Hereditary spastic paraplegia: genetic heterogeneity and genotype-phenotype correlation

Hereditary spastic paraplegia (HSP) is a group of disorders whose primary symptom is insidiously progressive, lower extremity spasticity and weakness. Neuropathological analysis of "pure" HSP reveals axonal degeneration that is maximal in the terminal portions of the longest descending and ascending tracts (crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis, respectively). HSP may be transmitted as an X-linked, autosomal recessive, or autosomal dominant trait, each of which is genetically heterogeneous: mutations in different genes cause clinically similar disorders. To date, there are at least three genetic loci for X-linked HSP; at least three genetic loci for autosomal recessive HSP; and at least six genetic loci for autosomal dominant HSP. The genetic basis for three of these twelve forms of HSP have been discovered. One form of autosomal recessive HSP (on chromosome 16) is due to mutations in the paraplegin gene, which encodes a mitochondrial protein homologous to metalloproteases. One form of X-linked HSP is caused by mutations in the proteolipoprotein gene, an intrinsic myelin protein. Mutation in this gene also causes the dysmyelinating disorder, Pelizeaus-Merzbacher disease. X-linked spastic paraplegia can be caused also by mutations in the L1CAM gene. This review summarizes our current understanding of genetic heterogeneity and genotype-phenotype correlation in HSP.