasia
    • Eye: Microphthalmia; Coloboma; Retinal dysplasia
  • Laboratory
    • Brain MRI: Joubert syndrome
    • Electroretinogram: Absent activity
  
  
• Joubert Syndrome 23 (JBTS23)
  ● KIAA0586 gene (KIAA0586; TALPID3) ; Chromosome 14q23.1; Recessive
  • Epidemiology: 9 patients; 2.5% of Joubert
  • Genetics
    • Mutations: Compound heterozygous or Homozygous
    • Common mutation: Truncating; 1-BP DEL, 428G
  • Clinical
    • Development: Delayed development
    • Eye movements: Abnormal
    • Breathing patterns: Abnormal
  • Laboratory
    • Brain MRI: Molar tooth sign; Brainstem heterotopia
  
  
• Joubert Syndrome 24 (JBTS24) ⁶¹
  ● Tectonic family, member 2 (TCTN2) ; Chromosome 12q24.31; Recessive
  • Epidemiology: Bangladeshi, Turkish families
  • Genetics
    • Mutation: Splice-acceptor & Stop; Homozygous
    • Allelic with: Meckel Syndrome 8 (MKS8)
  • Clinical
    • Onset: Congenital
    • Hypotonia
    • Eye & Renal: Normal
  • Brain MRI: Cerebellar vermis hypoplasia
  
  
• Joubert Syndrome 25 (JBTS25) ⁹¹
  ● Centrosomal protein of 104 kDa (CEP104) ; Chromosome 1p36.3; Recessive
  • Epidemiology: 32 French-Canadian families; Arab Israeli
  • Genetics
    • Mutations
      • Common: Homozygous c.735+2T>C; Splice-site
      • Other: Nonsense; Splice-site; Frameshift
  • CEP104 protein: Ciliogenesis
    • Regulates conversion of mother centriole into cilia basal body
  • Clinical
    • Onset age: Congenital
    • Global developmental delay
    • Oculomotor apraxia
    • Ataxia
    • Breathing abnormalities
  • Laboratory
    • Brain MRI: Molar tooth sign; Cerebellar atrophy
  
  
• Joubert Syndrome 26 (JBTS26)
  ● KIAA0556 ; Chromosome 16p12.1; Recessive
  • Epidemiology: Saudi Arabian family, 3 patients
  • Genetics
    • Mutation
      • Stop: Gln892X
  • KIAA0556 protein
    • Location: Cilium base
    • Function: Cilium integrity
    • Interactions
      • ARL13B
      • Colocalizes with acetylated alpha-tubulin: Binds to microtubules
  • Clinical: Joubert syndrome, mild
    • Onset age: Congenital
    • Developmental delay
    • Hypotonia
    • Breathing abnormalities: Tachypnea
    • Dysmorphic: Short stature, Ptosis, Frontal bossing, Hypertelorism
    • Nystagmus
  • Laboratory
    • MRI: Molar tooth sign; Cerebellar (vermis) & Pituitary hypoplasia; Pituitary posterior ectopic
    • Pan-Hypopituitarism: Hypothyroid; Growth hormone deficiency
  
  
• Joubert Syndrome 27 (JBTS27) ⁹¹
  ● B9 Domain-containing protein 1 (B9D1; MKSR1) ; Chromosome 17p11.2; Recessive
  • Epidemiology: 1 French-Canadian individual
  • Genetics
    • Mutations
      • Compound-heterozygous
      • Nonsense (c.493C>T; p.Gln165*; Missense (c.151T>C; p.Ser51Pro)
    • Allelic disorder: Meckel 9
  • B9D1 protein
    • Associates with basal bodies & primary cilia
    • Localize to transition zone complex within cilium
  • Clinical
    • Oculomotor apraxia
    • Ataxia
    • Breathing abnormalities
  • Laboratory
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome (JBTS) ¹³³
  ● C2 Calcium-dependent domain-containing protein 3 (C2CD3) ; Chromosome 11q13.4; Recessive
  • Epidemiology: 1 family, 2 French-Canadian individuals
  • Genetics
    • Mutations
      • Compound-heterozygous
      • Nonsense (c.5929C>T; p.Arg1977*); Missense (c.5227G>T; p.Gly1743Cys)
    • Allelic disorder: Orofaciodigital syndrome 14
  • C2CD3 protein: Regulates
    • Cilia formation
    • Hedgehog signaling
    • Embryonic patterning
    • Centriole length
  • Clinical
    • Global developmental delay: Severe
    • Oculomotor apraxia
    • Ataxia
    • Breathing abnormalities
    • No systemic features
  • Laboratory
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome (JBTS) ⁹¹
  ● Solute carrier family 30 (Zinc transporter), Member 7 (SLC30A7) ; Chromosome 1p21.2; Dominant de novo
  • Epidemiology: 2 patients
  • Mutations: Missense
  • SLC30A7 protein
    • Zinc efflux
  • Clinical
    • Postaxial polydactyly
    • Macrocephaly
    • Ataxia
    • Oculomotor apraxia
    • Neurodevelopmental delay
    • Precocious puberty
  • Laboratory
    • MRI: Molar tooth sign
  
  
• Joubert Syndrome (JBTS)
  ● Exocyst complex component 8 (EXOC8) ; Chromosome 1q42.2; Recessive
  • Epidemiology: 1 family
  • Genetics
    • Mutation: E265G
  • EXOC8 protein: Part of ciliary proteome
  • Clinical: No information
  
  
• Joubert Syndrome 28 (± Agenesis of Corpus Callosum) (JBTS 28) ⁹⁷
  ● MKS1 ; Chromosome 17q22; Recessive
  • Epidemiology: 12 patients
  • Genetics
    • Mutations: Missense' Deletion; Splice site
    • Allelic with: Meckel syndrome 1
  • MKS1 protein
    • Related to: Basal bodies; Primary cilia
  • Clinical
    • Facial dysmorphism
    • Camptodactyly
    • Ataxia
    • Developmental delay
  • Laboratory
    • Brain MRI: Molar tooth sign
  
  
• Joubert Syndrome 29 (JBTS29)
  ● TMEM107 ; Chromosome 17p13.1; Recessive
  • Epidemiology: 1 Caribbean patient
  • Genetics
    • Mutations: Stop
    • Allelic with
      • Meckel syndrome 13
      • Orofaciodigital syndrome XVI
  • Protein
    • Proximal region of ciliary axoneme
    • Regulating ciliary protein composition
  • Clinical
    • Psychomotor development: Delayed; Intellectual disabilit
    • Ataxia
    • Oculomotor apraxia
    • Retinopathy
    • Liver involvement
  • Laboratory
    • Cerebellar hypoplasia
    • Molar tooth sign
  
  
• Joubert Syndrome 30 (JBTS30) ⁹⁹
  ● LisH domain-containing protein ARMC9 (ARMC9; KIAA1868) ; Chromosome 2q37.1; Recessive
  • Epidemiology: 8 families; 1% of Joubert syndromes; Caucasian & Saudi Arabia
  • Genetics
    • Mutations: Missense or Stop
  • ARMC9 protein
    • Cilia
    • Basal body & Daughter centriole
    • Expression high in: Brain; Ovary
  • Clinical
    • Joubert syndrome
    • Developmental disability: Motor & Speech function
    • Eyes: Movements Abnormal; Ptosis
    • Renal & Hepatic: Normal
  • Laboratory
    • CNS: Molar tooth sign; Dysplasia of superior cerebellar folia
  
  
• Joubert Syndrome 31 (JBTS31)
  ● Centrosomal protein, 120-KD (CEP120) ; Chromosome 5q23.2; Recessive
  • Epidemiology: 4 families, 4 patients
  • Genetics
    • Mutations: Missense; Stop; Small insertion
    • Allelic disorder: Short-Rib Thoracic Dysplasia 13 (SRTD13)
  • CEP120 protein
    • Interkinetic nuclear migration (INM)
    • Regulation of centrosome-associated microtubules
  • Clinical
    • Onset age: Congenital
    • Hypotonia
    • Developmental delay: Cognitive impairment
    • Some patients: Ataxia; Neonatal breathing abnormalities
    • Other organs: Normal
  • Laboratory
    • Brain MRI: Molar tooth sign
  
  
• Joubert Syndrome 32 (JBTS32) ¹⁰²
  ● Suppressor of fused, drosophila, homolog of (SUFU) ; Chromosome 10q24.32; Recessive
  • Epidemiology: 2 families, 4 children
  • Genetics
    • Mutations: Missense
    • Allelic disorders
      • Basal cell nevus syndrome, Dominant
      • Medulloblastoma, desmoplastic, Dominant
      • Meningioma, familial, susceptibility to
      • Congenital ocular motor apraxia + mild Joubert
        • Mutations: Heterozygous truncating or splice
  • SUFU protein
    • Component of Sonic hedgehog (SHH) /Patched (PTCH) signaling pathway
    • Mutants: Reduced SUFU stability & GLI3 binding
  • Clinical
    • Onset: Congenital
    • Ataxia
    • Cranio-facial dysmorphisms: Hypertelorism, Depressed nasal bridge, Frontal bossing)
    • Postaxial polydactyly
    • Ocular motor apraxia, Congenital
  • Laboratory
    • Brain MRI
      • Cerebellum: Vermis hypoplasia; Elongated superior peduncles (mild "Molar tooth sign"M)
      • Polymicrogyria
  
  
• Joubert Syndrome 33 (JBTS33)
  ● Progesterone-induced blocking factor 1 (PIBF1) ; Chromosome 13q21.3-q22.1; Recessive
  • Epidemiology: 4 Hutterite families
  • Genetics
    • Mutations: Missense; In-frame deletions
  • PIBF1 protein
    • Produced by progesterone receptor -positive T lymphocytes, mainly gamma-delta T cells
    • Transcription factor
    • Cytokine
  • Clinical
    • Developmental delay, mild to moderate
    • Ataxia
  • Laboratory
    • Brain MRI: Molar tooth (60%); Vermian hypoplasia, Superior cerebellum dysplasia, Superior cerebellar peduncles thick
  
  
• Joubert Syndrome 34 (JBTS34)
  ● B9 domain-containing protein 2; (B9D2) ; Chromosome 19q13.2; Recessive
  • Epidemiology: 2 patients
  • Genetics
    • Mutations: Missense
    • Allelic disorder: Meckel syndrome (MKS10)
  • B9D2 protein
    • Colocalized with ciliary basal bodies
    • Present along ciliary axonemes
    • Interacts with gamma-tubulin
  • Clinical
    • Seizures
    • Polydactyly
    • Face: Dysmorphic
  • Laboratory
    • Brain MRI: Molar tooth sign; Hydrocephalus
  
  
• Joubert Syndrome 35 (JBTS35)
  ● ADP-Ribosylation factor-like 3 (ARL3) ; Chromosome 10q24.32; Recessive
  • Epidemiology: 2 families, 4 patients
  • Genetics
    • Mutations: Missense; R149H, R149C
  • ARL3 protein
    • GTP-binding protein: RAS family
    • Location: Centrosomes, Cytoplasmic punctae, Nucleus
  • Clinical
    • Ages: 5 to 21 years
    • Developmental delay
    • Hypotonia
    • Ataxia
    • Retinal rod-cone dystrophy: Night blindness: Visual loss, progressive
    • Renal: Variable involvement
    • Thermal regulation: Abnormal
    • Face: Dysmorphic
  • Laboratory
    • Brain MRI: Molar tooth sign; Cerebellar vermis hypoplasia
  
  
• Joubert Syndrome 36 (JBTS36)
  ● Family with sequence similarity 149, member B1 (FAM149B1) ; Chromosome 10q22.2; Recessive
  • Epidemiology: 4 Middle Eastern families, 6 patients
  • Genetics
    • Mutations: Frameshift; Nonsense; c.356_357delAG, c.439C-T
  • FAM149B1 protein
    • Ciliary development
    • Interacts with: TBC1D32
    • Mutation: Abnormal cilia in fibroblast culturs; SHH dysregulation
  • Clinical
    • Onset age: Early infancy
    • Developmental delay: Global; Hypotonia
    • Eyes: Strabismus; Ptosis; Oculomotor apraxioa
    • Mesoaxial polydactyly
  • Laboratory
    • Brain imaging: Molar tooth sign to Normal
  
  
• Joubert Syndrome 37 (JBTS37)
  ● TOG array regulator of axonemal microtubules 1 (TOGARAM1) ; Chromosome 14q21.2; Recessive
  • Epidemiology: 7 patients
  • Genetics
    • Mutations: Missense, Nonsense, Deletion
  • TOGARAM1 protein
    • Regulates cilia microtubule structure
  • Clinical
    • Onset age: Congenital
    • CNS
      • Neurodevelopmental delay: speech poor or absent
      • Hypotonia
      • Ataxia
      • Cognitive impairment
      • Behavioral abnormalities
    • Other
      • Systemic: Genital, Renal & Liver Δ
      • Polydactyly
      • Face: Dysmorphic; Microphthalmia
      • Microcephaly
  • Laboratory
    • Brain malformations: Cerebellar hypoplasia; Lissencephaly
  
  
• Joubert Syndrome 38 (JBTS38)
  ● KIAA0753 ; Chromosome 17p13.1; Recessive
  • Epidemiology: 2 patients, 1 family
  • Genetics
    • Mutations: Arg257Gly; Splice (IVS15AS, G-C, -1)
    • Allelic disorder
      • Orofaciodigital syndrome XV
  • KIAA0753 protein
    • Expression: Ubiquitous
  • Clinical
    • Onset age: Congenital
    • Hypotonia
    • Developmental delay, Global
    • Eye movements abnormal
    • Breathing disorders
  • Laboratory
    • Brain MRI: Cerebellar vermis hypoplastic; Superior cerebellar peduncles abnormal; Pituitary Δ
    • Growth hormone deficiency
  
  
• Joubert Syndrome 39 (JBTS39)
  ● Transmembrane Protein 218 (TMEM218) ; Chromosome 11q24.2; Recessive
  • Epidemiology: 3 families, 5 patients
  • Genetics
    • Mutations: Missense
    • Allelic disorder: Meckel syndrome
  • TMEM218 Protein
    • Component of a large macromolecular complex
    • Transition zone (TZ) at cilia base
    • Associations: Cep290; RPGRIP1L (MKS5)
  • Clinical
    • Developmental delay
    • Retinal abnormalities
  • Laboratory
    • Brain MRI: Molar tooth sign
  
  
• Joubert Syndrome 40 (IFT74)
  ● Intraflagellar Transport 74 (IFT74; CCDC2; CMG1) ; Chromosome 9p21.2; Recessive
  • Epidemiology: 4 Chinese families, 5 children
  • Genetics
    • Mutations
      • Compound Heterozygous
      • Missense (Gln179Glu) + Truncating
    • Allelic disorder: Bardet-Biedl syndrome 22 (BBS22)
  • IFT74 protein
    • Member of IFT-B complex: Involved in anterograde transport of ciliary proteins
    • Stabilizes IFT-B complex
    • Required for association of IFT-A & IFT-B complexes at base of flagellum
    • Involved in flagellar import of IFT-A
  • Clinical
    • Hypotonia
    • Global development delay: Impaired intellectual development
    • Eye (Some patients)
      • Oculomotor apraxia
      • Optic nerve: Hypoplasia
    • Postaxial polydactyly
  • Laboratory
    • Brain MRI: Molar tooth sign