Spastic paraplegia 5: Locus refinement, candidate gene analysis and clinical description

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Hereditary spastic paraplegias (HSP) are a group of inherited neurological disorders.
• Autosomal recessive forms (ARHSP) often present complex phenotypes, though SPG5, SPG24, and SPG28 are associated with pure forms.
• Genetic mapping has identified 33 HSP loci and 15 responsible genes.

Purpose of the Study:

• To perform a genome-wide scan in a large French family to identify novel loci for ARHSP.
• To fine-map the SPG5 locus in additional ARHSP families.
• To refine the genetic and phenotypic characterization of SPG5-linked ARHSP.

Main Methods:

• Genome-wide scan using microsatellite markers in a large French family.
• Fine mapping of the SPG5 region on chromosome 8q12 in 17 ARHSP families.
• Exclusion of known ARHSP loci and candidate gene sequencing.

Main Results:

• Evidence of linkage to a refined SPG5 region (5.9 Mb between D8S1113 and D8S544) with a maximal multipoint lod score of 2.6.
• Linkage to SPG5 locus supported in an Algerian family (lod score 2.3).
• Phenotype in SPG5-linked families includes spastic paraparesis, deep sensory loss, and mild cerebellar signs in some patients.
• SPG5 accounts for approximately 10% of ARHSP cases in the studied series.
• Refined SPG5 locus to a 3.8 cM interval.

Conclusions:

• The SPG5 locus has been refined, contributing to the genetic understanding of ARHSP.
• The phenotypic spectrum of SPG5-linked ARHSP is extended to include mild cerebellar signs.
• No mutations/polymorphisms were detected in seven candidate genes, suggesting further investigation is needed.