Spinocerebellar Ataxia Type 3, SCA3 - ATX3

Machado-Joseph disease, MJD

Klinische Symptomatik

SCA3 is characterized by progressive cerebellar ataxia and variable findings including a dystonic-rigid syndrome, a Parkinsonian syndrome, or a combined syndrome of dystonia and peripheral neuropathy.

Genetik

Machado-Joseph disease (MJD) is caused by expansion of a CAG repeat of the ATX3 (ataxin3, MJD) gene on the long arm of chromosome 14 (14q24.3-qter). The longer glutamine stretch leads to the formation of a structurally altered protein. Ataxin-3 is a ubiquitin-specific protease that binds and cleaves ubiquitin chains  As with other CAG repeat expansion disorders, an inverse relationship exists between the age of onset and the number of CAG repeats in the expanded allele. However, other genetic or non-genetic factors may also contribute. In addition, a loose correlation between the repeat number and the clinical phenotype has been described.

MJD is an autosomal dominant disease. Instability of the CAG repeat has been documented in transmission of the repeat from parent to child. Overall, repeat expansion (up to 8 tripletts) is more frequent than contraction (up to 5 tripletts); thus, anticipation (earlier age of onset and more severe disease manifestations in offspring) occurs. The probability of expansion may be greater with paternal than with maternal transmission.

 

	Repeats
normal allele	< 44
pathological allele, reduced penetrance	45-51
pathological allele	> 51

Häufigkeit

> 1:20 000
SCA3 is the most frequent form (25-35%) of the dominantly inherited SCAs

 

Diagnostik