Spinocerebellar Ataxia 20

A number sign (#) is used with this entry because spinocerebellar ataxia-20 (SCA20) is caused by a heterozygous 260-kb duplication on chromosome 11q12, and is thus a contiguous gene duplication syndrome.

Description

SCA20 is an autosomal dominant adult-onset disorder characterized by dysarthria due to spasmodic dysphonia followed by slowly progressive ataxia (summary by Knight et al., 2004).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Knight et al. (2004) reported a family of Anglo-Celtic origin with a relatively pure form of autosomal dominant spinocerebellar ataxia. Fourteen affected members were examined. The age at onset ranged from 19 to 64 years (mean and median both 46.5 years), with an average 10-year earlier onset in the children of affected parents. The most common presenting symptom was dysarthria (in 9 of 14 patients) due to spasmodic dysphonia, which was not associated with laryngeal muscle paralysis. Dysarthria and dysphonia were followed by gait ataxia in 7 patients and upper limb ataxia in 2. There was slow disease progression, with only 1 affected member becoming wheelchair-dependent after 40 years of symptoms. Other variable features included mild pyramidal signs, hypermetric saccades, and mild nystagmus. Palatal tremor or myoclonus was apparent in 10 patients. CT scan showed pronounced dentate calcification in 9 of 9 patients who were imaged. Direct testing for CAG and ATTCT repeat expansions was negative.

Coutinho et al. (2006) reported 6 Portuguese families in which a total of 19 individuals were affected with autosomal dominant spinocerebellar ataxia and spasmodic coughing episodes. Paroxysmal coughing attacks first occurred at 25 to 55 years of age, whereas signs of cerebellar ataxia developed later at 40 to 65 years of age. In most patients, the coughing came in bursts without clear precipitating factors, occurred daily, and lasted several minutes. The coughing episodes tended to decrease in frequency and severity with age and after the onset of cerebellar ataxia. There was no evidence of respiratory diseases, allergies, or gastric complaints. Ten patients with long-standing disease had downbeat nystagmus, and 1 patient had dentate calcifications. Coutinho et al. (2006) suggested that the disorder in these families may be similar to that reported by Knight et al. (2004) and may result from dysfunction of cerebellar neural networks that influence breathing and coughing reflexes.

Mapping

Genomewide linkage analysis of the family reported by Knight et al. (2004) identified a disease locus, designated SCA20, in a pericentromeric region on chromosome 11 (lod score of 4.47 at marker D11S4191). Haplotype analysis defined a 25.4-Mb interval between markers D11S903 and FGF3 (164950). Knight et al. (2004) noted that the SCA20 candidate region overlaps with that of SCA5 (600224).

Lorenzo et al. (2006) refined the SCA20 candidate region to a 23.6-Mb interval between D11S903 and KAD199. Although the SPTBN2 gene (604985), responsible for SCA5, maps within the SCA20 region, detailed molecular analysis in an affected member of the original SCA20 family (Knight et al., 2004) revealed no pathogenic mutations. Lorenzo et al. (2006) concluded that SCA20 and SCA5 are genetically distinct disorders.

Cytogenetics

In affected members of the family with SCA20 reported by Knight et al. (2004), Knight et al. (2008) identified a heterozygous 260-kb duplication at chromosome 11q12.2-12.3 between rs4963307 and rs10897193. The duplicated region was in direct orientation and contains at least 12 genes, including the DAGLA gene (614015), which is expressed in neurons. Knight et al. (2008) noted that SCA20 is the first spinocerebellar ataxia to implicate a copy number variation (CNV).