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The hereditary spastic paraplegias (HSPs) are a group of single gene disorders in which the corticospinal tracts fail to develop normally, or degenerate after initially normal development. The HSPs all share the principal clinical feature of progressive lower limb spastic paralysis, and are subdivided into pure and complicated forms, depending on the presence of additional neurological or non-neurological features.1,2
The pure HSPs tend to be associated with neurodegeneration, rather than abnormal development, and histopathological studies in pure HSP show a length-dependent “dying back” of the terminal ends of the corticospinal tract axons, with the longest axons being involved first.1 The SPG4 gene, spastin, is the most important pure HSP gene, being responsible for approximately 40% of definite autosomal dominant pure HSP and a smaller proportion of sporadic cases and cases with uncertain family history.3,4 The 616 amino acid spastin protein is a widely expressed AAA (ATPases associated with diverse cellular activities) protein.5 More than 100 different spastin mutations have been described, including numerous missense, nonsense, frameshift, and splice site mutations, as well as less frequent whole exon deletions. With only a few possible exceptions, the missense mutations are located in the AAA cassette, from amino acids 342–599. Splice site mutations almost exclusively involve exons 5–16. Nonsense and frameshift mutations are scattered across the gene, with the smallest predicted protein consisting of fewer than 40 amino acids, the largest 562 amino acids.2
It is likely that the molecular pathological mechanism of truncating and splice site spastin mutations is loss of function. The associated abnormal transcripts may be unstable, and recent data show …