Appendix - Classification of Spinocerebellar Ataxias

Name

Locus

Phenotype

SCA1 (autosomal dominant type1)

6p23 with > 40 CAG repeats (Exonic) Ataxin1

Ataxia with ophthalmoparesis, pyramidal and extrapyramidal findings, chorea, spasticity, neuropathy, ophthalmoplegia

SCA2 (autosomal dominant type 2)

12q24.1 with > 31CAG repeats (Exonic) Ataxin2

Ataxia with slow saccades, ophthalmoplegia, and minimal pyramidal and extrapyramidal findings, levodopa-responsive parkinsonism, tremor, chorea, myoclonus, seizures, areflexia, neuropathy, dementia

SCA3 (Machado-Joseph disease) (autosomal dominant type 3)

14q24.3-q31 with > 38 CAG repeats (Exonic) Allelic to Machado-Joseph disease (MJD) Ataxin3

Ataxia with ophthalmoparesis, diplopia and variable pyramidal and extrapyramidal signs, spasticity, muscle weakness, and amyotrophy, psychosis, dystonia, neuropathy. Gene has been also associated with parkinsonian phenotype.

SCA4 (autosomal dominant type 4)

16q22.1

Ataxia with normal eye movements, sensory axonal neuropathy, and pyramidal signs

SCA5 (autosomal dominant type 5) Also called Lincoln ataxia

Centromeric region of chromosome 11, 11p11-q11

Ataxia and dysarthria, early onset, slow course

SCA6 (autosomal dominant type 6)

19p13 with > 20 CAG repeats in α1A-voltage-dependent calcium channel gene, CACNA1A (Exonic)

Ataxia, dysarthria, diplopia, nystagmus, mild proprioceptive sensory loss, dystonia, normal life span, may be episodic

SCA7 (autosomal dominant type 7)

3p21.1-p12 with > 30 CAG repeats (Exonic) Ataxin7

Ophthalmoparesis, visual loss, ataxia, dysarthria, extensor plantar response, spasticity, pigmentary retinal degeneration, dementia

SCA8 (autosomal dominant type 8)

13q21 with > 91 CTG repeats (untranslated) (10q23-q24)

Gait ataxia, dysarthria, seizures, diplopia, nystagmus, tremor; leg spasticity and reduced vibratory sensation, normal life span

SCA9

Not assigned

-

SCA10 (autosomal dominant type 10)

22q13, > 800 ATTCT, noncoding, Ataxin10

Gait ataxia, dysarthria, nystagmus, partial complex and generalized motor seizures, tremor, spasticity, Mexican families

SCA11 (autosomal dominant type 11)

15q14-q21.3

Slowly progressive gait and extremity ataxia, dysarthria, vertical nystagmus, hyperreflexia, mild

SCA12 (autosomal dominant type 12)

5q31-q33, > 66 CAG repeats in the promotor region, coding for protein phosphatase 2A

Tremor, bradykinesia, parkinsonism, dementia, hyperreflexia

SCA13 (single French family)

19q13.3-q13.4 (6q27 with CAG repeats in the TATA binding protein gene)

Gait and extremity ataxia, hyperflexia, extensor plantar responses, dysarthria, dysphagia, mental retardation, dementia, short stature

SCA14 (autosomal dominant type 14)

19q13.4, Protein kinase C γ

Pure ataxia in late-onset (>39), myoclonus and ataxia in young-onset

SCA15 (one Australian family)

3p24.2-pter (6q27 with CAG repeats)

Pure ataxia, slowly progressive

SCA16 (one Japanese family)

8q22.1-24.1

Ataxia, head and hand tremor

SCA17

6q27 with > 42 CAG repeats, TATA-Box binding protein

Ataxia, chorea, dystonia, dementia, psychosis, seizures, HD-like phenotype

SCA18 (one Irish-American family)

7q22-q32

Neuropathy

SCA19 (one Dutch family)

1p21-q23

Dementia, myoclonus; might be allelic with SCA22

SCA19

-

-

SCA20 (autosomal dominant)

11 (but awaiting differentiation from SCA5)

Palatal myoclonus (tremor) and dysphonia, dentate calcification [Knight et al, 2004]

SCA21 (one French family)

7p21.3-p15.1

Ataxia, parkinsonism, tremor, hyporeflexia, dementia

SCA22 (one Chinese family)

1q21-q23

Chinese family, age at onset 10-46, gait ataxia, dysarthria, hyporeflexia, slowly progressive pure cerebellar ataxia and atrophy; might be allelic with SCA19

SCA23 (one Dutch family)

20p13-p12.3

Ataxia, decreased vibratory sense in lower extremities

Spinocerebellar ataxia with saccadic intrusions (formerly known as SCA24)

SCASI, 1p36, autosomal recessive

Ataxia, dysarthria, pyramidal signs, macrosaccadic oscillations, sensory loss of all modalities in legs and feet

SCA25 (autosomal dominant) (one French family)

2p15-21

French family with ataxia and sensory neuropathy, onset 17 months to 39 years, may be similar to Friedreich's ataxia

SCA26

19p13.3

Pure cerebellar ataxia, imaging demonstrating cerebellar atrophy sparing pons

SCA27

FGF14

Ataxia associated with high frequency hand tremor and orofacial dyskinesias

SCA28

AFG3L2, 18p11.22

Slowly progressive ataxia with ophthalmoparesis

SCA29

3p26

Autosomal dominant congenital nonprogressive cerebellar ataxia with or without cerebellar hypoplasia. Found to overlap with SCA15 gene.

SCA30

4q34.3-q35.1

Slowly progressive adult onset cerebellar ataxia with minor pyramidal signs and no neuropathy

SCA31 (Japanese form of SCA4)

16q22, PLEKHG4, puratrophin-1

Almost purely cerebellar ataxia, autosomal dominant

SCA35

20p13-12.2, TGM6

Autosomal dominant ataxia, tremor, cervical dystonia

Dentatorubropallidoluysian atrophy (DRPLA) (autosomal dominant)

12p13.31, > 36 CAG repeats, Atrophin-1, c-Jun NH(2)-terminal kinase (JNK)

Ataxia, choreoathetosis, dystonia, seizures, myoclonus, dementia parkinsonism, hyporeflexia

Friedreich's ataxia (autosomal recessive)

9q13-q21.1 with intronic GAA repeats, Frataxin

Ataxia, areflexia, extensor plantar responses, position sense deficits, cardiomyopathy, diabetes mellitus, scoliosis, foot deformities; defective iron transport from mitochondria

Friedreich's ataxia (autosomal recessive)

9p13 (intron 1), GAA repeats, Frataxin

Same as phenotype with maps to 9q but associated with vitamin E deficiency

Kearns-Sayre syndrome (sporadic)

MtDNA deletion and duplication mutations

Ptosis, ophthalmoplegia, pigmentary retinal degeneration, cardiomyopathy, diabetes mellitus, deafness, heart block, increased CSF protein, ataxia

Autosomal recessive spastic ataxia of Charlevoix-Saguenay

SACS 13q11-12

Childhood-onset, Ataxia, spasticity, retinal striations, dysarthria, axonal peripheral neuropathy, distal atrophy, atrophy of upper cerebellar vermis

Myoclonus 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

Leigh's disease; subacute necrotizing encephalopathy (maternal inheritance or autosomal recessive)

MtDNA complex V defect (ATPase gene at 8993) or mitochondrial protein synthesis defect (both maternally inherited); or complex IV defect (autosomal recessive)

Obtundation, hypotonia, cranial nerve defects, respiratory failure, hyperintense signals on T2-weighted magnetic resonance images in basal ganglia, cerebellum, or brainstem; ataxia

Ataxia telangiectasia (autosomal recessive)

11q22-23; ATM gene for regulation of cell cycle. Mitogenic signal transduction, and meiotic recombination

Telangiectasia, ataxia, slow saccades, ocular apraxia, dysarthria, dystonia and chorea may be present, pulmonary infections, neoplasms of lymphatic system; IgA and IgG deficiencies; diabetes mellitus, breast cancer

Infantile-onset spinocerebellar ataxia of Nikali et at. (autosomal recessive)

10q23.3-q24.1

Infantile ataxia, sensory neuropathy; athetosis, hearing deficit, ophthalmoplegia, optic atrophy; primary hypogonadism in females

Ataxia with oculomotor apraxia type 1 (AOA1) / Early-onset ataxia with oculomotor apraxia and hypoalbuminemia (EAOH); Shimazaki et al, 2002

APTX, Aprataxin , 9p13.3, autosomal recessive, associated with DNA single-strand and double-strand break repair machinery

Ataxia, oculomotor apraxia, may have chorea and peripheral neuropathy. Presentation similar to ataxia telangiectasia but without immune deficiencies and diabetes.

Ataxia with oculomotor apraxia type 2 (AOA2) (autosomal recessive); Le Ber et al 2004

SETX, Senataxin, linked to 9q34

Ataxia with later onset than AOA1, may be associated with oculomotor apraxia, elevated AFP, CK, and gamma globulin levels. SETX gene is also associated with Juvenile ALS Type 4.

Episodic Ataxia

Name

Locus

Phenotype

Episodic ataxia, type I (EA-1) (autosomal dominant)

12p; potassium channel gene KCNA-1

Episodic ataxia for minutes; provoked by startle or exercise; with facial and hand myokymia; cerebellar signs are not progressive; responds to phenytoin

Episodic ataxia, type II (EA-2) (autosomal dominant)

19p-13(CACNA1A) (allelic with SCA6) alpha1A-voltage dependent calcium channel subunit)

Episodic ataxia for days: provoked by stress, fatigue; with down-gaze nystagmus; cerebellar atrophy; progressive cerebellar signs; responds to acetazolamide. Gene also associated with familial hemiplegic migraine and idiopathic generalized epilepsy.

Episodic ataxia, type III (EA-3)

-

Episodic vestibular ataxia, vertigo, tinnitus and interictal myokymia. Responds to acetazolamide.

Episodic ataxia, type IV (EA-4)

PATX

Progressive ataxia, vertigo, diplopia

Episodic ataxia, type V (EA-5)

CACNB4

Dysarthria, episodic ataxia, spontaneous and gaze evoked nystagmus. Responds to acetazolamide. Gene also involved in juvenile myoclonic epilepsy.

Episodic ataxia, type VI (EA-6)

SLC1A3 involved in glutamate transport

Episodic ataxia with seizures, migraine, and alternating hemiplegia

Episodic ataxia, type VII (EA-7)

Autosomal dominant, 19q13

Episodic ataxia with weakness and dysarthria