Hereditary spastic paraplegia

Hereditary spastic paraplegia presents as progressive, symmetrical lower-limb spasticity and weakness, with hyperreflexia and extensor plantar responses; mild urinary urgency and distal vibration loss are commonly associated. Clinically, two forms are recognised: uncomplicated (pure) HSP is restricted to the corticospinal-tract phenotype, whereas complicated (complex) HSP combines lower-limb spasticity with additional neurologic or systemic features such as cerebellar ataxia, intellectual disability, peripheral neuropathy, optic atrophy, dysarthria, parkinsonism, thin corpus callosum, or seizures. Age of onset spans a broad range, from infancy (where early-onset forms can resemble spastic diplegic cerebral palsy) through the seventh decade, with the onset window depending on the underlying genetic subtype. In a well-defined Albertan cohort, complicated forms were reported in 58% of families, underscoring that complex phenotypes constitute a substantial share of the genetically determined spectrum.

The estimated prevalence is 1/100,000 to 1/10,000 (Hedera, GeneReviews, 2025). A well-defined Albertan cohort study reports an overall prevalence of 2.3/100,000.

More than 80 genetic loci have been associated with hereditary spastic paraplegia. The most common genetic cause is spastic paraplegia 4 (SPG4; SPAST), which accounts for approximately 40% of autosomal dominant uncomplicated HSP. Complicated forms include spastic paraplegia 7 (SPG7; HSP with cerebellar ataxia and optic atrophy) and spastic paraplegia 11 (SPG11; HSP with thin corpus callosum and intellectual disability)

The genetic conditions associated with hereditary spastic paraplegia follow heterogeneous inheritance patterns. Autosomal dominant forms predominate within uncomplicated HSP, accounting for approximately 75-80% of cases, while autosomal recessive forms make up most of the remainder; rarer X-linked forms also occur. Where the familial pathogenic variant is known, prenatal and preimplantation genetic testing are technically possible.

• Where hereditary spastic paraplegia is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Hedera P. Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview. 2000 Aug 15 [Updated 2025 Jun 5]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 20301682. Available from:
• Assaedi E, Ashtiani S, Estiar MA, Gan-Or Z, McKenzie ED, Shetty A, et al. Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population. Movement disorders clinical practice. 2025;12(9):1346-1356. doi: 10.1002/mdc3.70115. PMID: . PMCID: PMC12481434.
• Fereshtehnejad SM, Saleh PA, Oliveira LM, Patel N, Bhowmick S, Saranza G, et al. Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2023;44(3):947-959. doi: 10.1007/s10072-022-06516-8. PMID: . PMCID: PMC9925593.
• García-Carmona JA, Amores-Iniesta J, Soler-Usero J, Cerdán-Sánchez M, Navarro-Zaragoza J, López-López M, et al. Upregulation of Heat-Shock Protein (hsp)-27 in a Patient with Heterozygous SPG11 c.1951C>T and SYNJ1 c.2614G>T Mutations Causing Clinical Spastic Paraplegia. Genes. 2023;14(7). doi: 10.3390/genes14071320. PMID: . PMCID: PMC10379220.