Spastic Ataxia 4, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic ataxia-4 (SPAX4) is caused by homozygous mutation in the MTPAP gene (613669) on chromosome 10p11. One such family has been reported.

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

Clinical Features

Crosby et al. (2010) reported a large consanguineous family of Old Order Amish origin in which 7 individuals had early childhood onset of a slowly progressive neurodegenerative disorder characterized primarily by cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy. At the time of the report, the patients ranged in age from 2 to 27 years. Most patients had delayed walking with frequent falls and delayed speech development. The 4 older patients all had optic atrophy, and 2 had nystagmus. There was gait and limb ataxia, increased tone in the upper and lower limbs, hyperreflexia at the knee joint, and extensor plantar responses. The older individuals tended to have slow and spastic tongue movements, brisk jaw jerk, and loss of reflexes in the upper limb and ankles later in the disease, indicating the progressive nature of the disorder. All were still mobile without obvious intellectual deterioration, although some had learning disabilities and emotional lability.

Mapping

By genomewide linkage and homozygosity analysis of an Amish family with autosomal recessive spastic ataxia, Crosby et al. (2010) identified a 6.5-Mb region on chromosome 10p11.23 between markers rs1144522 and rs910967 (maximum lod score of 7.64).

Molecular Genetics

By candidate gene sequencing of a region on chromosome 10p11.23, Crosby et al. (2010) identified a homozygous mutation in the MTPAP gene (N478D; 613669.0001) in 6 affected members of a large consanguineous family of Old Order Amish origin with spastic ataxia-4.

Pathogenesis

Wilson et al. (2014) performed studies on fibroblasts from 2 patients and 1 unaffected obligate mutation carrier from the Amish family with SPAX4 reported by Crosby et al. (2010). Mitochondrial mRNA from patient cells showed a lack of polyadenylation and a concomitant increase in oligoadenylated species. Heterozygous cells were similar to controls, with a mild increase in oligoadenylated mRNA. Homozygous mutant cell lines showed a decrease in oxidative phosphorylation activity, as well as a severe decrease in the amounts and activities of mitochondrial complexes I and IV. The findings were consistent with a selective defect in mitochondrial gene expression, and the defects were rescued by expression of wildtype MTPAP.