Ataxias with autosomal dominant, autosomal recessive, X-linked, or mitochondrial forms of inheritance are present on a worldwide basis. Machado-Joseph disease (SCA3) (autosomal dominant) and Friedreich’s ataxia (autosomal recessive) are the most common types in most populations. Mutation markers are now commercially available to identify carriers at risk in their families, which allows for precise identification of the genetic mutation for correct diagnosis and also for family planning. Identification of positive mutation carriers with family planning has allowed for early detection of asymptomatic preclinical disease to reduce or eliminate the inherited form of ataxia in specific families on a global, worldwide basis.
TABLE 38-1CLASSIFICATION OF THE SPINOCEREBELLAR ATAXIAS (SCA)
| NAME | LOCUS | PHENOTYPE |
|---|---|---|
| SCA1 (autosomal dominant type 1) | 6p22-p23 with CAG repeats (exonic); leucine-rich acidic nuclear protein (LANP), region-specific interaction protein Ataxin-1 | Ataxia with ophthalmoparesis, pyramidal and extrapyramidal findings; genetic testing is available; 6% of all autosomal dominant (AD) cerebellar ataxia |
| SCA2 (autosomal dominant type 2) | 12q23-q24.1 with CAG repeats (exonic) Ataxin-2 | Ataxia with slow saccades and minimal pyramidal and extrapyramidal findings; genetic testing available; 13% of all AD cerebellar ataxia |
| Machado-Joseph disease/SCA3 (autosomal dominant type 3) | 14q24.3-q32 with CAG repeats (exonic); codes for ubiquitin protease (inactive with polyglutamine expansion); altered turnover of cellular proteins due to proteosome dysfunction MJD–ataxin-3 | Ataxia with ophthalmoparesis and variable pyramidal, extrapyramidal, and amyotrophic signs; dementia (mild); 23% of all AD cerebellar ataxia; genetic testing available |
| SCA4 (autosomal dominant type 4) | 16q22.1-ter; pleckstrin homology domain-containing protein, family G, member 4 (PLEKHG4; puratrophin-1: Purkinje cell atrophy associated protein-1, including spectrin repeat and the guanine-nucleotide exchange factor, GEF for Rho GTPases) | Ataxia with normal eye movements, sensory axonal neuropathy, and pyramidal signs; genetic testing available |
| SCA5 (autosomal dominant type 5) | 11p12-q12; β-III spectrin mutations; (SPTBN2); stabilizes glutamate transporter EAAT4; descendants of President Abraham Lincoln | Ataxia and dysarthria; genetic testing available |
| SCA6 (autosomal dominant type 6) | 19p13.2 with CAG repeats in α1A-voltage–dependent calcium channel gene (exonic); CACNA1A protein, P/Q type calcium channel subunit | Ataxia and dysarthria, nystagmus, mild proprioceptive sensory loss; genetic testing available |
| SCA7 (autosomal dominant type 7) | 3p14.1-p21.1 with CAG repeats (exonic); ataxin-7; subunit of GCN5, histone acetyltransferase-containing complexes; ataxin-7 binding protein; Cbl-associated protein (CAP; SH3D5) | Ophthalmoparesis, visual loss, ataxia, dysarthria, extensor plantar response, pigmentary retinal degeneration; genetic testing available |
| SCA8 (autosomal dominant type 8) | 13q21 with CTG repeats; noncoding; 3′ untranslated region of transcribed RNA; KLHL1AS | Gait ataxia, dysarthria, nystagmus, leg spasticity, and reduced vibratory sensation; genetic testing available |
| SCA10 (autosomal dominant type 10) | 22q13; pentanucleotide repeat ATTCT repeat; noncoding, intron 9 | Gait ataxia, dysarthria, nystagmus; partial complex and generalized motor seizures; polyneuropathy; genetic testing available |
| SCA11 (autosomal dominant type 11) | 15q14-q21.3 by linkage | Slowly progressive gait and extremity ataxia, dysarthria, vertical nystagmus, hyperreflexia |
| SCA12 (autosomal dominant type 12) | 5q31-q33 by linkage; CAG repeat; protein phosphatase 2A, regulatory subunit B, (PPP2R2B); protein PP2A, serine/threonine phosphatase | Tremor, decreased movement, increased reflexes, dystonia, ataxia, dysautonomia, dementia, dysarthria; genetic testing available |
| SCA13 (autosomal dominant type 13) | 19q13.3-q14.4; potassium channel voltage-gated; KCNC3 | Ataxia, legs > arms; dysarthria, horizontal nystagmus; delayed motor development; mental developmental delay; tendon reflexes increased; MRI: cerebellar and pontine atrophy; genetic testing available |
| SCA14 (autosomal dominant type 14) | 19q-13.4; protein kinase Cγ (PRKCG), missense mutations including in-frame deletion and a splice site mutation among others; serine/threonine kinase | Gait ataxia; leg > arm ataxia; dysarthria; pure ataxia with later onset; myoclonus; tremor of head and extremities; increased deep tendon reflexes at ankles; occasional dystonia and sensory neuropathy; genetic testing available |
| SCA15 (autosomal dominant type 15) | 3p24.2-3pter; inositol 1,4,5- triphosphate receptor type 1 (ITPRI) | Gait and extremity ataxia, dysarthria; nystagmus; MRI: superior vermis atrophy; sparing of hemispheres and tonsils |
| SCA16 (autosomal dominant type 16) | 8q22.1-24.1 | Pure cerebellar ataxia and head tremor, gait ataxia, and dysarthria; horizontal gaze–evoked nystagmus; MRI: cerebellar atrophy; no brainstem changes |
| SCA17 (autosomal dominant type 17) | 6q27; CAG expansion in the TATA-binding protein (TBP) gene | Gait ataxia, dementia, parkinsonism, dystonia, chorea, seizures; hyperreflexia; dysarthria and dysphagia; MRI shows cerebral and cerebellar atrophy; genetic testing available |
| SCA18 (autosomal dominant type 18) | 7q22-q32 | Ataxia; motor/sensory neuropathy; head tremor; dysarthria; extensor plantar responses in some patients; sensory axonal neuropathy; EMG denervation; MRI: cerebellar atrophy |
| SCA19 (autosomal dominant type 19) | 1p21-q21; KCND3; missense mutations; T352P; M373I; S390N; allelic with SCA22; overlaps with the locus of SCA22 | Ataxia, tremor, cognitive impairment, myoclonus; MRI: atrophy of cerebellum |
| SCA20 (autosomal dominant) | 11p13-q11; 260 kb duplication | Dysarthria; gait ataxia; ocular gaze–evoked saccades; palatal tremor; dentate calcification on CT; MRI: cerebral atrophy |
| SCA21 (autosomal dominant) | 7p21.3-p15.1 | Ataxia, dysarthria, extrapyramidal features of akinesia, rigidity, tremor, cognitive defect; reduced deep tendon reflexes; MRI: cerebellar atrophy, normal basal ganglia and brainstem |
| SCA22 (autosomal dominant) | 1p21-q23; deletion (in frame); V338E; G345V; T377M; allelic with SCA19; KCND3; Kv4.3 channels | Pure cerebellar ataxia; dysarthria; dysphagia; nystagmus; MRI: cerebellar atrophy |
| SCA23 (autosomal dominant) | 20p13-12.3; prodynorphin (PDYN protein); missense R138S; L211S; R212W; R215C | Gait ataxia; dysarthria; extremity ataxia; ocular nystagmus, dysmetria; leg vibration loss; extensor plantar responses; MRI: cerebellar atrophy |
| SCA25 (autosomal dominant) | 2p15-p21 | Ataxia, nystagmus; vibratory loss in the feet; pain loss in some; abdominal pain; nausea and vomiting may be prominent; absent ankle reflexes; sensory nerve action potentials are absent; MRI: cerebellar atrophy, normal brainstem |
| SCA26 (autosomal dominant) | 19p13.3 | Gait ataxia; extremity ataxia; dysarthria; nystagmus; MRI: cerebellar atrophy |
| SCA27 (autosomal dominant) | 13q34; fibroblast growth factor 14 protein; mutation F145S; produces reduced protein stability | Tremor in extremities and head and orofacial dyskinesia; ataxia of arms > legs, gait ataxia; dysarthria; nystagmus; psychiatric symptoms; cognitive defect; MRI: cerebellar atrophy; genetic testing available |
| SCA28 (autosomal dominant) | 18p11.22-q11.2; ATPase family gene 3- like 2 (AFG3L2 protein) mutations: N432T; S674L; E691K; A694E; R702Q | Extremity and gait ataxia; dysarthria; nystagmus; ophthalmoparesis; leg hyperreflexia and extensor plantar responses; MRI: cerebellar atrophy |
| SCA30 (autosomal dominant) | 4q34.3-q35.1; candidate gene ODZ3 | Candidate gene ODZ3; gait ataxia, dysarthria, saccades; nystagmus, brisk tendon reflexes in legs; MRI: cerebellar atrophy |
| SCA31 (autosomal dominant) | 16q22.1; associated with NEDD4 (BEAN) | Pentanucleotide (TGGAA)n repeat insertions; previously called SCA4; gait ataxia; limb dysmetria; MRI: cerebellar atrophy |
| SCA32 (autosomal dominant) | 7q32-q33 | Ataxia, azoospermia, mental retardation; absent germ cells on testicular biopsy |
| SCA35 (autosomal dominant) | 20p13;TGM6 protein; transglutaminase 6 | Ataxia; ocular dysmetria; upper motor neuron signs; extensor plantars; onset fifth decade |
| SCA36 (autosomal dominant) | 20p13; large intronic expansion of GGCCTG (1500–2500); also phe265leu mutation; RNA gain of function; microRNA; MIR 1292 suppression | Ataxia; onset fifth to sixth decades; motor neuron disorder; grouped atrophy (muscle biopsy) fasciculations; increased reflexes; flexor plantars |
| Prion disease (autosomal dominant) | 20p13;pro102leu; ala 117 val mutations; proteinase k resistant form PrP27-30 accumulates in brain; eponym: Gerstmann-Straüssler-Scheinker disease Glu200Lys mutation; increased octapeptide repeats; eponym: Creutzfeldt-Jakob disease | Ataxia; dementia third to seventh decades Ataxia; dementia; rigidity |
| Multiple hamartoma syndrome (autosomal dominant) | 10q23.31; phosphatase and tensin homolog (PTEN); Cowden’s; Lhermitte-Duclos syndrome | Skin hamartomas; ataxia; mental retardation; increased intracranial pressure; epilepsy |
| Cerebellar ataxia, deafness, and narcolepsy (autosomal dominant) | 19p13.2; exon 21; missense ala570val; val606phe mutations | Ataxia; deafness; narcolepsy cataplexy; REM sleep disorder |
| Cerebellar ataxia (nonprogressive) mental retardation (autosomal dominant) | 1p36.31-p36.23 | Ataxia, mental retardation |
| Familial dementia with amyloid angiopathy and spastic ataxia (autosomal dominant) | 13q14.2; integral membrane protein 2B (ITM2B) | Ataxia; dementia; amyloid angiopathy |
| Dentatorubropallidoluysian atrophy (autosomal dominant) | 12p13.31 with CAG repeats (exonic) Atrophin 1 | Ataxia, choreoathetosis, dystonia, seizures, myoclonus, dementia; genetic testing available |
| Friedreich’s ataxia (autosomal recessive) | 9q13-q21.1 with intronic GAA repeats, in intron at end of exon 1 Frataxin defective; abnormal regulation of mitochondrial iron metabolism; iron accumulates in mitochondria in yeast mutants | Ataxia, areflexia, extensor plantar responses, position sense deficits, cardiomyopathy, diabetes mellitus, scoliosis, foot deformities; optic atrophy; late-onset form, as late as 50 years with preserved deep tendon reflexes, slower progression, reduced skeletal deformities, associated with an intermediate number of GAA repeats and missense mutations in one allele of frataxin; genetic testing available |
| Vitamin E deficiency syndrome (autosomal recessive) | 8q13.1-q13.3 (α-TTP deficiency) | Same as phenotype that maps to 9q but associated with vitamin E deficiency; genetic testing available |
| Sensory ataxic neuropathy and ophthalmoparesis (SANDO) with dysarthria (autosomal recessive) | 15q25; mutations in DNA polymerase-gamma (POLG) gene that leads to mtDNA deletions | Young adult–onset ataxia, sensory neuropathy, ophthalmoparesis, hearing loss, gastric symptoms; a variant of progressive external ophthalmoplegia; MRI: cerebellar and thalamic abnormalities; mildly increased lactate and creatine kinase |
| Von Hippel-Lindau syndrome (autosomal dominant) | 3p26-p25 | Cerebellar hemangioblastoma; pheochromocytoma |
| Baltic myoclonus (Unverricht-Lundborg) (recessive) | 21q22.3; cystatin B; extra repeats of 12–base pair tandem repeats | Myoclonus epilepsy; late-onset ataxia; responds to valproic acid, clonazepam; phenobarbital |
| Marinesco-Sjögren syndrome (recessive) | 5q31; SIL 1 protein, nucleotide exchange factor for the heat-shock protein 70 (HSP70); chaperone HSPA5; homozygous 4-nucleotide duplication in exon 6; also compound heterozygote | Ataxia, dysarthria; nystagmus; retarded motor and mental maturation; rhabdomyolysis after viral illness; weakness; hypotonia; areflexia; cataracts in childhood; short stature; kyphoscoliosis; contractures; hypogonadism |
| Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) | Chromosome 13q12; SACS gene; loss of sacsin peptide activity | Childhood onset of ataxia, spasticity, dysarthria, distal muscle wasting, foot deformity, retinal striations, mitral valve prolapse |
| Kearns-Sayre syndrome (sporadic) | mtDNA deletion and duplication mutations | Ptosis, ophthalmoplegia, pigmentary retinal degeneration, cardiomyopathy, diabetes mellitus, deafness, heart block, increased CSF protein, ataxia |
| Myoclonic epilepsy and ragged red fiber syndrome (MERRF) (maternal inheritance) | Mutation in mtDNA of the tRNAlys at 8344; also mutation at 8356 | Myoclonic epilepsy, ragged red fiber myopathy, ataxia |
| Mitochondrial encephalopathy, lactic acidosis, and stroke syndrome (MELAS) (maternal inheritance) | tRNAleu mutation at 3243; also at 3271 and 3252 | Headache, stroke, lactic acidosis, ataxia |
| Neuropathy; ataxia; retinitis pigmentosa (NARP) | ATPase6 (Complex 5); mtDNA point mutation at 8993 | Neuropathy; ataxia; retinitis pigmentosa; dementia; seizures |
| Episodic ataxia, type 1 (EA-1) (autosomal dominant) | 12p13; potassium voltage-gated channel gene, KCNA1; Phe249Leu mutation; variable syndrome | Episodic ataxia for minutes; provoked by startle or exercise; with facial and hand myokymia; cerebellar signs are not progressive; choreoathetotic movements; responds to phenytoin; genetic testing available |
| Episodic ataxia, type 2 (EA-2) (autosomal dominant) | 19p-13 (CACNA1A) (allelic with SCA6) (α1A-voltage–dependent calcium channel subunit); point mutations or small deletions; allelic with SCA6 and familial hemiplegic migraine | Episodic ataxia for days; provoked by stress, fatigue; with down-gaze nystagmus; vertigo; vomiting; headache; cerebellar atrophy results; progressive cerebellar signs; responds to acetazolamide; genetic testing available |
| Episodic ataxia, type 3 (autosomal dominant) | 1q42 | Episodic ataxia; 1 min to over 6 h; induced by movement; vertigo and tinnitus; headache; responds to acetazolamide |
| Episodic ataxia, type 4 (autosomal dominant) | Not mapped | Episodic ataxia; vertigo; diplopia; ocular slow pursuit defect; no response to acetazolamide |
Episodic ataxia, type 5 (autosomal dominant) Episodic ataxia type 6 with seizures, migraine, and alternating hemiplegia (autosomal dominant) | 2q22-q23; CACNB4β4 protein SLC1A3; 5p13; EAAT1 protein; missense mutations; glial glutamate transporter (GLAST); 1047 C to G; proline to arginine | Episodic ataxia; hours to weeks; seizures Ataxia, duration 2–4 days; episodic hypotonia; delayed motor milestones; seizures; migraine; alternating hemiplegia; mild truncal ataxia; coma; febrile illness as a trigger; MRI: cerebellar atrophy |
| Episodic ataxia, type 7 (autosomal dominant) | 19q13 | Episodic ataxia; vertigo, weakness; less than 24 h |
| Episodic ataxia with paroxysmal choreoathetosis and spasticity (dystonia-9) (DYT9; CSE) (autosomal dominant) | 1p | Ataxia; involuntary movements; dystonia; headache; spastic paraplegia; responds on occasion to acetazolamide |
| Fragile X tremor/ataxia syndrome (FXTAS) X-linked dominant | Xq27.3; CGG premutation expansion in FMR1 gene; expansions of 55–200 repeats in 5’ UTR of the FMR-1 mRNA; presumed dominant toxic RNA effect | Late-onset ataxia with tremor, cognitive impairment, occasional parkinsonism; males typically affected, although affected females also reported; syndrome is of high concern if affected male has grandson with mental retardation (fragile X syndrome); MRI shows increased T2 signal in middle cerebellar peduncles, cerebellar atrophy, and occasional widespread brain atrophy; genetic testing available |
| Ataxia telangiectasia (autosomal recessive) | 11q22-23; ATM gene for regulation of cell cycle; mitogenic signal transduction and meiotic recombination; elevated serum alpha-fetoprotein level; immunoglobulin deficiency | Telangiectasia, ataxia, dysarthria, pulmonary infections, neoplasms of lymphatic system; IgA and IgG deficiencies; diabetes mellitus, breast cancer; genetic testing available; chorea; dystonia |
| Early-onset cerebellar ataxia with retained deep tendon reflexes (autosomal recessive) | 13q11-12 | Ataxia; neuropathy; preserved deep tendon reflexes; impaired cognitive and visuospatial functions; MRI, cerebellar atrophy |
| Ataxia with oculomotor apraxia (AOA1) (autosomal recessive) | 9p21; protein is member of histidine triad superfamily, role in DNA repair; elevation of serum LDL cholesterol and low serum albumin level; APTX, aprataxin | Ataxia; dysarthria; limb dysmetria; dystonia; oculomotor apraxia; optic atrophy; motor neuropathy; late sensory loss (vibration); genetic testing available |
| Ataxia with oculomotor apraxia 2 (AOA2) (autosomal recessive) | 9q34; senataxin protein, involved in RNA maturation and termination; helicase superfamily 1; elevated serum alpha-fetoprotein level; SETX, senataxin | Gait ataxia; choreoathetosis; dystonia; oculomotor apraxia; neuropathy, vibration loss, position sense loss, and mild light touch loss; absent leg deep tendon reflexes; extensor plantar response; genetic testing available |
| Cerebellar ataxia with muscle coenzyme Q10 deficiency (autosomal recessive) | 9p13 | Ataxia; hypotonia; seizures; mental retardation; increased deep tendon reflexes; extensor plantar responses; coenzyme Q10 levels reduced with about 25% of patients with a block in transfer of electrons to complex 3; may respond to coenzyme 10 |
| Refsum’s disease (autosomal recessive) | 10pter; elevated serum phytanic acid level; phytanoyl-COH hydroxylase and PEX7 | Retinitis pigmentosa; ataxia; sensorineural deafness; demyelinating neuropathy |
| Cerebrotendinous xanthomatosis (autosomal recessive) | 2p33; elevated cholesterol level; CYP27; sterol 27 hydroxylase | Spastic ataxia; mental retardation; dementia; tendon xanthomas; diarrhea; cataracts |
| Joubert’s syndrome (autosomal recessive) | 9q34.3 | Ataxia; ptosis; mental retardation; oculomotor apraxia; nystagmus; retinopathy; rhythmic tongue protrusion; episodic hyperpnea or apnea; dimples at wrists and elbows; telecanthus; micrognathia |
| Sideroblastic anemia and spinocerebellar ataxia (X-linked recessive) | Xq13; ATP-binding cassette 7 (ABCB7; ABC7) transporter; mitochondrial inner membrane; iron homeostasis; export from matrix to the intermembrane space | Ataxia; elevated free erythrocyte protoporphyrin levels; ring sideroblasts in bone marrow; heterozygous females may have mild anemia but not ataxia |
| Infantile-onset spinocerebellar ataxia of Nikali et al (autosomal recessive) | 10q23.3-q24.1; twinkle protein (gene); homozygous for Tyr508Cys missense mutations | Infantile ataxia, sensory neuropathy; athetosis, hearing deficit, reduced deep tendon reflexes; ophthalmoplegia, optic atrophy; seizures; primary hypogonadism in females |
| Hypoceruloplasminemia with ataxia and dysarthria (autosomal recessive) | Ceruloplasmin gene; 3q23-q25 (trp 858 ter) | Gait ataxia and dysarthria; hyperreflexia; cerebellar atrophy by MRI; iron deposition in cerebellum, basal ganglia, thalamus, and liver; onset in the fourth decade |
| Spinocerebellar ataxia with neuropathy (SCAN1) (autosomal recessive) | Tyrosyl-DNA phosphodiesterase-1 (TDP-1) 14q31-q32 | Onset in second decade; gait ataxia, dysarthria, seizures, cerebellar vermis atrophy on MRI, dysmetria |
| Cerebellar ataxia type 1 (autosomal recessive) | 6p25 SCAR8; SYNE1; spectrin repeats-nuclear envelope 1 | Pure ataxia |
| Cerebellar ataxia type 2 (autosomal recessive) | 1q42;ADCK3 (CABC1); aarf-domain containing kinase 3; elevation of serum lactate and decreased coenzyme Q10 level | Ataxia; mental retardation; myoclonus; epilepsy; exercise intolerance; stroke or transient ischemic-like episodes |
| Niemann-Pick type C disease | 18q11; NPCI; NPCH1 and 2; skin biopsy (filipin staining) | Ataxia; vertical supranuclear ophthalmoplegia; splenomegaly; dystonia; impaired cognition |
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