Spinocerebellar ataxia (repeat expansion analysis)

All forms share the leading symptom of progressive ataxia. In addition to gait instability, disorders of oculomotor function and speech, trunk and limb ataxia, intention tremor, and further neurological symptoms may occur. Depending on the subtype, additional features include ophthalmoplegia, dementia, extrapyramidal signs, optic atrophy, amyotrophy, and retinal degeneration. The age of manifestation is usually between 30 and 50 years, but onset may also occur in childhood or after the sixth decade of life.

Depending on clinical manifestation, three ADCA types are distinguished:

ADCA type 1 is characterised by cerebellar ataxia combined with ophthalmoplegia, dementia, extrapyramidal signs, optic atrophy, and amyotrophy. One form of ADCA type 1 is SCA17, which is phenotypically variable and complex. Due to its broad clinical spectrum, SCA17 can mimic other neurodegenerative diseases such as Huntington disease, Parkinson disease, other movement disorders, and cerebellar diseases. Patients have also been described who present exclusively with psychiatric symptoms, including dementia, bipolar psychosis, and paranoia, without ataxia or movement disorders. Due to the clinical similarity to Huntington disease, SCA17 is also called Huntington disease-like syndrome 4 (HDL4).

ADCA type 2 includes only SCA7 and is characterised by progressive cerebellar ataxia and retinal degeneration.

ADCA type 3 comprises a group of ‘pure’ cerebellar ataxias, of which SCA6 is the most common form.

The prevalence of autosomal dominantly inherited spinocerebellar ataxias is estimated at 0.001–0.005%.

The most common forms of ADCA are polyglutamine (PolyQ) expansion disorders involving ATXN1 (SCA1), ATXN2 (SCA2), ATXN3 (SCA3), CACNA1A (SCA6), ATXN7 (SCA7), TBP (SCA17), and ATN1 (DRPLA). These disorders are caused by pathological CAG triplet repeat expansions within different genes. As with other triplet repeat disorders, anticipation is observed within families, characterised by an earlier age of onset and a more severe disease course in successive generations. The genetic cause has not yet been clarified for all ADCA subtypes.

Spinocerebellar ataxias of the ADCA group are inherited in an autosomal dominant manner.

If clinical symptoms are not clearly attributable to a specific subtype, molecular genetic diagnostics can be used to support classification, particularly in clinically variable forms such as SCA17.

SCA17 shows a broad and complex phenotype and can mimic other neurodegenerative disorders, including Huntington disease, Parkinson disease, other movement disorders, and cerebellar diseases. Patients with SCA17 may also present exclusively with psychiatric symptoms such as dementia, bipolar psychosis, or paranoia, without ataxia or movement disorders.

• Coarelli et al. 2018, F1000Research 7(F1000 Faculty Rev):1781
• Ashizawa et Xia 2016, Continuum (Minneap Minn) 22:1208
• Sun et al. 2016, Clin Genet 90:305
• Reetz et al. 2011, PLoS ONE 6:e15125
• Manto et Marmolino 2009, Curr Opin Neurol 22:419
• Gao et al. 2008, Eur J Hum Genet 16:215
• Ranum et Cooper 2006, Annu Rev Neurosci 29:259
• Riess et al. 2001, Dt Ärzteblatt 23:1319
• David et al. 1997, Nature Genet 17:65
• Zhuchenko et al. 1997, Nature Genet 15:62
• Imbert et al. 1996, Nature Genet 14:285
• Kawaguchi et al. 1994, Nature Genet 8:221