Spastic Paraplegia 42, Autosomal Dominant

A number sign (#) is used with this entry because spastic paraplegia-42 (SPG42) is caused by heterozygous mutation in the SLC33A1 gene (603690).

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Clinical Features

Lin et al. (2008) reported a large Chinese family in which at least 20 individuals were diagnosed with autosomal dominant SPG. There was at least 1 case of incomplete penetrance in an obligate carrier. Age at onset varied widely, ranging from 4 to 42 years, although most affected individuals had onset in the first 2 decades of life. Classic features included spastic gait, increased lower limb tone, hyperreflexia, weakness and atrophy of the lower limb muscles, extensor plantar responses, and pes cavus. None of the patients became wheelchair-bound, and there were no additional neurologic symptoms.

Mapping

By linkage analysis of a large Chinese family with autosomal dominant SPG, Lin et al. (2008) mapped the disease locus, SPG42, to chromosome 3q24-q26 (maximum lod score of 5.085 at D3S1746).

Molecular Genetics

In affected members of a Chinese family with SPG42, Lin et al. (2008) identified a heterozygous mutation in the SLC33A1 gene (603690.0001). The authors postulated haploinsufficiency as the disease mechanism.

Schlipf et al. (2010) did not find pathogenic mutations in the SLC33A1 gene in 220 patients with autosomal dominant SPG who were negative for mutations in the SPAST gene (604277). The patients were of German, French, and Norwegian descent. The findings suggested that SLC33A1 mutations are not a common cause of SPG in the European population.