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Handb Clin Neurol. 2018;148:633-652. doi: 10.1016/B978-0-444-64076-5.00041-7.

Hereditary spastic paraplegia.

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1
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. Electronic address: blackstc@ninds.nih.gov.

Abstract

The hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurologic disorders with the common feature of prominent lower-extremity spasticity, resulting from a length-dependent axonopathy of corticospinal upper motor neurons. The HSPs exist not only in "pure" forms but also in "complex" forms that are associated with additional neurologic and extraneurologic features. The HSPs are among the most genetically diverse neurologic disorders, with well over 70 distinct genetic loci, for which about 60 mutated genes have already been identified. Numerous studies elucidating the molecular pathogenesis underlying HSPs have highlighted the importance of basic cellular functions - especially membrane trafficking, mitochondrial function, organelle shaping and biogenesis, axon transport, and lipid/cholesterol metabolism - in axon development and maintenance. An encouragingly small number of converging cellular pathogenic themes have been identified for the most common HSPs, and some of these pathways present compelling targets for future therapies.

KEYWORDS:

Strümpell–Lorrain; autophagy; bone morphogenetic protein; endoplasmic reticulum; lipid metabolism; lysosome; motor; paraplegia; spasticity; thin corpus callosum

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