Wilkinson, P.; (2007) A clinical, genetic and biochemical study of hereditary spastic paraplegia. Doctoral thesis , University of London.

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Abstract

The hereditary spastic paraplegias (HSPs) represent a clinically and genetically heterogeneous group of neurological disorders. The phenotype is classified as pure or uncomplicated when the spastic paraparesis occurs in isolation and complicated when there are significant additional neurological or other clinical features. Inheritance may be autosomal dominant, autosomal recessive or X-linked. Twenty families from the UK were identified with autosomal recessive HSP. Clinical analysis of affected individuals demonstrated a variety of different phenotypes with a slight preponderance of complicated cases. Genetic linkage analysis in the largest of these families identified linkage to the previously described SPG5A locus with a maximum LOD score of 4.84. Marker saturation analysis subsequently refined the locus to a 23.6cM region on chromosome 8q. In 6 of the remaining families linkage to the SPG7 locus could not be excluded. An affected individual from each of these families and 29 sporadic HSP cases were subsequently screened for SPG7 gene mutations using a combination of SSCP and sequencing. Three sporadic patients were found to have compound heterozygous SPG7 mutations, five of which were novel and one that had been described previously. Muscle biopsies in two of the patients with SPG7 mutations failed to demonstrate histological evidence of oxidative phophorylation defects but did reveal mitochondrial respiratory chain complex I-III defects in muscle and complex I deficiency in cultured myoblasts. A similar combination of SSCP and sequencing was used to screen a group of 12 families with early onset autosomal dominant HSP for SPG3A gene mutations. Only the previously reported R239C mutation was identified in one family suggesting that SPG3A mutations are relatively uncommon in this population. Genome wide linkage analysis in a consanguineous Bedouin family from Kuwait with a complicated HSP phenotype including cognitive impairment, dysarthria and distal amyotrophy identified linkage to a 22.8cM interval on chromosome 12 with a maximum LOD score of 5.1. No coding sequence mutations were identied in the KIF5A gene, associated with pure autosomal dominant HSP, located within this region. This interval has therefore been proposed as a novel locus for complicated autosomal recessive HSP (SPG26).

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