RARE DISEASE
Autosomal recessive spastic paraplegia type 15
Autosomal recessive spastic paraplegia type 15
Autosomal recessive spastic paraplegia type 15
Synonyms: Hereditary spastic paraparesis type 15, Kjellin syndrome, SPG15, Spastic paraplegia-retinal degeneration syndrome
Synonyms: Hereditary spastic paraparesis type 15, Kjellin syndrome, SPG15, Spastic paraplegia-retinal degeneration syndrome
Synonyms: Hereditary spastic paraparesis type 15, Kjellin syndrome, SPG15, Spastic paraplegia-retinal degeneration syndrome
Drug discovery
0
drugs
With orphan designations
Overview
Autosomal recessive spastic paraplegia type 15 (SPG15) is a progressive neurodegenerative disorder caused by biallelic ZFYVE26 mutations, disrupting autophagy and lysosomal function [1][2][6]. It manifests in childhood/adolescence with lower limb spasticity, gait disturbances, thin corpus callosum, and multisystem involvement including mild intellectual disability, peripheral neuropathy, cerebellar ataxia, and retinal degeneration [1][2][6]. Disease progression leads to upper limb involvement, parkinsonism, and potential wheelchair dependence [2][6][13].
Therapies
Symptomatic management: Physical therapy, antispastic agents (baclofen, tizanidine), botulinum toxin injections, and bladder control medications (oxybutynin) [7][11]
Experimental approaches: Autophagy modulators (SMER28, trehalose) and lysosomal enhancers showing promise in preclinical models [3][7]
Supportive care: Mobility aids, neuropsychological support, and retinal degeneration monitoring [1][13]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
42 drug discovery papers about Autosomal recessive spastic paraplegia type 15, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
42 drug discovery papers about Autosomal recessive spastic paraplegia type 15, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-11-06 | Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.
2022-11-23 | Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
Hereditary spastic paraplegias are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive hereditary spastic paraplegias, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates neurofilament disruption in both SPG11 and SPG48 knockdown cortical projection neurons, confirming the contribution of hereditary spastic paraplegia gene deficiency to subsequent neurofilament and mitochondrial defects. Strikingly, neurofilament aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical projection neurons. Reduced ATP levels and accumulated neurofilament aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wild-type SPG11 in cortical projection neurons derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and neurofilament aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.
2019-04-10 | Functional effects of botulinum toxin type A in the hip adductors and subsequent stretching in patients with hereditary spastic paraplegia
To investigate the functional effects of bilateral botulinum toxin A treatment and subsequent stretching of spastic hip adductors on gait and reactive lateral stepping responses in patients with pure hereditary spastic paraplegia.Explorative pre-post intervention study.Twenty-five patients with pure hereditary spastic paraplegia.Patients were treated with bilateral botulinum toxin A injections in the hip adductors and performed daily self-administered stretching exercises for 16 weeks. Before the intervention (T0), and 6 (T1) and 16 (T2) weeks thereafter, gait width, gait speed, and leg angles at first stepping-foot contact after lateral balance perturbations were assessed, as well as the corresponding success rates of reactive lateral steps.Compared with baseline, gait width increased by 12.6% and 9.7% and comfortable gait speed by 8.3% and 11.5% at T1 and T2, respectively. In known perturbation directions, leg angles increased by 5.9% at T1 and 8.0% at T2, while success rates increased from 70% at baseline to 90% at T1 and T2. No effects were found for maximal gait speed or lateral stepping responses in unknown perturbation directions.Bilateral botulinum toxin A treatment and subsequent stretching of the hip adductors may improve gait and reactive lateral stepping in patients with pure hereditary spastic paraplegia.
2006-10-23 | Botulinum toxin injection in patients with hereditary spastic paraparesis
In an open label study, we analyzed the efficacy of botulinum toxin injection at the lower limbs of patients with hereditary spastic paraparesis (HSP). Fifteen patients who showed disabling spasticity with no or poor effect of oral treatment were recruited consecutively. Botulinum toxin was injected (400 U; Botox ® ) into the spastic muscles identified by clinical examination (equinus, varus, and pathological hip adduction). Patients were regularly assessed from the first day to the fifth month: spasticity (Ashworth), motor strength, range of movements, Functional Ambulation Categories (FAC), gait parameter, Rivermead Motor Assessment, self‐analysis of benefit and satisfaction. We observed a moderate and significant ( P < 0.05) reduction of ankle plantar flexor and hip adductor spasticity, with a partial increase in the range of the active and passive motion at the ankle and in gait velocity. At an individual level, six of 15 patients showed an increase in gait velocity. The FAC and RMA did not change. Patients often reported partial improvement in foot position and lower limb propulsion, and fair satisfaction. In conclusion, botulinum toxin injection can be effective in HSP patients with relatively ancient spasticity. This technique can be introduced into the therapeutic panel, which also includes physiotherapy, oral treatment and baclofen pump.
small molecules
2026-01-15 | Hereditary spastic paraplegia: from decades of therapy to future innovations.
Hereditary spastic paraplegia (HSP) groups rare, clinically and genetically heterogeneous neurodegenerative disorders, characterized by progressive lower-limb spasticity and weakness. Over the past decades, diagnostic strategies have evolved from pure clinical assessment to the integration of molecular tools, with next-generation and long-read sequencing (LRS) substantially increasing diagnostic yield and refining genotype-phenotype correlations. Neuroimaging provides complementary information, especially in specific subtypes such as SPG11 and SPG15, supporting diagnosis and guiding testing. Treatment has historically focused on symptomatic care, including physiotherapy, antispastic agents, and botulinum toxin, with dalfampridine explored for gait improvement in selected patients. More recently, research has expanded into disease-modifying avenues, such as drug repurposing (e.g., statins in SPG5, menatetrenone in ALS2) and early gene-based interventions in ultra-rare subtypes. At the same time, advances in technology, ranging from quantitative imaging and digital gait analysis to induced pluripotent stem cell models and artificial intelligence, are beginning to influence both clinical management and trial design. This review traces the trajectory of HSP care from its historical foundations to present standards and emerging innovations, outlining how technological progress is shaping realistic prospects for future therapeutic strategies.
2025-12-02 | Spectrum of Movement Disorders in Early-Onset Hereditary Spastic Paraplegia: A Study of 428 Cases.
Movement disorders occur in early-onset hereditary spastic paraplegia (HSP), but their prevalence, genotype associations, and clinical impact are not well defined. To delineate the spectrum and frequency of movement disorders across childhood-onset HSP genotypes and assess associations with clinician- and caregiver-reported outcomes. We performed a cross-sectional analysis of 428 children and young adults with molecularly confirmed HSP enrolled in a multicenter natural history study. Standardized clinical phenotyping and video examinations were reviewed. Movement and motor disorders (dystonia, ataxia, parkinsonism, tremor, choreoathetosis) were identified using predefined criteria. Associations with SPATAX-EUROSPA disability stage (SPATAX), Spastic Paraplegia Rating Scale (SPRS; total and spasticity subscore), Modified Ashworth Scale, and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) quality-of-life scores were analyzed with nonparametric tests and multivariable linear models adjusted for age and sex. Movement disorders were present in 27.6% (118/428) of participants; 22.8% of these had ≥2 movement disorders. Dystonia (16.4%) and ataxia (10.0%) predominated. Distinct genotype-specific patterns were observed: dystonia in SPG4, SPG3A, and AP-4-HSP; parkinsonism in SPG11; and ataxia in SPG15, SPG76, SPG7, SPG5a, and SPG46. Presence of any movement disorder correlated with greater disability and motor burden and lower quality of life. In adjusted models, dystonia and parkinsonism were associated with higher SPATAX and SPRS scores, whereas ataxia and tremor correlated with lower scores; dystonia showed the largest decrement in CPCHILD. Movement disorders are common, genotype-specific, and clinically impactful features of childhood-onset HSP. Routine screening and genotype-tailored management of movement disorders, especially dystonia, may improve functional outcomes and quality of life. © 2025 International Parkinson and Movement Disorder Society.
2025-06-24 | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes.
SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient's derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients.
2024-09-03 | Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia
Abstract In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15 -/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8 + T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8 + T cells potentially contributing to disease progression in Spg15 -/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15 -driven neuropathology. Targeting activated microglia, CD8 + T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.
2024-02-02 | Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients
Abstract Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1 + cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11 –/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
gene therapies
2026-07-23 | Genotypic and Phenotypic Profile of Hereditary Spastic Paraplegia in Children: A Single-Centre Study from Northern India.
To characterize the genotypic and phenotypic spectrum of children with genetically confirmed hereditary spastic paraplegia (HSP) at a tertiary care center in Northern India. This prospective case series included patients with genetically confirmed (whole exome sequencing or clinical exome sequencing) HSP attending the Medical Genetics Clinic of a tertiary care center in Northern India between 2018 and 2023. Neurological and radiological assessments were also conducted. A total of 21 patients from 16 families were included. The median (q1, q3) age of onset of symptoms was 5 (1.5, 8.5) years, and the median (q1, q3) age of diagnosis was 8 (5, 13.5) years. The most common features at diagnosis were toe walking with progressive spasticity of lower limbs. Genetic testing identified 18 variants across eight different genes, including six pathogenic variants, 10 likely pathogenic variants, and two variants of uncertain significance (VUS). Thirteen families had autosomal recessive (AR) HSP, two had autosomal dominant (AD) HSP, and one had X-linked HSP. The most frequently identified subtype was SPG35 (spastic paraplegia type 35), observed in six families, followed by SPG11 in three families and SPG52 in two families. There was one family each with SPG18B, SPG15, CSPSD (cataracts, spastic paraplegia, and speech delay), SPG4, and SPG2. Hereditary spastic paraplegia exhibits genotypic and phenotypic heterogeneity with a predominance of AR inheritance. Five novel variants and some recurrent variants, suggesting potential founder effects, were noted. HSP should be suspected in cases with slowly progressive spasticity in lower limbs, even without a family history, which may mimic cerebral palsy.
2026-05-13 | Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families.
Hereditary spastic paraplegia (HSP) refers to a heterogeneous group of genetic disorders with more than 90 causative genes. Clinically, HSP is classified into pure and complicated forms. Pure forms are characterized primarily by lower-limb spasticity and weakness, whereas complicated forms include additional neurological or non-neurological symptoms alongside spasticity and weakness. We aimed to characterize the clinical and genetic landscapes of HSP in an Iranian cohort. Whole-exome sequencing (WES) was performed on 103 unrelated clinically suspected HSP probands. Multiple ligation-dependent probe amplification (MLPA) was performed to validate identified copy number variants (CNVs) in two probands. 71 pathogenic/likely pathogenic and VUS variants were identified in 81 probands; total genetically solved probands: 78.6%. Among these solved cases, 64 probands harbored variants in known HSP genes, 14 had variants in other neuromuscular/neurodegenerative-related genes, and the remaining 3 probands carried variants in four novel candidate genes including NMNAT1, SEMA3A, KCNJ14, and EMP3. Among all 71 identified genomic variants, two were CNVs and one was a trinucleotide repeat expansion. Taken together, these variants were located in 37 genes; 21 of these genes have been previously implicated in HSP, and four common HSP subtypes (SPG11, SPG4, SPG7, and SPG15) accounted for ~40% of our cohort. This study demonstrates significant clinical and genetic heterogeneity of HSP within our cohort. In addition to variants in 21 known HSP-related genes, we identified variants in 14 genes related to other neurological disorders -highlighting shared biological pathways- as well as variants in four novel candidate genes. Notably, a genetic diagnosis could not be established in 22 probands, underscoring that additional, as yet unidentified genes likely contribute to HSP pathogenesis.
2025-10-31 | Investigating Hereditary Spastic Paraplegia Axonal Degeneration by Characterizing SPG15-Induced Pluripotent Stem Cells
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders caused by axonal degeneration of the cortical motor neurons. HSP affects around two out of 100,000 people worldwide. Symptoms of HSP involve spasticity, numbness and tingling sensations in the lower limb muscles.
2025-04-23 | Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.
In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.
2025-04-07 | “Ear of Lynx Sign” - A Radiodiagnostic clue for Complicated Hereditary Spastic Paraplegia: A Familial Case Report (P11-6.009)
To report the rare neuroimaging sign associated with a common autosomal recessive variant of complicated Hereditary Spastic Paraplegia HSP 11 and 15.
proteins
2025-11-06 | Small peptide P110 mitigates axonal degeneration of SPG15 patient iPSC-derived neurons by targeting mitochondrial dysfunction.
Hereditary Spastic Paraplegias (HSPs) are a group of heterogeneous neurological diseases characterized by axonal degeneration of corticospinal motor neurons. SPG15, a common autosomal recessive form of HSP, is caused by mutations in the ZFYVE26 gene that encodes the spastizin protein. Spastizin partially localizes to mitochondria, suggesting a potential role in mitochondrial function. To investigate this possibility and explore treatments to mitigate neurodegeneration caused by spastizin deficiency, SPG15 patient-specific induced pluripotent stem cells (iPSCs) were generated from patient fibroblasts and differentiated into cortical projection neurons. The SPG15 iPSC-derived neurons exhibited reduced ATP production compared to control neurons, indicating mitochondrial dysfunction in spastizin-deficient neurons. Also, given increased fragmentation of mitochondria in SPG15 neurons, we examined whether restoring mitochondrial morphology dynamics using P110, a peptide inhibitor of the mitochondrial fission protein DRP1, could protect SPG15 neurons. Indeed, treatment with P110 significantly suppressed the accumulated axonal swellings in SPG15 neurons. Further examination of the underlying mechanisms revealed that P110 restored mitochondrial morphology, ameliorated mitochondrial oxidative stress, and improved mitochondrial health, but it did not affect necrosis-related membrane integrity, suggesting specific targeting of mitochondrial deficits by P110. Furthermore, P110 significantly mitigated disease-related apoptosis in SPG15 neurons. Collectively, these findings reveal that restoring mitochondrial morphology and function using P110 lessens mitochondrial oxidative stress and mitigates degeneration of SPG15 neurons, offering a novel therapeutic approach for SPG15.
2022-11-23 | Inhibiting mitochondrial fission rescues degeneration in hereditary spastic paraplegia neurons.
Hereditary spastic paraplegias are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive hereditary spastic paraplegias, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates neurofilament disruption in both SPG11 and SPG48 knockdown cortical projection neurons, confirming the contribution of hereditary spastic paraplegia gene deficiency to subsequent neurofilament and mitochondrial defects. Strikingly, neurofilament aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical projection neurons. Reduced ATP levels and accumulated neurofilament aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wild-type SPG11 in cortical projection neurons derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and neurofilament aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically.
2019-04-10 | Functional effects of botulinum toxin type A in the hip adductors and subsequent stretching in patients with hereditary spastic paraplegia
To investigate the functional effects of bilateral botulinum toxin A treatment and subsequent stretching of spastic hip adductors on gait and reactive lateral stepping responses in patients with pure hereditary spastic paraplegia.Explorative pre-post intervention study.Twenty-five patients with pure hereditary spastic paraplegia.Patients were treated with bilateral botulinum toxin A injections in the hip adductors and performed daily self-administered stretching exercises for 16 weeks. Before the intervention (T0), and 6 (T1) and 16 (T2) weeks thereafter, gait width, gait speed, and leg angles at first stepping-foot contact after lateral balance perturbations were assessed, as well as the corresponding success rates of reactive lateral steps.Compared with baseline, gait width increased by 12.6% and 9.7% and comfortable gait speed by 8.3% and 11.5% at T1 and T2, respectively. In known perturbation directions, leg angles increased by 5.9% at T1 and 8.0% at T2, while success rates increased from 70% at baseline to 90% at T1 and T2. No effects were found for maximal gait speed or lateral stepping responses in unknown perturbation directions.Bilateral botulinum toxin A treatment and subsequent stretching of the hip adductors may improve gait and reactive lateral stepping in patients with pure hereditary spastic paraplegia.
2006-10-23 | Botulinum toxin injection in patients with hereditary spastic paraparesis
In an open label study, we analyzed the efficacy of botulinum toxin injection at the lower limbs of patients with hereditary spastic paraparesis (HSP). Fifteen patients who showed disabling spasticity with no or poor effect of oral treatment were recruited consecutively. Botulinum toxin was injected (400 U; Botox ® ) into the spastic muscles identified by clinical examination (equinus, varus, and pathological hip adduction). Patients were regularly assessed from the first day to the fifth month: spasticity (Ashworth), motor strength, range of movements, Functional Ambulation Categories (FAC), gait parameter, Rivermead Motor Assessment, self‐analysis of benefit and satisfaction. We observed a moderate and significant ( P < 0.05) reduction of ankle plantar flexor and hip adductor spasticity, with a partial increase in the range of the active and passive motion at the ankle and in gait velocity. At an individual level, six of 15 patients showed an increase in gait velocity. The FAC and RMA did not change. Patients often reported partial improvement in foot position and lower limb propulsion, and fair satisfaction. In conclusion, botulinum toxin injection can be effective in HSP patients with relatively ancient spasticity. This technique can be introduced into the therapeutic panel, which also includes physiotherapy, oral treatment and baclofen pump.
small molecules
2026-01-15 | Hereditary spastic paraplegia: from decades of therapy to future innovations.
Hereditary spastic paraplegia (HSP) groups rare, clinically and genetically heterogeneous neurodegenerative disorders, characterized by progressive lower-limb spasticity and weakness. Over the past decades, diagnostic strategies have evolved from pure clinical assessment to the integration of molecular tools, with next-generation and long-read sequencing (LRS) substantially increasing diagnostic yield and refining genotype-phenotype correlations. Neuroimaging provides complementary information, especially in specific subtypes such as SPG11 and SPG15, supporting diagnosis and guiding testing. Treatment has historically focused on symptomatic care, including physiotherapy, antispastic agents, and botulinum toxin, with dalfampridine explored for gait improvement in selected patients. More recently, research has expanded into disease-modifying avenues, such as drug repurposing (e.g., statins in SPG5, menatetrenone in ALS2) and early gene-based interventions in ultra-rare subtypes. At the same time, advances in technology, ranging from quantitative imaging and digital gait analysis to induced pluripotent stem cell models and artificial intelligence, are beginning to influence both clinical management and trial design. This review traces the trajectory of HSP care from its historical foundations to present standards and emerging innovations, outlining how technological progress is shaping realistic prospects for future therapeutic strategies.
2025-12-02 | Spectrum of Movement Disorders in Early-Onset Hereditary Spastic Paraplegia: A Study of 428 Cases.
Movement disorders occur in early-onset hereditary spastic paraplegia (HSP), but their prevalence, genotype associations, and clinical impact are not well defined. To delineate the spectrum and frequency of movement disorders across childhood-onset HSP genotypes and assess associations with clinician- and caregiver-reported outcomes. We performed a cross-sectional analysis of 428 children and young adults with molecularly confirmed HSP enrolled in a multicenter natural history study. Standardized clinical phenotyping and video examinations were reviewed. Movement and motor disorders (dystonia, ataxia, parkinsonism, tremor, choreoathetosis) were identified using predefined criteria. Associations with SPATAX-EUROSPA disability stage (SPATAX), Spastic Paraplegia Rating Scale (SPRS; total and spasticity subscore), Modified Ashworth Scale, and Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) quality-of-life scores were analyzed with nonparametric tests and multivariable linear models adjusted for age and sex. Movement disorders were present in 27.6% (118/428) of participants; 22.8% of these had ≥2 movement disorders. Dystonia (16.4%) and ataxia (10.0%) predominated. Distinct genotype-specific patterns were observed: dystonia in SPG4, SPG3A, and AP-4-HSP; parkinsonism in SPG11; and ataxia in SPG15, SPG76, SPG7, SPG5a, and SPG46. Presence of any movement disorder correlated with greater disability and motor burden and lower quality of life. In adjusted models, dystonia and parkinsonism were associated with higher SPATAX and SPRS scores, whereas ataxia and tremor correlated with lower scores; dystonia showed the largest decrement in CPCHILD. Movement disorders are common, genotype-specific, and clinically impactful features of childhood-onset HSP. Routine screening and genotype-tailored management of movement disorders, especially dystonia, may improve functional outcomes and quality of life. © 2025 International Parkinson and Movement Disorder Society.
2025-06-24 | Naringenin and SMER28 target lysosomal reformation and rescue SPG11 and SPG15 hereditary spastic paraplegia phenotypes.
SPG11 and SPG15 are two hereditary spastic paraplegia forms characterized by autophagosome accumulation, reduced free lysosomes and defects in autophagic lysosomal reformation (ALR). We demonstrated that attempts to rescue ALR and/or lysosome biogenesis are critical strategies for SPG15 phenotype and that SMER28 improved lysosomal reformation rescuing locomotor deficit in a SPG15 Drosophila model. Here we assessed the therapeutic potential of two FDA-approved compounds, tideglusib and naringenin, that target lysosomal function and regeneration, both registered for clinical use. Their effects were compared with those of SMER28 and of miglustat, the latter tested in a phase II clinical trial in SPG11 patients, in both SPG15 and SPG11 patient's derived cells and in the corresponding Drosophila models. We demonstrated that naringenin and SMER28 restored lysosomal and autophagic parameters in SPG15 and SPG11 cells and fly models, rescued ALR and improved locomotor deficit in vivo. Both compounds induced lysosomal tubulation, downstream of mTOR, promoting lysosomal reformation. Our work indicates that lysosomal reformation is a good strategy for herditary spastic parapegia forms with impaired lysosomal function and identifies naringenin as new modulator of this process, offering further hand to planning phase II clinical trials in SPG11-SPG15 patients.
2024-09-03 | Disease-associated microglia and activation of CD8+ T cells precede neuronal cell loss in a model of hereditary spastic paraplegia
Abstract In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is amplified by the prolonged nature of these diseases, complicating the delineation of brain-resident and infiltrating cells. Here, we conducted a comprehensive profiling of innate and adaptive immune cells across various CNS regions in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia (HSP). Using fate-mapping of bone marrow-derived cells via genetic labeling, we identified microgliosis and microglial MHC-II upregulation accompanied by infiltration and local expansion of T cells in the CNS of Spg15 -/- mice. Single-cell analysis revealed an increase of disease-associated microglia (DAM) and clonal expansion of effector CD8 + T cells across CNS regions occurring prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8 + T cells potentially contributing to disease progression in Spg15 -/- mice. In summary, we identified a shift in microglial phenotypes associated with recruitment and clonal expansion of T cells as a new characteristic of Spg15 -driven neuropathology. Targeting activated microglia, CD8 + T cells and their communication represent promising avenues to prevent the loss of neuronal function in HSP.
2024-02-02 | Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients
Abstract Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11–HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11–HSP, including examination of three human postmortem brain donations, immunophenotyping of patients’ peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL). We delineate a previously unknown role of innate immunity in SPG11–HSP. Neuropathological analysis of SPG11–HSP patient brain tissue revealed profound microgliosis in areas of neurodegeneration, downregulation of homeostatic microglial markers and cell-intrinsic accumulation of lipids and lipofuscin in IBA1 + cells. In a larger cohort of SPG11–HSP patients, the ratio of peripheral classical and intermediate monocytes was increased, along with increased serum levels of IL-6 that correlated with disease severity. Stimulation of patient-specific iMGLs with IFNγ led to increased phagocytic activity compared to control iMGL as well as increased upregulation and release of proinflammatory cytokines and chemokines, such as CXCL10. On a molecular basis, we identified increased STAT1 phosphorylation as mechanism connecting IFNγ-mediated immune hyperactivation and SPG11 loss of function. STAT1 expression was increased both in human postmortem brain tissue and in an Spg11 –/– mouse model. Application of an STAT1 inhibitor decreased CXCL10 production in SPG11 iMGL and rescued their toxic effect on SPG11 neurons. Our data establish neuroinflammation as a novel disease mechanism in SPG11–HSP patients and constitute the first description of myeloid cell/ microglia activation in human SPG11–HSP. IFNγ/ STAT1-mediated neurotoxic effects of hyperreactive microglia upon SPG11 loss of function indicate that immunomodulation strategies may slow down disease progression.
gene therapies
2026-07-23 | Genotypic and Phenotypic Profile of Hereditary Spastic Paraplegia in Children: A Single-Centre Study from Northern India.
To characterize the genotypic and phenotypic spectrum of children with genetically confirmed hereditary spastic paraplegia (HSP) at a tertiary care center in Northern India. This prospective case series included patients with genetically confirmed (whole exome sequencing or clinical exome sequencing) HSP attending the Medical Genetics Clinic of a tertiary care center in Northern India between 2018 and 2023. Neurological and radiological assessments were also conducted. A total of 21 patients from 16 families were included. The median (q1, q3) age of onset of symptoms was 5 (1.5, 8.5) years, and the median (q1, q3) age of diagnosis was 8 (5, 13.5) years. The most common features at diagnosis were toe walking with progressive spasticity of lower limbs. Genetic testing identified 18 variants across eight different genes, including six pathogenic variants, 10 likely pathogenic variants, and two variants of uncertain significance (VUS). Thirteen families had autosomal recessive (AR) HSP, two had autosomal dominant (AD) HSP, and one had X-linked HSP. The most frequently identified subtype was SPG35 (spastic paraplegia type 35), observed in six families, followed by SPG11 in three families and SPG52 in two families. There was one family each with SPG18B, SPG15, CSPSD (cataracts, spastic paraplegia, and speech delay), SPG4, and SPG2. Hereditary spastic paraplegia exhibits genotypic and phenotypic heterogeneity with a predominance of AR inheritance. Five novel variants and some recurrent variants, suggesting potential founder effects, were noted. HSP should be suspected in cases with slowly progressive spasticity in lower limbs, even without a family history, which may mimic cerebral palsy.
2026-05-13 | Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families.
Hereditary spastic paraplegia (HSP) refers to a heterogeneous group of genetic disorders with more than 90 causative genes. Clinically, HSP is classified into pure and complicated forms. Pure forms are characterized primarily by lower-limb spasticity and weakness, whereas complicated forms include additional neurological or non-neurological symptoms alongside spasticity and weakness. We aimed to characterize the clinical and genetic landscapes of HSP in an Iranian cohort. Whole-exome sequencing (WES) was performed on 103 unrelated clinically suspected HSP probands. Multiple ligation-dependent probe amplification (MLPA) was performed to validate identified copy number variants (CNVs) in two probands. 71 pathogenic/likely pathogenic and VUS variants were identified in 81 probands; total genetically solved probands: 78.6%. Among these solved cases, 64 probands harbored variants in known HSP genes, 14 had variants in other neuromuscular/neurodegenerative-related genes, and the remaining 3 probands carried variants in four novel candidate genes including NMNAT1, SEMA3A, KCNJ14, and EMP3. Among all 71 identified genomic variants, two were CNVs and one was a trinucleotide repeat expansion. Taken together, these variants were located in 37 genes; 21 of these genes have been previously implicated in HSP, and four common HSP subtypes (SPG11, SPG4, SPG7, and SPG15) accounted for ~40% of our cohort. This study demonstrates significant clinical and genetic heterogeneity of HSP within our cohort. In addition to variants in 21 known HSP-related genes, we identified variants in 14 genes related to other neurological disorders -highlighting shared biological pathways- as well as variants in four novel candidate genes. Notably, a genetic diagnosis could not be established in 22 probands, underscoring that additional, as yet unidentified genes likely contribute to HSP pathogenesis.
2025-10-31 | Investigating Hereditary Spastic Paraplegia Axonal Degeneration by Characterizing SPG15-Induced Pluripotent Stem Cells
Hereditary Spastic Paraplegia (HSP) is a group of inherited neurodegenerative disorders caused by axonal degeneration of the cortical motor neurons. HSP affects around two out of 100,000 people worldwide. Symptoms of HSP involve spasticity, numbness and tingling sensations in the lower limb muscles.
2025-04-23 | Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.
In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.
2025-04-07 | “Ear of Lynx Sign” - A Radiodiagnostic clue for Complicated Hereditary Spastic Paraplegia: A Familial Case Report (P11-6.009)
To report the rare neuroimaging sign associated with a common autosomal recessive variant of complicated Hereditary Spastic Paraplegia HSP 11 and 15.
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