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.
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.
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 134-1Genetic Types of HSP (updated from Fink JK, 2011) |Favorite Table|Download (.pdf) Table 134-1 Genetic Types of HSP (updated from Fink JK, 2011)
|Spastic Gait (SPG) Locus ||OMIM Number ||Protein (genetic locus if protein is unknown) ||Clinical Syndrome |
|Autosomal dominant HSP || || |
|SPG3A ||182600 ||Atlastin ||Uncomplicated HSP: symptoms usually begin in childhood (and may be nonprogressive); symptoms may also begin in adolescence or adulthood and worsen insidiously. Genetic non-penetrance reported. De novo mutation reported presenting as spastic diplegic cerebral palsy. |
|SPG4 ||128601 ||Spastin ||Uncomplicated HSP, symptom onset in infancy through senescence, single most common cause of autosomal dominant HSP (~40%); some subjects have late-onset cognitive impairment. |
|SPG6 ||600363 ||Not imprinted in Prader-Willi/Angelman 1 (NIPA1) ||Uncomplicated HSP: prototypical late-adolescent, early-adult onset, slowly progressive uncomplicated HSP |
|SPG8 ||603563 ||KIAA0196/strumpellin ||Uncomplicated HSP |
|SPG9 ||601162 ||(10q23.3-q24.2) ||Complicated: spastic paraplegia associated with cataracts, gastroesophageal reflux, and motor neuronopathy |
|SPG10 ||604187 ||Kinesin heavy chain (KIF5A) ||Uncomplicated HSP or complicated by distal muscle atrophy |
|SPG12 ||604805 ||Reticulon 2 (RTN2) ||Uncomplicated HSP |
|SPG13 ||605280 ||Chaperonin 60 (heat shock protein 60, HSP60) ||Uncomplicated HSP: adolescent and adult onset |
|SPG17 ||270685 ||BSCL2/seipin ||Complicated: spastic paraplegia associated with amyotrophy of hand muscles (Silver Syndrome) |
|SPG19 ||607152 ||(9q33-q34) ||Uncomplicated HSP |
|SPG29 ||609727 ||(1p31.1-21.1) ||Complicated: spastic paraplegia associated with hearing impairment; persistent vomiting due to hiatal hernia inherited |
|SPG31 ||610250 ||Receptor expression enhancing protein 1 (REEP1) ||Uncomplicated HSP or occasionally associated with peripheral neuropathy |
|SPG33 ||610244 ||ZFYVE27/protrudin ||Uncomplicated HSP |
|SPG36 ||613096 ||(12q23-24) ||Onset age 14 to ...|
Pop-up div Successfully Displayed
This div only appears when the trigger link is hovered over.
Otherwise it is hidden from view.