Molecular Genetics of Hereditary Spastic Paraplegias

Abstract Hereditary spastic paraplegias (HSPs) are a group of single‐gene disorders in which the axons of the corticospinal tract either fail to develop normally or undergo progressive degeneration. The main clinical feature of all HSPs is a bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities, which occurs in relative isolation in pure or uncomplicated HSPs (PHSPs) or in combination with other features in complicated HSPs (CHSPs). So far, about 40 different chromosomal HSP loci have been identified by genetic linkage analysis and an increasing number of gene mutations are being identified, representing one of the most significant examples of genetic heterogeneity. Autosomal and X‐linked patterns of inheritance, both dominant and recessive, have been described. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis. Key Concepts: Hereditary spastic paraplegias (HSP) are a group of single‐gene disorders characterized by bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities (pure or uncomplicated HSPs). The phenotype can be complicated by additional features (complicated HSPs). HSPs affect 1/10 000 individuals. Pathogenesis depends on abnormalities in intracellular trafficking, trasnsport and endocytosis, neural cell recognition and signalling, myelination and mitochondrial proteins. About 40 different chromosomal loci and 20 genes have been identified indicating the extraordinarly strong genetic heterogeneity. Patterns of inheritance include autosomal and X‐linked, both recessive and dominant. Mutations in Spastin (SPG4) account for approximately 40% of autosomal dominant HSPs, and more then any other HSP defect. Autosomal recessive HSP account for approximately 15–20% of all types of HSPs. Genotype–phenotype correlation and penetrance can be extremely variable even among the same family and/or gene defect. Genetic counselling is particularly challenging because of genetic heterogeneity and should take in consideration pattern of inheritance, geographical epidemiology and clinical evaluation with a multidisciplinary approach. To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.