The hereditary spastic paraplegias (HSPs) are 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, which occurs in relative isolation in the pure HSPs (PHSPs) or in combination with other features in the complicated HSPs (CHSPs).

Autosomal dominant, autosomal recessive, and X-linked recessive inheritance patterns of HSPs have been described. However, these reports gave no indication of the genetic heterogeneity of HSP that has been discovered in the past 10 years. The recent report by Hodgkinson and colleagues1 brings the number of autosomal recessive HSP loci that have been identified to seven. When combined with the ten known loci for autosomal dominant HSP and the two loci for X-linked HSP, the number of loci associated with HSP is remarkable. It is now clear that some genes can be associated with a specific clinical presentation—eg, mutations in atlastin are almost exclusively associated with childhood onset autosomal dominant PHSP. In contrast, other genes are associated with various clinical presentations: different mutations in the proteolipid protein (PLP) gene on the Xchromosome can cause PHSP, CHSP, or the more severe Pelizaeus–Merzbacher disease. Many HSPs, and probably all PHSPs, are associated with neurodegeneration rather than abnormal neurodevelopment. This neurodegeneration has been characterised in histopathological studies as a length dependent “dying back” of axons in the corticospinal tract and the dorsal column. The identification of genes associated with PHSP is helping to elucidate the causes of disease at the molecular level. Six genes associated with PHSP have been identified and broadly characterised into three groups. 2