RARE DISEASE
Hereditary spastic paraplegia
Hereditary spastic paraplegia
Hereditary spastic paraplegia
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Synonyms: Familial spastic paraplegia, HSP, Hereditary spastic paraparesis, SPG, Strümpell-Lorrain disease
Drug discovery
3
drugs
With orphan designations
Overview
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness due to corticospinal tract degeneration. Classified as pure (focused on motor symptoms) or complex (with additional neurological/Systemic features like ataxia, cognitive impairment, or neuropathy), HSP is diagnosed through clinical evaluation, exclusion of mimics, and genetic testing. While no disease-modifying therapies exist, management includes spasticity-reducing medications (e.g., baclofen, botulinum toxin), physical therapy, and assistive devices. Progression varies, with some requiring wheelchairs, but life expectancy is typically unaffected in pure forms [1][2][6][12].
Burden
Progressive mobility loss often necessitates assistive devices (20–40% require wheelchairs). Complications include urinary dysfunction, chronic pain, and comorbidities like depression (19%), psoriasis, and gastrointestinal issues. Complex HSP increases caregiver dependency and reduces quality of life [1][9][11].
Therapies
Pharmacological: Muscle relaxants (oral/intrathecal baclofen, tizanidine), botulinum toxin injections, gabapentin [2][3][6].
Non-pharmacological: Physical therapy (stretching, gait training), orthotics, and surgical interventions (selective dorsal rhizotomy) [3][6][13].
Emerging targets: Rapamycin, N-acetyl cysteine, and PCSK9 inhibitors in preclinical/clinical trials [8][13][18].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
592 drug discovery papers about Hereditary spastic paraplegia, with 5 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
592 drug discovery papers about Hereditary spastic paraplegia, with 5 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-01 | SPG4 Hereditary Spastic Paraplegia: From Etiology to Therapy.
Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of heritable neurodegenerative disorders resulting from mutations in a wide variety of genes. HSP locomotor symptoms include lower limb weakness and spasticity that arise from progressive degeneration of corticospinal axons projecting from the motor cortex to the distal spinal cord. Ensuing gait defects typically lead to wheelchair dependence. Degeneration of other tracts can also occur, expanding the constellation of symptoms to potentially include urinary, fecal, and speech problems, as well as intellectual disability. SPG4-HSP, the most common variant, is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Significant progress has been made in developing preclinical models for SPG4-HSP and in elucidating its mechanistic etiology. On this basis, progress is being made on developing a flexible therapeutic regimen for patients at all stages of disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-07-29 | Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability.
Alu elements are primate-specific retrotransposons known to mediate structural genomic alterations associated with neurological disorders, yet their underlying disease mechanism remains incompletely understood. Here, we leveraged human pluripotent stem cell-derived cortical organoids and xenografts to model an Alu-mediated exon 17 deletion in the SPAST gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between SPAST and the downstream gene SLC30A6, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by SLC30A6. In SPASTΔe17 organoids, we detected pronounced cytosolic zinc accumulation, Golgi fragmentation, lipid dysregulation, and increased aggregation of Aβ and ubiquitin. These phenotypes were further exacerbated in xenograft models, concomitant with ubiquitin-positive inclusions resembling those found in patients' brains. Knockdown of SLC30A6 in control organoids recapitulated the neurodegenerative features, supporting a critical role of ZnT6 in maintaining neuronal homeostasis. Intervention with TPEN, a zinc-specific chelator, or a GRASP55-blocking antibody to prevent Golgi fragmentation significantly restored Golgi integrity and reduced Aβ levels. Notably, immunohistochemistry revealed heterogeneous ZnT6 expression in AD brains; however, both ZnT6-low and ZnT6-high cases consistently exhibited elevated p-GM130, a marker of Golgi fragmentation. Finally, we detected a SPAST-SLC30A6 chimeric transcript in brain tissue from a sporadic AD patient. Together, our findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6-Golgi axis may represent a vulnerability and therapeutic target in structural variant-driven neurodegeneration and possibly in a subset of sporadic cases.
2026-07-16 | Clinical and genetic characteristics of pediatric hereditary spastic paraplegia in the Eastern Levant.
Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness primarily of the lower extremities. Data describing pediatric HSP from the Levant region remain limited. This study characterizes the clinical and genetic spectrum of pediatric HSP patients with an identified variant in an HSP-associated gene evaluated at a tertiary referral center serving the Eastern Levant. A retrospective descriptive review of pediatric and adolescent patients with a clinical diagnosis of HSP and an identified variant in an HSP-associated gene, evaluated between 2010 and 2024 was conducted. Demographic, clinical, neuroimaging and genetic data were extracted from medical records. Genetic diagnoses were established using next-generation sequencing-based approaches and interpreted according to American College of Medical Genetics and Genomics guidelines. Data were summarized descriptively. A total of 21 pediatric patients were included. Nineteen patients (90.5%) had an autosomal recessive inheritance, 71.4% were progeny from consanguineous families. Clinically relevant variants were identified across 11 HSP-associated genes, including CYP2U1, SPG11, ARL6IP1, B4GALNT1, DDHD2, RNF170, AMPD2, as well as variants in AP-4 complex genes (AP4B1, AP4M1, AP4S1). Additionally, the autosomal dominant SPAST gene was also featured. Age at symptom onset ranged from infancy to late childhood. Ambulatory status at last follow-up ranged from independent ambulation to dependence on assistive devices or caregiver support. Clinical presentations spanned pure spastic paraplegia and complex phenotypes, the latter being associated with variable combinations of features such as intellectual disability, ataxia or seizures. Brain magnetic resonance imaging findings were variable and encompassed thinning of the corpus callosum and nonspecific white matter abnormalities. The cases discussed provide a descriptive overview of the clinical and genetic characteristics of pediatric HSP in Lebanon, Syria and Iraq. The relatively high number of CYP2U1 and AP-4 complex variants observed in this referral cohort, together with the predominance of autosomal recessive and complex forms, highlight the value of broad molecular testing in populations with high rates of consanguinity, such as the Eastern Levant.
2026-07-14 | Hereditary spastic paraplegia in three siblings with distinct genetic mutations.
Hereditary spastic paraplegia is characterized by progressive motor features, including spastic gait and lower limb weakness, and encompasses numerous genetic subtypes. We report a family of six siblings born to asymptomatic consanguineous parents, in which three siblings exhibited overlapping spastic paraplegia phenotypes with developmental delay. The index patient demonstrated significant lower limb weakness and spasticity despite multiple orthopedic interventions. Next-generation sequencing identified a homozygous SELENOI c.797C > T (p.Pro266Leu) variant of uncertain significance, interpreted cautiously in the context of his SPG81-like phenotype. His older sister reportedly harbored a homozygous LAMA1 c.4579C > T (p.Gln1527Ter) variant consistent with Poretti-Boltshauser syndrome, explaining her cerebellar ataxia and nonprogressive course. His younger brother carried the same homozygous SELENOI variant as the index patient together with a de novo SATB2 c.860C > T (p.Pro287Leu) variant of uncertain significance, which was interpreted as a possible contributor to his mixed neurodevelopmental presentation. This report highlights that siblings presenting with similar early-onset spastic gait phenotypes may have distinct underlying genetic findings, supporting the value of comprehensive genetic evaluation even within a single family.
2026-07-09 | Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
Mutations in ATL1 are a frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), yet patients display a wide range of clinical severity, from slowly progressive "pure" to severe, early-onset "complex" forms. The cellular mechanisms underlying this heterogeneity remain poorly defined, and mammalian model systems have thus far failed to distinguish between these subtypes. This study investigates the cellular basis of these clinically distinct forms of HSP using Drosophila models carrying homologous disease-causing mutations in the gene encoding Atlastin-1 (ATL1). Drosophila harbouring a complex ATL1-HSP mutation display reduced locomotor function, impaired development, and decreased survival relative to those carrying mutations associated with pure ATL1-HSP, recapitulating key aspects of clinical heterogeneity. Moreover, cellular analyses identify distinct pathological features across genotypes. Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist. In contrast, complex ATL1-HSP Drosophila lack lipid droplet abnormalities and do not respond to LXR activation but instead show disruption of the neuronal endoplasmic reticulum, consistent with aberrant ER network regulation. Together, these findings suggest that different mutations in Atl give rise to distinct cellular perturbations, suggesting a potential basis for phenotypic heterogeneity in ATL1-HSP.
2026-08-01 | SPG4 Hereditary Spastic Paraplegia: From Etiology to Therapy.
Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of heritable neurodegenerative disorders resulting from mutations in a wide variety of genes. HSP locomotor symptoms include lower limb weakness and spasticity that arise from progressive degeneration of corticospinal axons projecting from the motor cortex to the distal spinal cord. Ensuing gait defects typically lead to wheelchair dependence. Degeneration of other tracts can also occur, expanding the constellation of symptoms to potentially include urinary, fecal, and speech problems, as well as intellectual disability. SPG4-HSP, the most common variant, is caused by mutations in the SPAST gene, which encodes spastin, a microtubule-severing protein with membrane-related properties. Significant progress has been made in developing preclinical models for SPG4-HSP and in elucidating its mechanistic etiology. On this basis, progress is being made on developing a flexible therapeutic regimen for patients at all stages of disease progression. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
2026-07-29 | Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability.
Alu elements are primate-specific retrotransposons known to mediate structural genomic alterations associated with neurological disorders, yet their underlying disease mechanism remains incompletely understood. Here, we leveraged human pluripotent stem cell-derived cortical organoids and xenografts to model an Alu-mediated exon 17 deletion in the SPAST gene, a frequent cause of hereditary spastic paraplegia (SPG4) with dementia. This deletion generates fusion transcripts between SPAST and the downstream gene SLC30A6, resulting in reduced expression of ZnT6, the Golgi-resident zinc transporter encoded by SLC30A6. In SPASTΔe17 organoids, we detected pronounced cytosolic zinc accumulation, Golgi fragmentation, lipid dysregulation, and increased aggregation of Aβ and ubiquitin. These phenotypes were further exacerbated in xenograft models, concomitant with ubiquitin-positive inclusions resembling those found in patients' brains. Knockdown of SLC30A6 in control organoids recapitulated the neurodegenerative features, supporting a critical role of ZnT6 in maintaining neuronal homeostasis. Intervention with TPEN, a zinc-specific chelator, or a GRASP55-blocking antibody to prevent Golgi fragmentation significantly restored Golgi integrity and reduced Aβ levels. Notably, immunohistochemistry revealed heterogeneous ZnT6 expression in AD brains; however, both ZnT6-low and ZnT6-high cases consistently exhibited elevated p-GM130, a marker of Golgi fragmentation. Finally, we detected a SPAST-SLC30A6 chimeric transcript in brain tissue from a sporadic AD patient. Together, our findings identify a primate-specific cascade linking Alu-mediated genomic rearrangements to zinc dyshomeostasis and Golgi pathology and suggest that dysregulation of the ZnT6-Golgi axis may represent a vulnerability and therapeutic target in structural variant-driven neurodegeneration and possibly in a subset of sporadic cases.
2026-07-16 | Clinical and genetic characteristics of pediatric hereditary spastic paraplegia in the Eastern Levant.
Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness primarily of the lower extremities. Data describing pediatric HSP from the Levant region remain limited. This study characterizes the clinical and genetic spectrum of pediatric HSP patients with an identified variant in an HSP-associated gene evaluated at a tertiary referral center serving the Eastern Levant. A retrospective descriptive review of pediatric and adolescent patients with a clinical diagnosis of HSP and an identified variant in an HSP-associated gene, evaluated between 2010 and 2024 was conducted. Demographic, clinical, neuroimaging and genetic data were extracted from medical records. Genetic diagnoses were established using next-generation sequencing-based approaches and interpreted according to American College of Medical Genetics and Genomics guidelines. Data were summarized descriptively. A total of 21 pediatric patients were included. Nineteen patients (90.5%) had an autosomal recessive inheritance, 71.4% were progeny from consanguineous families. Clinically relevant variants were identified across 11 HSP-associated genes, including CYP2U1, SPG11, ARL6IP1, B4GALNT1, DDHD2, RNF170, AMPD2, as well as variants in AP-4 complex genes (AP4B1, AP4M1, AP4S1). Additionally, the autosomal dominant SPAST gene was also featured. Age at symptom onset ranged from infancy to late childhood. Ambulatory status at last follow-up ranged from independent ambulation to dependence on assistive devices or caregiver support. Clinical presentations spanned pure spastic paraplegia and complex phenotypes, the latter being associated with variable combinations of features such as intellectual disability, ataxia or seizures. Brain magnetic resonance imaging findings were variable and encompassed thinning of the corpus callosum and nonspecific white matter abnormalities. The cases discussed provide a descriptive overview of the clinical and genetic characteristics of pediatric HSP in Lebanon, Syria and Iraq. The relatively high number of CYP2U1 and AP-4 complex variants observed in this referral cohort, together with the predominance of autosomal recessive and complex forms, highlight the value of broad molecular testing in populations with high rates of consanguinity, such as the Eastern Levant.
2026-07-14 | Hereditary spastic paraplegia in three siblings with distinct genetic mutations.
Hereditary spastic paraplegia is characterized by progressive motor features, including spastic gait and lower limb weakness, and encompasses numerous genetic subtypes. We report a family of six siblings born to asymptomatic consanguineous parents, in which three siblings exhibited overlapping spastic paraplegia phenotypes with developmental delay. The index patient demonstrated significant lower limb weakness and spasticity despite multiple orthopedic interventions. Next-generation sequencing identified a homozygous SELENOI c.797C > T (p.Pro266Leu) variant of uncertain significance, interpreted cautiously in the context of his SPG81-like phenotype. His older sister reportedly harbored a homozygous LAMA1 c.4579C > T (p.Gln1527Ter) variant consistent with Poretti-Boltshauser syndrome, explaining her cerebellar ataxia and nonprogressive course. His younger brother carried the same homozygous SELENOI variant as the index patient together with a de novo SATB2 c.860C > T (p.Pro287Leu) variant of uncertain significance, which was interpreted as a possible contributor to his mixed neurodevelopmental presentation. This report highlights that siblings presenting with similar early-onset spastic gait phenotypes may have distinct underlying genetic findings, supporting the value of comprehensive genetic evaluation even within a single family.
2026-07-09 | Mutation-specific cellular mechanisms in Drosophila models of ATL1-associated hereditary spastic paraplegia.
Mutations in ATL1 are a frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), yet patients display a wide range of clinical severity, from slowly progressive "pure" to severe, early-onset "complex" forms. The cellular mechanisms underlying this heterogeneity remain poorly defined, and mammalian model systems have thus far failed to distinguish between these subtypes. This study investigates the cellular basis of these clinically distinct forms of HSP using Drosophila models carrying homologous disease-causing mutations in the gene encoding Atlastin-1 (ATL1). Drosophila harbouring a complex ATL1-HSP mutation display reduced locomotor function, impaired development, and decreased survival relative to those carrying mutations associated with pure ATL1-HSP, recapitulating key aspects of clinical heterogeneity. Moreover, cellular analyses identify distinct pathological features across genotypes. Models of pure ATL1-HSP display disrupted lipid homeostasis, including lipid droplet accumulation within nerves comprising long motor neuron axons, which is partially ameliorated by treatment with a liver X receptor (LXR) agonist. In contrast, complex ATL1-HSP Drosophila lack lipid droplet abnormalities and do not respond to LXR activation but instead show disruption of the neuronal endoplasmic reticulum, consistent with aberrant ER network regulation. Together, these findings suggest that different mutations in Atl give rise to distinct cellular perturbations, suggesting a potential basis for phenotypic heterogeneity in ATL1-HSP.
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Drug Discovery Landscape
3 orphan drug designations for Hereditary spastic paraplegia.
3 orphan drug designations for Hereditary spastic paraplegia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Self-complimentary adeno-associated virus 9 gene therapy containing codon optimized human AP4M1 (melpida) | gene therapies | FDA | 2022-12-01 | — | Elpida Therapeutics |
adeno-associated virus serotype 9 gene transfer vector expressing human AP4B1 cDNA | gene therapies | FDA | 2021-02-16 | — | BlackfinBio Limited |
L-threonine | small molecules | FDA | 1992-07-24 | — | Interneuron Pharmaceuticals, Inc. |
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