Inherited neurological disorders - spinocerebellar ataxia

Description

Spinocerebellar ataxias (SCAs) - a genetically heterogeneous group of predominantly autosomal dominant disorders causing progressive cerebellar ataxia, often with additional neurological features depending on the specific subtype

Numbered SCA subtypes (SCA1, SCA2, SCA3/Machado-Joseph disease - the most common worldwide, SCA6, and many others) each caused by a different gene, most commonly via trinucleotide (CAG) repeat expansion

Most common subtypes are caused by CAG trinucleotide repeat expansion, producing an expanded polyglutamine tract in the resulting protein that causes toxic protein aggregation and progressive neuronal loss, predominantly in the cerebellum and its connections - the same general mechanism as Huntington disease, though in different genes

Anticipation - repeat expansions can lengthen further when transmitted to the next generation, producing progressively earlier onset and/or greater severity in successive generations, a hallmark feature of trinucleotide repeat disorders (see trinucleotide repeat inheritance)
Progressive gait/limb ataxia, dysarthria, and oculomotor abnormalities are common across subtypes; specific additional features (peripheral neuropathy, pyramidal signs, cognitive change, retinopathy) vary by the specific SCA subtype and can help narrow the differential clinically before genetic confirmation
Genetic testing (repeat-length analysis for the common trinucleotide-repeat subtypes) confirms the specific SCA and its inheritance pattern

No disease-modifying treatment currently exists - management is supportive: physiotherapy/occupational therapy for mobility and function, speech therapy for dysarthria, and management of specific associated features
Genetic counselling addresses the autosomal dominant inheritance pattern (50% risk to offspring) and the anticipation phenomenon, which has specific implications for family planning discussions

Huntington disease (shares the CAG-repeat/polyglutamine mechanism), other trinucleotide repeat disorders, multiple system atrophy (an important non-genetic mimic causing acquired, sporadic ataxia)

Anticipation means a young person from a family with a known SCA may develop a more severe, earlier-onset form than their affected parent - a distinctive and clinically important feature of counselling for this condition

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