Spastic paraplegia type 5A belongs to a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by muscle stiffness (spasticity) and severe weakness in the lower limbs (paraplegia). Hereditary spastic paraplegias are often divided into two types: pure and complex. The pure types involve spasticity and weakness only in the lower limbs, while the complex types involve additional problems with other areas of the body. Additional features can include changes in vision, changes in intellectual functioning, brain abnormalities, and disturbances in nerve function (neuropathy). Spastic paraplegia type 5A is usually classified as a pure hereditary spastic paraplegia, although complex-type features have been reported in some individuals.

The signs and symptoms of spastic paraplegia type 5A usually appear in adolescence, but they can begin at any time between infancy and mid-adulthood. In addition to spasticity and weakness, people with spastic paraplegia type 5A can lose the ability to sense the position of their limbs or detect vibrations with their lower limbs. They may also have muscle wasting (amyotrophy), reduced bladder control, or high arches of the feet (pes cavus). Some affected individuals have low bone density (osteopenia) or vitamin D deficiency. Affected individuals eventually require walking support, usually around 20 years after symptoms begin, or wheelchair assistance, around 30 years after symptoms begin.

There are more than 80 different types of hereditary spastic paraplegia, and the combined prevalence of all these types is estimated to be 1 to 18 in 100,000 people worldwide. Spastic paraplegia type 5A likely accounts for only a small percentage of all hereditary spastic paraplegia cases. More than 50 cases of spastic paraplegia type 5A have been described in the scientific literature.

Genetic changes that cause disease are called pathogenic variants. Spastic paraplegia type 5A is caused pathogenic variants in the CYP7B1 gene. This gene provides instructions for making an enzyme called oxysterol 7-alpha-hydroxylase. In the brain, oxysterol 7-alpha-hydroxylase is involved in a pathway that converts certain forms of cholesterol into hormones called neurosteroids. Neurosteroids increase the ability of nerve cells (neurons) to send signals (excitability). Oxysterol 7-alpha-hydroxylase helps maintain normal cholesterol levels and regulates the effects of neurosteroids.

The CYP7B1 gene variants that cause spastic paraplegia type 5A can reduce or eliminate the activity of oxysterol 7-alpha-hydroxylase. This can prevent the production of neurosteroids and cause cholesterols to accumulate in the brain. The abnormal buildup of cholesterols impairs neuron function and leads to neuron death. Low neurosteroid levels likely further impair neuron function by affecting their signaling ability. The loss of neurons results in the deterioration of nervous system functions (neurodegeneration) and causes the movement problems, weakness, and other signs and symptoms that are characteristic of spastic paraplegia type 5A.

Genetic Testing Information

• Genetic Testing Registry: Hereditary spastic paraplegia
• Genetic Testing Registry: Hereditary spastic paraplegia 5A

Genetic and Rare Diseases Information Center

• Autosomal recessive spastic paraplegia type 5A
• Hereditary spastic paraplegia

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• SPASTIC PARAPLEGIA 5A, AUTOSOMAL RECESSIVE; SPG5A

Scientific Articles on PubMed

• PubMed

• Chou CT, Soong BW, Lin KP, Tsai YS, Jih KY, Liao YC, Lee YC. Clinical characteristics of Taiwanese patients with Hereditary spastic paraplegia type 5. Ann Clin Transl Neurol. 2020 Apr;7(4):486-496. doi: 10.1002/acn3.51019. Epub 2020 Mar 22. Citation on PubMed
• Ehnert S, Hauser S, Hengel H, Hoflinger P, Schule R, Lindig T, Baets J, Deconinck T, de Jonghe P, Histing T, Nussler AK, Schols L, Rattay TW. Vitamin D3 deficiency and osteopenia in spastic paraplegia type 5 indicate impaired bone homeostasis. Sci Rep. 2024 Mar 27;14(1):7335. doi: 10.1038/s41598-024-53057-5. Citation on PubMed
• Gasser T, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schols L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Harbo HF; EFNS. EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. Eur J Neurol. 2010 Feb;17(2):179-88. doi: 10.1111/j.1468-1331.2009.02873.x. Epub 2009 Dec 28. Citation on PubMed
• Hedera P. Uncomplicated (Pure) Hereditary Spastic Paraplegia Overview. 2000 Aug 15 [updated 2025 Jun 5]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK1509/ Citation on PubMed
• Pashaei M, Davarzani A, Hajati R, Zamani B, Nafissi S, Larti F, Nilipour Y, Rohani M, Alavi A. Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families. J Neurogenet. 2021 Mar-Jun;35(2):84-94. doi: 10.1080/01677063.2021.1895146. Epub 2021 Mar 26. Citation on PubMed
• Perez-Torre P, Garcia Galloway E, Lopez-Sendon Moreno JL. Hereditary spastic paraparesis due to SPG5/CYP7B1 mutation with potential therapeutic implications. Neurologia (Engl Ed). 2023 Nov-Dec;38(9):710-711. doi: 10.1016/j.nrleng.2023.10.005. Epub 2023 Oct 17. No abstract available. Citation on PubMed
• Resch D, Alecu JE, Yang K, Quiroz V, Schierbaum L, Bernardi K, Zaman Z, Agianda HAP, Rong J, Battaglia N, Carty S, Tam A, Kieslich M, Santorelli FM, Gonzalez-Salazar C, Franca Junior MC, Ebrahimi-Fakhari D. Spectrum of Movement Disorders in Early-Onset Hereditary Spastic Paraplegia: A Study of 428 Cases. Mov Disord. 2025 Dec 2. doi: 10.1002/mds.70141. Online ahead of print. Citation on PubMed
• Schols L, Rattay TW, Martus P, Meisner C, Baets J, Fischer I, Jagle C, Fraidakis MJ, Martinuzzi A, Saute JA, Scarlato M, Antenora A, Stendel C, Hoflinger P, Lourenco CM, Abreu L, Smets K, Paucar M, Deconinck T, Bis DM, Wiethoff S, Bauer P, Arnoldi A, Marques W, Jardim LB, Hauser S, Criscuolo C, Filla A, Zuchner S, Bassi MT, Klopstock T, De Jonghe P, Bjorkhem I, Schule R. Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial. Brain. 2017 Dec 1;140(12):3112-3127. doi: 10.1093/brain/awx273. Citation on PubMed
• Schule R, Wiethoff S, Martus P, Karle KN, Otto S, Klebe S, Klimpe S, Gallenmuller C, Kurzwelly D, Henkel D, Rimmele F, Stolze H, Kohl Z, Kassubek J, Klockgether T, Vielhaber S, Kamm C, Klopstock T, Bauer P, Zuchner S, Liepelt-Scarfone I, Schols L. Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol. 2016 Apr;79(4):646-58. doi: 10.1002/ana.24611. Epub 2016 Mar 11. Citation on PubMed