Spastic Ataxia 3, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spastic ataxia-3 (SPAX3) is caused by homozygous or compound heterozygous complex genomic rearrangements involving the MARS2 gene (609728) on chromosome 2q33.

For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).

Clinical Features

Thiffault et al. (2006) reported 23 French Canadian individuals from 17 families with spastic ataxia and brain white matter changes. The transmission pattern was consistent with autosomal recessive inheritance. Age at onset ranged from 2 to 59 years with a mean age of 15 years. All patients had ataxic gait, spasticity, and hyperreflexia. Other variable features included urinary urgency (57%), dysarthria (74%), dystonic positioning (57%), mild horizontal nystagmus (44%), scoliosis (35%), and mild hearing impairment (13%). Ten (44%) seemed to have mild cognitive impairment, although formal testing was not performed. Fifty-two percent of individuals were wheelchair-bound at a mean age of 36.6 years. Neuroimaging studies showed cerebellar atrophy in all patients and cerebral atrophy in 43%. About half of patients had nonspecific focal white matter changes in periventricular and deep white matter regions. There was no evidence of a peripheral neuropathy in any patients.

Inheritance

The transmission pattern of SPAX3 in the families reported by Thiffault et al. (2006) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of 3 French Canadian families with autosomal recessive spastic ataxia with leukoencephalopathy, Thiffault et al. (2006) identified a 11.62-cM candidate locus on chromosome 2q33-q34 between markers D2S273 and D2S2321 (maximum multipoint lod score of 5.95). Haplotype analysis delineated a 2.51-cM critical region between D2S1782 and D2S2274 and suggested a founder effect. Sequencing analysis excluded mutations in 4 known genes within the 2.51-cM critical region.

Molecular Genetics

In 54 patients from 38 French-Canadian families with autosomal recessive spastic ataxia-3, most of whom were originally reported by Thiffault et al. (2006), Bayat et al. (2012) identified complex duplication rearrangements of the MARS2 gene. Haplotype analysis indicated that 3 duplication events (609728.0001-609728.0003) involving the MARS2 gene had occurred in their SPAX3 cohort. All patients carried these rearrangements in homozygous or compound heterozygous state, and the rearrangements segregated with the disorders in the families; in addition, a Brazilian patient with a similar phenotype also carried a homozygous duplication. The rearrangements were found using PCR, array CGH, sequencing, and Southern blot analysis. These data suggested that homologies among repeat elements were responsible for complex rearrangements, and Bayat et al. (2012) hypothesized that the numerous repetitive elements present in this gene induced genomic instability and caused template switching during DNA replication, as well as recombination errors. Cultured patient cells showed reduced complex I activity, increased levels of reactive oxygen species, and decreased cell proliferation rates compared to controls. Patient cells had increased levels of MARS2 mRNA, but decreased protein levels. The paradoxical decrease in protein levels may be due to an RNAi-mediated mechanism. Knockdown of MARS2 in HEK293 cells using shRNA caused some decreases in mitochondrial translation, with significant decreases only when protein levels were reduced beyond a certain level. Genotype/phenotype correlation analysis showed that patients with the Dup/Del rearrangement (609728.0001) tended to have an earlier age at onset, as did patients who were homozygous for the Dup1 rearrangement (609728.0002).

Animal Model

Bayat et al. (2012) identified a Drosophila strain homozygous for mutations in the homolog of the human MARS2 gene. Mutant flies had age-dependent degeneration of photoreceptors in the eye, consistent with defects in neuronal function and survival. Other features of these flies included reduced life span, muscle degeneration with abnormal myofibrils and abnormal mitochondria, and impaired cell proliferation in epithelial tissues. Cellular studies of the mutant flies showed defects in oxidative phosphorylation, increased reactive oxygen species, and an upregulation of the mitochondrial unfolded protein response.