Autosomal dominant spastic paraplegia with sensory deficits and muscle wasting (SPG36) maps to chromosome 12q23–24

Background: Spastic paraplegias are a genetically heterogenous group of disorders. So far, over 30 genes or loci for SP have been described, among them 13 loci for autosomal dominant disease.

Objective: Mapping of a novel autosomal dominant SP locus, sequencing of candidate genes and phenotypic description.

Design/methods: A genome wide linkage analysis using Human Mapping 10K SNP Microarrays was performed in a large three generation family with pure autosomal dominant SP. Linkage to known loci of autosomal dominant SP loci was excluded previously. DNA of 14 family members (7 affected, 7 healthy) was available. Additional microsatellite markers were examined for possible loci (NPL score >1.5). Fine-mapping and haplotype reconstruction were used to define the borders of the novel locus. Over 25 dominant SP-families were examined for linkage to the novel locus. Candidate genes were sequences.

Results: The genome wide linkage analysis using a 10K SNP chip yielded four genomic regions with NPL scores >1,5. Mapping of additional microsatellite markers provided evidence of linkage at two consecutive markers on chromosome 12 with a significant multipoint LOD score of 3.2. Haplotype reconstruction defined D12S318 and D12S1023 as borders of the novel locus, comprising a genomic region of about 12MB. The other possible locations were excluded when additional microsatellite markers were used.

Two additional families were identified compatible with linkage to SPG36 but no further refinement of the locus was possible. Sequencing of CKAP4, IQCD and ATXN2 revealed no coding sequence variations in affected family members.

Affected family members showed sensible deficits (touch sense, temperature discrimination, vibration sense) and distal muscle atrophy of the lower extremities in addition to signs and symptoms of pure spastic paraplegia. Mean age at onset was 23,5±7,1yrs.

Conclusions/relevance: We describe a novel locus for autosomal dominant spastic paraplegia with sensory deficits and lower extremity muscle waisting on chromosome 12q23–24.