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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)   ● Sacsin (SACS) ; Chromosome 13q12.12; Recessive Epidemiology Family locations: French-Canadian (Quebec); Tunisia 3; Worldwide Genetics Deletions or point mutations in sacsin gene Produce stop codon Most common Missense mutations also described Similar locus to Early onset cerebellar ataxia with retained reflexes Tunisian family with milder phenotype 3 Variant syndromes Sacsin protein Expressed in fibroblasts, brain, skeletal muscle Subcellular: Mitochondria Interacts with: Dynamin-related protein 1 ? Function in 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 Neurologic Cerebellar Ataxia: Dysarthria; Gait disorder Ocular: Nystagmus (100%); Poor ocular pursuit Eye Conjugate gaze defects Retina: Prominent myelinated nerve fibers (Variable frequency) Motor Spasticity Paraparesis with gait disorder: Most patients Extensor plantar responses Progressive No spasticity: Homozygous Phe304Ser mutation Distal wasting & weakness Legs > Arms More apparent in older patients Sensory: Loss of deep sensations Tendon reflexes: Brisk except at ankles Bladder: Urgency in 65% Dystonia: Mild; Occasional 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 biopsy 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 variant: 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
  • 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)
  • 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