Spinocerebellar Ataxia 21 with Retardation

Investigators at Universite de Lille Nord de France, and other centers in France, report the identification of a novel causative gene for spinocerebellar ataxia 21, an autosomal dominant disorder, initially mapped to chromosome 7 and designated as SCA21. The gene, TMEM240, has various mutations in eight SCA families. The ataxia was first described in a large French family with slowly progressive cerebellar ataxia, mental retardation, and severe cognitive impairment in two young children. The present researchers identified a coding mutation in the TMEM240 gene in the original SCA21 pedigree. To date, 37 different genetic loci have been associated with SCA subtypes, and 22 causative genes have been identified. Screening by whole exome sequencing of 368 French families from the SPATAX network of hereditary paraplegias and cerebellar ataxias detected the causative mutation in two other unrelated families.

The clinical features of patients with TMEM240 mutations are as follows: 1) early onset with delayed cognitive and motor skills; 2) mental retardation with frontal behavior disorders (impulsivity, aggressive, apathy); 3) clumsiness presenting age 2 to 20 years; and 4) cerebellar ataxia. Cognitive impairments in 3 children tested at age 9-13 yrs and 3 adults (25-54 yrs) involved abstract reasoning, visual working memory, visual episodic memory, executive functions, visuospatial functions, speed of information processing, and selective attention. MRI shows cerebellar atrophy of the vermis and hemispheres with sparing of brainstem. Mild iron overload is noted in several cases, most severe in red nucleus and pallidum. [1]

COMMENTARY. Childhood onset SCAs and their clinical features in addition to ataxia include dentatorubropallidoluysian atrophy (chorea, dystonia, seizures, dementia), SCA13 (mental retardation), SCA with tremor, cognitive defects, and facial dyskinesia, and Friedreich ataxia variant [2]. Testing for SCA21 is recommended in families with early onset mild or slowly progressive ataxia, particularly when associated with moderate to severe cognitive impairment. The causative gene in SCA21, TMEM240, is highly expressed in the cerebellum, dentate gyrus, putamen and caudate nucleus. The authors note that another transmembrane protein (TMEM237) is involved in Joubert syndrome-related disorders, characterized by midbrain malformation with hypoplasia of the cerebellar vermis [3].