134: The Hereditary Spastic Paraplegias

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.