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Pharmacol Ther. 2006 Jan;109(1-2):42-56. Epub 2005 Jul 7.

Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias.

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  • 1Cellular Neurology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.


The hereditary spastic paraplegias (HSPs) comprise a clinically and genetically diverse group of inherited neurological disorders in which the primary manifestation is progressive spasticity and weakness of the lower limbs. The identification of over 25 genetic loci and 11 gene products for these disorders has yielded new insights into the molecular pathways involved in the pathogenesis of HSPs. In particular, causative mutations in proteins implicated in mitochondrial function, intracellular transport and trafficking, axonal development, and myelination have been identified. In many cases, the proper intracellular trafficking and distribution of molecules and organelles are ultimately thought to be involved in HSP pathogenesis. In fact, deficits in intracellular cargo trafficking and transport are concordant with the length dependence of the distal axonopathy of upper motor neurons observed in HSP patients. Through a better understanding of the functions of the HSP gene products, novel therapeutic targets for treatment and prevention are being identified.

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