Spinocerebellar Ataxia, X-Linked 1

A number sign (#) is used with this entry because of evidence that X-linked spinocerebellar ataxia-1 (SCAX1) is caused by mutation in the ATP2B3 gene (300014) on chromosome Xq28. One such family has been reported.

Description

SCAX1 is an X-linked recessive neurologic disorder characterized by hypotonia at birth, delayed motor development, gait ataxia, difficulty standing, dysarthria, and slow eye movements. Brain MRI shows cerebellar ataxia (summary by Bertini et al., 2000).

Genetic Heterogeneity of X-linked Spinocerebellar Ataxia

X-linked recessive spinocerebellar ataxia (SCAX) is a clinically and genetically heterogeneous disorder. See also SCAX2 (302600), SCAX3 (301790), SCAX4 (301840), and SCAX5 (300703).

Clinical Features

Shokeir (1970) described 3 kindreds in which a total of 16 affected individuals had cerebellar ataxia transmitted in an X-linked recessive pattern of inheritance. In 1 family, onset of lower limb weakness, unsteady gait, and incoordination occurred between 16 and 20 years of age, followed by dysarthria and nystagmus. The disorder was rapidly progressive until about age 30 years and later became stable. The proband, a 62-year-old man, also had lower limb spasticity with extensor plantar responses. There were no skeletal deformities or sensory deficits. Affected males in the second family were born of a father-daughter union, although a maternal uncle and great-uncle were reportedly affected. The proband in this family had onset at age 18 of progressive incoordination, dysarthria, dysmetria, nystagmus, tremor, and mild spasticity. The third family had a similar onset and disease course; 1 of the affected persons in this family was a female with the XO Turner syndrome, consistent with X-linked recessive inheritance. The disease did not seem to affect life span, and intelligence was unimpaired.

The propositus of the family studied by Bertini et al. (2000) was first evaluated at age 1 year for delayed motor development. Hypotonia, mild dysphagia, and delayed motor development were noted from birth. At the age of 4 years, he showed action tremor of the upper limbs and slow eye movements, but no pyramidal signs. Brain MRI at age 2 years was normal, but at age 3 years showed global atrophy of the cerebellum. A maternal uncle had had a similar course since birth and had been similarly delayed in achieving psychomotor skills. When examined at age 36 years, he showed moderate dysarthria, unsteady gait with truncal and locomotor ataxia, intention tremor, and limitation of vertical gaze with slow conjugate eye movements. Brain MRI showed severe global atrophy of the cerebellar vermis and hemispheres.

Mapping

Illarioshkin et al. (1996) mapped a locus for X-linked recessive congenital ataxia in a Russian family to a large genetic interval (54 cM) on Xp11.21-q24. In an Italian family with clinical features very similar to those in the Russian pedigree, Bertini et al. (2000) performed a linkage study that narrowed the interval by 24 cM. Exclusion of the interval between DXS990 and DXS424 left 2 critical regions: one of 10 cM at Xq23-q24 and a second of 20 cM at Xp11.21-q21.3.

Heterogeneity

Clinical Heterogeneity

Young et al. (1987) reported a family in which 3 boys, 2 full brothers and a half brother, presented with marked delay in motor milestones, severe limb and truncal ataxia, nystagmus, speech delay and moderate global retardation. Inheritance was most consistent with X-linked recessive.

Lutz et al. (1989) described apparent X-linked inheritance of a relatively pure cerebellar degeneration. Clinical features included infantile onset, cerebellar ataxia, very slow progression, mental retardation, and cerebellar degeneration with involvement of the olive and pons demonstrated by neuroimaging techniques.

In describing a Turkish family with ataxia combined with spastic diplegia in 7 males, Apak et al. (1989) pointed out the confusing state of the nosology of X-linked (spino)cerebellar ataxia/spastic paraplegia. The family they reported showed onset of nystagmus in infancy, with ataxia and pyramidal signs noted at age 2 to 3 years. The patients were never able to walk. Dysarthria, orthopedic impairment, and mild mental retardation appeared later as the disorder progressed. Death occurred in the third or fourth decade from infections. The features did not agree completely with any previously reported X-linked disorders.

Molecular Genetics

In the boy and his uncle with X-linked spinocerebellar ataxia-1 originally reported by Bertini et al. (2000), Zanni et al. (2012) identified a mutation in the ATP2B3 gene (G1107D; 300014.0001). The mutation was identified by X-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutant protein had decreased extrusion of intracellular calcium compared to wildtype, suggesting that the disorder resulted from defective calcium homeostasis in neurons.

History

A kindred with X-linked inheritance of what the authors thought was probably 'Friedreich ataxia' was reported by Turner and Roberts (1938). Onset was at about 5 years of age and the victim was bedfast by about 20 years. The first carrier female in the kindred was of English extraction. Brandenberg (1910) described 4 males with 'Friedreich ataxia' in 3 generations of a family, related through females in a pattern consistent with X-linkage.