Spinocerebellar Ataxia 21

A number sign (#) is used with this entry because spinocerebellar ataxia-21 (SCA21) is caused by heterozygous mutation in the TMEM240 gene (616101) on chromosome 1p36.

Description

Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurologic disorder characterized by onset in the first decades of life of slowly progressive cerebellar ataxia, which is associated with cognitive impairment in most patients (summary by Delplanque et al., 2014).

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

Clinical Features

Devos et al. (2001) reported a 4-generation French family segregating an autosomal dominant form of spinocerebellar ataxia. Eleven affected members showed variable symptoms of cerebellar ataxia, limb ataxia and akinesia, dysarthria, dysgraphia, hyporeflexia, postural tremor, rigidity, resting tremor, cognitive impairment, and cerebellar atrophy. Eye movements were generally normal, with 1 case of microsaccadic pursuit and square wave jerks. Age of onset ranged from 6 to 30 years, and 10 informative parent-child pairs suggested genetic anticipation. By mutation or linkage analysis, Devos et al. (2001) excluded known causative genes and loci for SCA.

Delplanque et al. (2008) reported follow-up of the large family from northeastern France reported by Devos et al. (2001). At least 17 individuals were affected. The average age at onset was 16.5 years (range, 1 to 30), and there was some evidence of genetic anticipation. All affected individuals had mild gait ataxia, and most had extrapyramidal signs, including parkinsonism, tremor, cogwheel rigidity, and mild akinesia. Treatment with L-DOPA did not improve the symptoms. Ophthalmologic examination showed intermittent microsaccadic pursuits and square wave jerks without ophthalmoplegia; 1 patient had nystagmus. Most patients, even the young ones, had mild cognitive impairment. Brain MRI of 1 patient showed cerebellar atrophy. Postmortem examination of an affected individual who died of cancer showed only a mild decrease of Purkinje cells in the cerebellar vermis, with no intracellular inclusions. No patients had motor or sensory deficits, extensor plantar responses, or fasciculations.

Delplanque et al. (2014) reported another follow-up of the French family with SCA21 originally reported by Devos et al. (2001) and also described 7 additional French families with the disorder. Most patients had delayed psychomotor development beginning in early childhood and later showed mild to severe mental retardation with frontal behavioral abnormalities, such as impulsivity, aggression, and apathy. Most patients had onset of gait ataxia and clumsiness between 1 and 20 years of age, although the single probands in 3 of the families presented much later, between 40 and 61 years of age. Additional features included dysarthria, dysgraphia, nystagmus, slow ocular saccades, and cerebellar atrophy on brain imaging. More variable features included tremor, increased or decreased deep tendon reflexes, and extensor plantar responses. The disorder was slowly progressive.

Inheritance

The transmission pattern of SCA21 in the family reported by Devos et al. (2001) was consistent with autosomal dominant inheritance. Delplanque et al. (2008) presented evidence of genetic anticipation in this family.

Mapping

By linkage analysis in the large French family with SCA21 originally reported by Devos et al. (2001), Delplanque et al. (2014) found linkage to a 3.58-Mb candidate region on chromosome 1p36.33-p36.32 (maximum 2-point lod score of 6.64 at D1S243).

Molecular Genetics

In affected members of 8 unrelated French families with SCA21, Delplanque et al. (2014) identified 6 different heterozygous mutations in the TMEM240 gene (see, e.g., 616101.0001-616101.0005). There were 5 missense mutations and 1 truncating mutation. The mutation in the first family was found by linkage analysis combined with whole-exome sequencing. Mutations in the 7 additional families were found by direct sequencing of the TMEM240 gene in 368 French pedigrees with autosomal dominant SCA. The mutations affected highly conserved residues, but functional studies of the variants were not performed.

History

Using genomewide linkage analysis in the family reported by Devos et al. (2001), Vuillaume et al. (2002) mapped the SCA21 locus to 24-cM region flanked by markers D7S2464 and D7S516 on chromosome 7p21.3-p15.1. By direct sequencing, Delplanque et al. (2008) excluded mutations in 10 genes within the candidate SCA21 region on chromosome 7q in the family reported by Devos et al. (2001). The disorder in this family was later mapped by Delplanque et al. (2014) to chromosome 1p36.33-p36.32