Spinocerebellar Ataxia, Autosomal Recessive 2

A number sign (#) is used with this entry because of evidence that autosomal recessive spinocerebellar ataxia-2 (SCAR2) is caused by homozygous or compound heterozygous mutation in the PMPCA gene (613036) on chromosome 9q34.

Description

Autosomal recessive spinocerebellar ataxia-2 is an neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by Jobling et al., 2015).

Clinical Features

Norman (1940) described 3 sibs in 1 family and 2 sibs in another who had cerebellar ataxia and mental deficiency since early life. Postmortem examinations showed severe cerebellar granule cell loss. One child showed delayed motor development and mental deficiency in infancy. Other features included small head, cataracts, increased knee jerks, and intention tremor. He died at age 20 years. Postmortem examination showed marked cerebellar atrophy with complete absence of granule cells in the lateral lobes of the cerebellum and the superior part of the vermis. There were heterotopic Purkinje cells and gliosis (Weiner and Konigsmark, 1971).

Scherer (1933) described 2 affected sibs, and Jervis (1950) 3 affected sibs. Jervis (1954) also observed the disorder in monozygotic Italian twin sisters.

In many members of an inbred Christian Maronite family originating from a village in the northeast of Lebanon, Megarbane et al. (1999) described hereditary congenital nonprogressive cerebellar ataxia. The 12 affected members were thought to have the autosomal recessive Norman type of cerebellar atrophy, also known as primary granular cell atrophy of the cerebellum. The patients in the Lebanese family were of short stature, varying from 136 cm in a 44-year-old female to 164 cm in a 40-year-old male.

Jobling et al. (2015) provided follow-up on the family reported by Megarbane et al. (1999). There were 12 affected individuals, ranging in age from 22 to 46 years, with ataxic gait. All had delayed psychomotor development with delayed speech acquisition and intellectual disability. Additional features included dysarthria, dysmetria, and gaze-evoked nystagmus; brain imaging showed cerebellar atrophy, dilated fourth ventricle, and a large cisterna magna. More variable features included brisk deep tendon reflexes, spasticity, hypotonia, slightly decreased muscle strength, flat feet, and visuospatial deficits. Jobling et al. (2015) also reported 4 patients from 2 additional families of Lebanese descent. These patients had similar ataxic gait, although in some cases the gait abnormalities appeared between 11 and 15 months of age after normal initial development. Features included truncal and gait ataxia, difficulty in fine motor skills, saccadic smooth pursuit, dysmetria, dysdiadochokinesis, and tremor. All but 1 had intellectual disability and delayed speech with dysarthria. A fourth family, of French descent, contained 2 affected sibs, including 1 living 58-year-old man with gait ataxia, dysmetria, gaze-evoked nystagmus, and dysarthria. He had normal intellectual development and his neurologic status was stable over time. An affected sister died at age 29 years.

Choquet et al. (2016) reported 2 brothers of French Canadian descent with SCAR2. There was clinical variability: one developed symptoms of impaired gait, dysdiadochokinesis, dysmetria, and mild distal atrophy in adolescence, whereas the other developed more severe symptoms around age 5; the younger brother also had hemidystonia and sensorineural hearing loss. Neither had intellectual disability, but both had mild learning difficulties. The disorder was slowly progressive in these patients.

Inheritance

The transmission pattern of SCAR2 in the families reported by Jobling et al. (2015) was consistent with autosomal recessive inheritance.

Mapping

By genomewide analysis of the large consanguineous Lebanese family reported by Megarbane et al. (1999), Delague et al. (2001) found linkage to a 12.1-cM interval on chromosome 9q34-qter between markers D9S67 and D9S312.

Molecular Genetics

In 16 individuals from 3 unrelated families of Lebanese descent, including the family reported by Megarbane et al. (1999), Jobling et al. (2015) identified a homozygous missense mutation in the PMPCA gene (A377T; 613036.0001). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the families; haplotype analysis indicated a founder effect. Western blot analysis of affected patients showed markedly decreased levels of the mutant protein (range, 25-50% of control values). Patient cells showed some evidence of improper mitochondrial processing of FXN (606829) with abnormal accumulation of the FXN42-210 isoform and decreased levels of the FXN81-210 isoform, as well as evidence of an increased oxidation/reduction ratio in the mitochondria compared to controls. Direct functional studies of the variant were not performed. Direct sequencing of the PMPCA gene in 46 French individuals with a similar phenotype identified compound heterozygous missense mutations (613036.0002 and 613036.0003) in 1 individual.

In 2 brothers of French Canadian descent with SCAR2, Choquet et al. (2016) identified a homozygous missense mutation in the PMPCA gene (V256M; 613036.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient cells showed abnormal accumulation of the FXN42-210 isoform and decreased levels of the FXN81-210 isoform. Functional studies of the variant were not performed.

Nomenclature

A form of autosomal recessive spinocerebellar ataxia previously designated SCAR1 has been reclassified as autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN2; 606002). A form previously designated SCAR5 has been reclassified as Galloway-Mowat syndrome-1 (GAMOS1; 251300).

Animal Model

Weiner and Konigsmark (1971) noted that infection of the fetal rat by rat virus (Margolis and Kilham, 1968) and of the fetal kitten by panleukopenia virus (Kilham and Margolis, 1966) can result in granule cell hypoplasia.