Regular articleAdvances in the hereditary spastic paraplegias
Introduction
The hereditary spastic paraplegia (HSPs) are inherited disorders in which the primary neurologic syndrome is bilateral, approximately symmetric, lower extremity spastic weakness. This is often accompanied by urinary urgency. Progressive lower extremity spastic weakness is also a feature of many other inherited disorders including inherited leukodystrophies, Friedreich's ataxia, Machado-Joseph disease, multiple sclerosis, and familial Alzheimer's disease. Major neurologic signs (such as peripheral neuropathy, ataxia, dementia, and pseudobulbar involvement) distinguish these other conditions from the HSPs, in which the predominant neurologic syndrome is spastic gait. For recent reviews of HSP see Charvin et al., 2002, Fink, 2002b, Fink, 2003.
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HSP symtoms
HSP symptoms initially are stumbling and tripping due to lower extremity stiffness and weakness. This may begin at any age from infancy to senescence. As symptoms progress subjects may have marked lower extremity spastic weakness and require cane, walker, or wheelchair. Age of symptom onset, rate of progression, and degree of disability are often variable between different genetic types of HSP (Fink and Hedera, 1999), as well as within individual families in which all subjects have precisely
Neurologic findings
Neurologic findings in subjects with “uncomplicated” HSP (defined below) consist of bilateral lower extremity spasticity and weakness (in varying proportions), lower extremity hyperreflexia, extensor plantar responses, and often, mildly impaired vibratory sensation in the distal lower extremities. Although upper extremity deep tendon reflexes are often brisk, muscle strength and tone in the upper extremities is normal in uncomplicated HSP.
Diagnosis of HSP
Diagnosis of HSP is made by the presence of (1) typical symptoms of gait disturbance (which range from childhood onset, essentially nonprogressive spastic diplegia, to childhood-through-adult onset of insidiously progressive spastic weakness in the legs), which are often associated with urinary urgency; (2) neurologic findings of corticospinal tract deficits (spasticity, weakness, hyperreflexia, extensor plantar responses) that are limited to lower extremities (note, upper extremity reflexes
Classification of HSP
HSP is classified (Harding, 1983) as uncomplicated if neurologic findings are limited to bilateral lower extremity spastic weakness, lower extremity hyperreflexia, extensor plantar responses, and often, mildly impaired vibratory sensation in the distal lower extremities. HSP is classified as “complicated” (Harding, 1983) if, in addition to signs of uncomplicated HSP, the inherited syndrome includes other neurologic or systemic impairments (including cataracts, motor neuropathy, mental
Neuropathologic studies
Neuropathologic studies (Behan and Maia, 1974) show that uncomplicated HSP involves axonal degeneration of selected motor (corticospinal tracts) and sensory (dorsal column fibers) within the spinal cord. Axonal degeneration is particularly prominent in the distal aspects of these fibers. Anterior horn cells are generally preserved in uncomplicated HSP.
Genetic types of HSP
Autosomal dominant (ADHSP), autosomal recessive (ARHSP), and X-linked HSP are each genetically heterogeneous. Twenty genetic types of HSP have been defined by genetic linkage analysis. HSP loci (Table 1) are designated SPG (“spastic paraplegia”) 1 through 21 in order of their discovery (SPG18 is reserved for an as-yet unpublished locus). Thus far, 10 loci for ADHSP, seven loci for ARHSP, and three loci for X-linked HSP have been discovered. Nine HSP genes have been identified (summarized in
Genetic testing
Genetic testing for the most common forms of dominantly inherited HSP is available commercially (Athena Diagnostic Laboratories, Boston, MA). Testing for mutations in the SPG4 and SPG3A genes will diagnose approximately 50% of dominantly inherited HSP. Mutation analysis of other genes for other dominantly inherited HSP and for recessive and X-linked forms of HSP is available only on a research basis.
Genetic testing is useful to confirm the clinical diagnosis of dominantly inherited HSP.
Molecular basis for axonal degeneration
Molecular mechanisms underlying axonal degeneration in HSP are diverse and poorly understood. At this stage, five different molecular processes appear to be involved in different genetic types of HSP.
- 1.
Myelin composition affecting long, central nervous system axons. X-linked SPG2 HSP is due to proteolipid protein gene mutation, an intrinsic myelin protein Hudson et al., 1987, Dautigny et al., 1986, Cambi et al., 1995, Dube et al., 1997.
- 2.
Embryonic development of corticospinal tracts. X-linked SPG1
Treatment for HSP
Treatment for HSP is presently limited to reducing muscle spasticity through exercise and medication. Lioresal is particularly useful in this regard. Dosages need to be individualized because some subjects will have mainly weakness with less spasticity (and thus will not benefit from large doses of Lioresal); while other individuals will have significant spasticity and require high doses of Lioresal (given either orally or via intrathecal pump). Tizanidine, Dantrolene, and Botox have also been
Acknowledgements
This research is supported by grants from the Veterans Affairs Merit Review, the National Institutes of Health (NINDS R01NS33645, R01NS36177, and R01NS38713), and the National Organization for Rare Disorders (NORD) to J.K.F. We gratefully acknowledge the participation of HSP subjects and their families without whom our investigations of HSP would not be possible.
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