Hereditary Spastic Paraplegia

Hereditary Spastic Paraplegia is a heterogeneous group of genetic neurological disorders unified by selective degeneration of the distal axons of corticospinal motor neurons. Over 80 genetic forms are recognized (SPG1-SPG81), each caused by mutations in different genes encoding proteins involved in various cellular processes: axonal transport, mitochondrial function, membrane trafficking, lipid metabolism, and protein degradation. The common pathological feature is degeneration of the longest corticospinal tract axons, affecting the ability to control leg movement. HSP manifests with progressive lower extremity spasticity, weakness, and difficulty walking. The spasticity develops insidiously over months to years, with progressive stiffness of leg muscles and hyperreflexia. Some patients show relatively pure HSP with only lower extremity involvement, while others (complex HSP) have associated features including cognitive impairment, seizures, ataxia, peripheral neuropathy, vision loss, or hearing loss depending on the genetic subtype. Disease progression varies widely by subtype: some forms have static or very slowly progressive disease allowing lifelong ambulation, while others show rapidly progressive paraplegia requiring wheelchair use within years of onset. Genetic heterogeneity means that even within the same family, disease expression can vary.