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Key Points


  • Disease summary:

    • The hereditary spastic paraplegias (HSPs) are genetically heterogeneous disorders in which progressive difficulty walking due to spastic weakness of both legs is the predominant neurologic syndrome.

    • HSP clinical syndromes may be limited to difficulty walking due to lower extremity spastic weakness (“uncomplicated HSP”) or may include other neurologic or systemic disturbances (“complicated HSP”).

    • There may be wide variability in age-of-symptom onset, rate of worsening, degree of disability, and presence (and severity) of additional of neurologic involvement both within and between different genetic types of HSP.

    • Neuropathologic analyses of uncomplicated HSP generally reveals degeneration of corticospinal tract axons that is maximal in the thoracic spinal cord; degeneration of fasciculus gracilis fibers that is maximal in the cervicomedullary region; and a degree of demyelination that is considered to be secondary to axon degeneration.

    • Proteins encoded by HSP genes have diverse functions including mitochondrial function, axon transport, microtubule processing, protein folding and chaperone, endoplasmic reticulum morphology, and myelin structure.

  • Hereditary basis:

    • More than 50 genetic types of HSP have been described (Table 134-1). Autosomal dominant, autosomal recessive, X-linked forms of HSP are each genetically heterogeneous. In addition, HSP due to ATP6 gene mitochondrial gene mutation (and therefore, with maternally inherited HSP) has been recently described.

  • Differential diagnosis:

    • Many different conditions have overlapping signs and symptoms. The differential diagnosis should include structural abnormalities of the brain and spinal cord, leukodystrophies, inflammatory disorders, metabolic disturbances, and infection.

Table Graphic Jump Location
Table 134-1Genetic Types of HSP (updated from Fink JK, 2011)

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