Spinocerebellar Ataxia Type 1, SCA1 - ATX1

Klinische Symptomatik

The typical age of onset for SCA1 is in the third or fourth decade. The clinical picture includes gait and limb ataxia, dysarthria, hyperreflexia and choreatic movements. The majority of patients initially presents with difficulties in gait, slurred speech, or nystagmus. Mild dysphagia, indicated by coughing after eating, may also occur early in the disease. As the disease progresses, dysdiadochokinesia, extrapyramidal signs such as chorea and dystonia, bulbar difficulties, and fasciculations become apparent. Severe dysphagia may lead to aspiration and pneumonia. Optic nerve atrophy, variable degrees of ophthalmoparesis, and mild cognitive impairment may be detected in some patients. Imaging studies reveal olivopontocerebellar atrophy (OPCA).

Genetik

Spinocerebellar ataxia is caused by an expansion of a CAG repeat in the ATX (ataxin1) gene on the short arm of chromosome 6 (6p22-p23). The repeat expansion is located in the translated region of the ataxin 1 gene. The larger number of glutamine residues results in a structurally altered protein. Many transcriptional co-regulators and proteins involved in RNA binding and metabolism have been shown to interact with ataxin-1.
SCA1 is inherited as autosomal dominant disease. An increase in the severity of the phenotype in later generations, a phenomenon known as anticipation, has been observed in large SCA1 pedigrees. A tendency of the CAG repeat to expand is seen in about two thirds of transmissions to subsequent generations. Expansions are more likely to occur when the mutation is paternally transmitted (about +3.3 CAG repeats), and contractions are more typical of maternal transmissions.

 

	Repeats
normal allele	6 - 35
premutation allele, meiotic unstable (uninterrupted by CAG repeats)	36 - 38
pathological allele	> 38

Häufigkeit

1 : 20 000
In Middle-Europe, SCA1 along with SCA2 is the second most common form of the dominantly inherited ataxias

 

Diagnostik