Autosomal dominant cerebellar ataxia type III: a review of the phenotypic and genotypic characteristics

Abstract

Autosomal Dominant Cerebellar Ataxia (ADCA) Type III is a type of spinocerebellar ataxia (SCA) classically characterized by pure cerebellar ataxia and occasionally by non-cerebellar signs such as pyramidal signs, ophthalmoplegia, and tremor. The onset of symptoms typically occurs in adulthood; however, a minority of patients develop clinical features in adolescence. The incidence of ADCA Type III is unknown. ADCA Type III consists of six subtypes, SCA5, SCA6, SCA11, SCA26, SCA30, and SCA31. The subtype SCA6 is the most common. These subtypes are associated with four causative genes and two loci. The severity of symptoms and age of onset can vary between each SCA subtype and even between families with the same subtype. SCA5 and SCA11 are caused by specific gene mutations such as missense, inframe deletions, and frameshift insertions or deletions. SCA6 is caused by trinucleotide CAG repeat expansions encoding large uninterrupted glutamine tracts. SCA31 is caused by repeat expansions that fall outside of the protein-coding region of the disease gene. Currently, there are no specific gene mutations associated with SCA26 or SCA30, though there is a confirmed locus for each subtype. This disease is mainly diagnosed via genetic testing; however, differential diagnoses include pure cerebellar ataxia and non-cerebellar features in addition to ataxia. Although not fatal, ADCA Type III may cause dysphagia and falls, which reduce the quality of life of the patients and may in turn shorten the lifespan. The therapy for ADCA Type III is supportive and includes occupational and speech modalities. There is no cure for ADCA Type III, but a number of recent studies have highlighted novel therapies, which bring hope for future curative treatments.

Figure 1

This flowchart explains diagnostic algorithm for ADCA Type III. After excluding the cases presenting with cerebellar signs plus non-cerebellar features and secondary cerebellar ataxias, we suggest the appropriate genetic testing based on geographic distribution (patient’s country of origin). If the genetic tests are negative for known ADCA Type III gene mutations, we suggest to perform genetic testing for subtypes of ADCA Type I, which could possibly present with pure cerebellar syndrome at the early stage of illness. After excluding these diseases, other familial forms of disorders presenting with cerebellar signs should be considered. ADCA: autosomal dominant cerebellar ataxia; MRI: magnetic resonance imaging; SCA: spinocerebellar ataxia; USA: the United States of America.