Spectrum of SPG4 mutations in a large collection of North American families with hereditary spastic paraplegia.

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Abstract
HEREDITARY SPASTIC paraplegia (HSP), also known as familial spastic paraplegia (FSP) or Strümpell-Lorrain syndrome, comprises a heterogeneous group of neurodegenerative disorders characterized by progressive lower limb spasticity and weakness associated with bladder disturbance in approximately 50% of the cases.1,2 Clinically, there are 2 types of HSP: the pure form, which is characterized exclusively by leg spasticity often with bladder disturbance; and the complicated form, which includes additional neurological abnormalities such as optic neuropathy, dementia, ataxia, deafness, mental retardation, and extrapyramidal disturbance.1,2 The main neuropathological feature is axonal degeneration of the distal ends of the longest ascending and descending tracts. This neurodegeneration results in spasticity of the lower limbs, which causes difficulty walking; in severe cases, the patients become wheelchair bound.3,4 The age of onset varies greatly, even within families, from early childhood to the mid-80s. The genetic heterogeneity in individuals with HSP is demonstrated by the number of loci (SPG1 through SPG17) that have been mapped. These include 3 X-linked,5-7 9 autosomal dominant,8-16 and 5 autosomal recessive17-21 loci. Of all described families, 40% are linked to an autosomal dominant locus known as SPG4 (MIM182601).22 The defective gene for SPG4 was cloned recently and encodes a 616–amino acid protein named spastin. The protein is an adenosine triphosphatase associated with various cellular activities (AAA) protein family member with a characteristic AAA cassette in the C terminus from amino acid 342 to amino acid 599. According to computer predictions, the protein possesses a nuclear localization signal, Walker motif A and B, an AAA minimal consensus sequence, leucine zipper motifs, and a helix-loop-helix domain. Furthermore, the protein shows strong homology to 2 yeast proteins (Yta6p and Sap1) and to the mouse Skd1 protein. Recent evidence23 suggests that spastin might interact with tubulin, but its main function remains unknown despite its homology to other proteins and functional domains. To date, more than 50 mutations have been reported in the spastin encoding gene, including splice-site, nonsense, missense, and frameshift mutations (insertion and deletion), affecting either directly or indirectly the conserved AAA cassette,24-32 suggesting the functional importance of the AAA cassette. No clear genotype-phenotype correlation has been reported, but most articles23 suggest that SPG4 is caused by the haplo-insufficiency of spastin, which implies a critical spastin threshold.