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Spinocerebellar ataxias (SCA) are a group of progressive, autosomal dominantly inherited cerebellar ataxias (ADCA). Common clinical sign of all subtypes include ataxia, dysarthria and nystagmus. Characteristic features of each subtype are summarized in the attached table. From a clinical point of view one can distinguish three subtypes of ADCA: ADCA I with cerebellar and extracerebellar symptoms; ADCA II with cerebellar symptoms and pigmentary retinal degeneration; and ADCA III with purely cerebellar symptoms. Symptoms of the respective subtypes overlap significantly, making a precise clinical diagnosis difficult in many cases. The prevalence of all ADCA in Europe is 1-2 per 100.000. In the table the relative frequencies of each subtype are given. SCA3 (35%) and SCA6 (25%) are the most common SCA subtypes in Western Germany. As these frequencies differ significantly in different populations, these values are only correct for Western Germany and maybe quite different in other countries.
In most SCA types in which the genetic cause has been elucidated, an abnormal expansion of a polymorphic nucleotide repeat block has been found (exception: SCA14). Most of these microsatellites are coding (CAG)n blocks within the respective gene, making these subtypes members of the family of polyglutamine diseases (like Huntington’s disease, DRPLA and others). Instability of the (CAG)n block, leading to further expanded alleles, accounts for the clinical phenomenon of anticipation, i.e. earlier onset and possibly more severe disease course in subsequent generations.
SCA type % of all ADCA
(Western Germany)
genomic localisation gene mutation characteristics SCA1 approx. 10% 6p23 ATXN1 coding CAG expansion (>39) pyramidal signs; peripheral neuropathy; sometimes external ophthalmoplegia and/or dementia SCA2 approx. 10% 12q24.1 ATXN2 coding CAG expansion (>32) slow saccades; poor tendon reflexes; tremor SCA3/MJD approx. 35% 14q21 ATXN3/
MJD1
coding CAG expansion (>52) dystonia; rigor/spasticity; protusio bulbi; facio lingual myokyma; with 53/54 CAG sometimes only peripheral symptoms (neuropathy; restless legs) SCA6 approx. 25% 19q13.4 CACNA1A coding CAG expansion (>20) later onset; slow progression;
sometimes peripheral neuropathy and pyramidal signs; point mutations in the CACNA1A gene are associated with episodic ataxia type 2 and familial hemiplegic migrainSCA7 rare 3p21.1-p12 ATXN7 coding CAG expansion (>36) pigmentary degeneration of the retina (sometimes before the onset of cerebellar symptoms); strong anticipation phenomena esp. with paternal transmission SCA8 rare 13q21 KLHL1AS CTG expansion (3'UTR) (>80) sometimes spasticity; impaired vibration sensitivity; pathogenetic relevance of the expansion is not confirmed formally
(rare polymorphism?)SCA10 very rare 22q13 ATXN10 ATTCT expansion (intron) (>280) most patients are of Mexican orogin; epilepsy; pyramidal signs; peripheral neuropathy SCA12 very rare 5q31 PPP2R2B CAG expansion (promotor) (54) onset with tremor; slow progression; sometimes dementia SCA14 rare 19q13.4 PRKCG point mutations observed in European and Japanese families; cerebellar symptoms,
variable symptoms, sometimes with myokclonus; head tremorSCA17 rare 6q27 TBP coding CAG expansion (>44) dystonia; parkinsonism; spasticity; dementia; sometimes resembling Huntington's disease For most of the other hereditary SCA types genomic loci have also been mapped. However, the specific disease responsible gene has not yet been identified. Direct molecular genetic testing is therefore not yet available for these SCA types.
Dr. med. S. Wieczorek
Humangenetik
Gebäude MA 5
Ruhr-Universität
Universitätsstr. 150
44801 Bochum
GermanyTel.: +49 234 32 23831
Fax: +49 234 32 14196
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