RARE DISEASE
Spastic paraplegia type 7
Spastic paraplegia type 7
Spastic paraplegia type 7
Synonyms: SPG7
Synonyms: SPG7
Synonyms: SPG7
Drug discovery
37
papers
On emerging therapies
Overview
Spastic Paraplegia Type 7 (SPG7) is an autosomal recessive neurodegenerative disorder caused by biallelic SPG7 mutations, leading to progressive lower-limb spasticity, cerebellar ataxia, and frequent extraspinal features (optic atrophy, dysarthria, dysphagia, parkinsonism). Onset is typically in adulthood (10–72 years), with multisystem involvement including mitochondrial dysfunction. Diagnosis relies on genetic testing, and management focuses on symptom relief.
Burden
Therapies
Symptomatic: Oral/intrathecal baclofen, botulinum toxin, antispasmodics (tizanidine), and physical/occupational therapy [1][2][12].
Supportive: Management of bladder dysfunction (oxybutynin), parkinsonism (levodopa), and dysphagia [1][8][12].
Emerging: Targeted genomic therapies (antisense oligonucleotides, gene replacement) in preclinical stages [3][16].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders
Research Papers
37 drug discovery papers about Spastic paraplegia type 7, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
37 drug discovery papers about Spastic paraplegia type 7, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-05-12 | Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families
Abstract Background 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. Results 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. Conclusions 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.
2025-08-09 | Charting the genetic landscape of autosomal recessive hereditary spastic paraplegia: A deep dive into 10 exceptionally rare cases.
Hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Autosomal recessive HSPs (AR HSPs) are rare and account for approximately 30% of cases, with a higher prevalence in populations with increased consanguinity rates. In this study, we investigated 10 patients diagnosed with AR HSPs and identified pathogenic variants in SPART, FA2H, AP4B1, SPG7, SPG11, CYP2U1, and CYP7B1, with three cases harboring novel variants. Clinical presentations ranged from pure spastic paraplegia to complex phenotypes involving intellectual disability, ataxia, dysarthria, joint abnormalities, and systemic features. Exome sequencing and detailed bioinformatics analyses were employed to identify causative variants, which were classified based on ACMG criteria. The study expands the known genetic spectrum of AR HSPs by reporting previously undescribed variants and providing insight into their potential pathogenic mechanisms. The presence of distinct clinical features in patients with the same genetic variant emphasizes the complexity of genotype-phenotype correlations in HSP. Our findings highlight the importance of genetic testing in early diagnosis and clinical management of HSP, enabling more precise prognostic evaluations and potential therapeutic interventions. Given the high consanguinity rates in certain populations, targeted genetic screening may facilitate early detection and personalized treatment strategies. Further functional studies are needed to elucidate the molecular impact of these novel variants and their role in disease progression, potentially paving the way for future gene-based therapies.
2025-08-05 | Decoding Genomic Variants in a Turkish Cohort of Patients with Spasticity
Hereditary spastic paraplegia (HSP) is a complex neurological disorder with significant genetic heterogeneity. Overlapping clinical presentations and population-specific genetic variants pose challenges to differential diagnosis and genetic studies. To identify and characterize genetic variants associated with HSP and related syndromes in a Turkish cohort, emphasizing potential novel findings and inheritance patterns. 45 patients were clinically diagnosed with HSP or related phenotypes and their demographic and clinical details were recorded. Clinical exome sequencing (CES) was employed to identify pathogenic and likely pathogenic variants. Variants were classified using ACMG guidelines and critical variants were confirmed by Sanger sequencing. The cohort included 16 females (35.5%) and 29 males (64.5%), aged 3 months to 72 years. Consanguinity was identified in 70.4% of cases with reported parental data. Pathogenic or likely pathogenic variants were detected in 66.7% of patients. Commonly affected genes included SPAST (17.8%), SPG7 (13.3%), and SPG11 (11.1%). Fifteen novel variants were identified, expanding the known genetic spectrum of HSP. This study highlights the clinical utility of CES in diagnosing HSP and related disorders, identifies novel genetic variants, and provides evidence for complex inheritance mechanisms. These findings enhance the understanding of the genetic landscape of HSP, particularly in the Turkish population.
2025-05-05 | Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population.
Hereditary spastic paraplegias (HSP) are rare disorders sharing common features of leg spasticity with gait impairment. Simple and complex forms are recognized; over 50% of cases remain unsolved genetically. Little is known about the genetics of HSP among Indigenous Peoples. To describe clinical, radiological, and genetic features of HSP in Alberta, Canada, and evaluate genetic variability among ethnic groups. Patients with HSP were recruited between 2012 and 2021, and enrolled in an observational study. Genetic testing through research and/or clinical laboratories was performed. 100 patients from 86 Albertan families were enrolled. Overall prevalence was 2.3 per 100,000, with 2.8 per 100,000 in the Indigenous population. Forty-eight families (56%) were found to have pathogenic variants in 17 genes, including SPAST (29.2%), SPG7 (20.8%), SPG11 (8.3%), CAPN1 (6.3%), and SACS (6.3%). 58% of families had complex HSP. 36/66 White (European) families, 5/8 Indigenous families, 4/8 Asian families and 2/3 Middle Eastern families were confirmed with a genetic diagnosis. One Black (African) family was enrolled and tested positive for PI4KA. In Indigenous families, pathogenic variants were found in CTNNB1, SACS, SPG7, and SYNE1. Abnormalities of brain MRI were more frequently observed in patients with SACS, SPG7, SPG11, and ANO10. This study details findings in HSP patients in Alberta and is the first study to examine prevalence and types of HSP in the Indigenous Peoples of Alberta. It highlights the need for familiarity with the phenotypes and genotypes in the different ethnic populations in Alberta.
2025-02-21 | Expanding the Phenotypic Spectrum of SPG7 Rare Damaging Variants: Insights From a Hungarian Cohort.
Mitochondria-associated paraplegin dysfunction is primarily linked to spastic paraplegia; however, genetic alterations in SPG7 have been associated with a broader spectrum of clinical symptoms. To identify disease-causing variants in the SPG7 gene, 437 patients with spastic ataxia, mitochondrial dysfunction-associated symptoms, or motoneuron lesions detected by EMG have been tested. We aimed to assess the clinical spectrum and determine the frequency of damaging variants within patient groups, particularly those less studied. Using ACMG criteria, we identified 10 pathogenic or likely pathogenic variants, 5 variants of uncertain significance with predicted damaging effects, and a probable risk factor variant in 58 patients. We identified 25 biallelic and 33 monoallelic cases. The most common variant was p. Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). The point prevalence of SPG7-associated conditions in Hungary in 2024 is 0.46 per 100 000. In addition to well-characterized cohorts, SPG7 alterations were frequently identified in cohorts with multisystemic mitochondrial disease and lower motoneuron lesions. Multiple mtDNA deletions and histological abnormalities were consistently observed across all groups. In monoallelic cases, no evidence of a digenic effect involving AFG3L2 was found. Both autosomal dominant and recessive inheritance patterns were documented, with monoallelic cases typically presenting with a milder phenotype.
small molecules
2026-06-30 | Berberine improves motor deficits in the spastic paraplegia SPG7 mutant mice
Abstract Hereditary spastic paraplegia type 7 (SPG7) is a neurodegenerative disorder characterized by progressive motor impairment and cerebellar dysfunction. Mutations in the SPG7 gene, encoding the mitochondrial metalloprotease paraplegin, disrupt mitochondrial homeostasis and lead to neuronal vulnerability and deficits in motor coordination. Recent studies have identified defective flickering of the mitochondrial permeability transition pore (mPTP) in SPG7 models, suggesting that altered pore dynamics may represent a functional biomarker of mitochondrial dysfunction. Here, we investigated whether pharmacological modulation of mPTP activity could improve mitochondrial function and motor performance in SPG7 models. Mitochondrial flickering was assessed in vitro , while motor behavior was evaluated in vivo following chronic treatment with berberine, a natural isoquinoline alkaloid known to modulate mitochondrial bioenergetics. Spg7 −/− mice and age-matched Spg7 +/ littermate controls received daily oral berberine administration for several weeks, and motor coordination was assessed using the accelerating rotarod test. Untreated Spg7 −/− mice exhibited reduced rotarod performance compared with controls, indicating impaired motor coordination. Berberine treatment significantly improved motor performance in pre-symptomatic mutant mice. These findings indicate that pharmacological modulation of mitochondrial permeability transition pore dynamics can ameliorate motor dysfunction associated with SPG7 deficiency and highlight mPTP flickering as a functional readout of mitochondrial health.
2026-06-29 | Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons.
Biallelic pathogenic variants in SPG7 are a frequent cause of hereditary spastic paraplegia leading to progressive disability due to a length-dependent degeneration of cerebellar and cortical projection neurons. While underlying mechanisms have been linked to impaired mitochondrial function, no disease-modifying therapy is available. We generated induced pluripotent stem cell-derived cortical neurons from SPG7 patients with non-sense or truncating variants and from matched controls. We performed detailed phenotyping of neuronal differentiation, as well as mitochondrial and neuritic morphology and function. We explored the effects of Bz-423, a modulator of the mitochondrial permeability transition pore, as a potential rescue of SPG7-specific cellular phenotypes. We successfully differentiated SPG7 patient-derived neurons, without quantitative differences in differentiation compared with controls. However, we delineate neurite-specific aberrations of mitochondrial morphology and ultrastructure. Moreover, anterograde axonal mitochondrial transport was impaired in SPG7. Exposure to Bz-423 rescued ultrastructural and functional phenotypes. In summary, our data show impaired neuritic mitochondria in a patient-specific human model, and we here demonstrate for the first time beneficial effects of Bz-423 on neuritic ultrastructure and function in a human neuronal SPG7 system. Moreover, we identify the mitochondrial permeability transition pore as a molecular target to rescue phenotypes also in carriers of non-sense or truncating SPG7 variants.
2026-01-26 | Pharmacological Restoration of Mitochondrial Permeability Transition Pore Flickering by High-Content Drug Repurposing
Abstract The mitochondrial permeability transition pore (mPTP) is a voltage- and calcium-regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2,000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from two SPG7 patients and healthy controls confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.
2025-04-16 | Broadening the Horizons of Mitochondrial Parkinsonism
Sir, Spastic paraplegia 7 (SPG-7) is characterized by insidiously progressive spastic paraparesis with diminished vibration sense. Additional features including ataxia, spastic dysarthria, dysphagia, pale optic discs, nystagmus, strabismus, ptosis, hearing loss, neuropathy, amyotrophy, skeletal abnormalities, and urinary disturbances may also be seen. However, literature has also shown the presence of Parkinsonism. Our case manifested as pure Parkinsonian syndrome disguising the actual pathology. A 45-year-old female, born to non-consanguineous parents, a homemaker, came to us with a slowness of activities of daily living for 1 year followed by right-hand tremor and change of speech. She never sustained any fall. There was no history of heavy metal or farming exposure with non-contributory family history. She exhibited hypomimia with hypophonic speech. Her mini-mental status examination score (MMSE) was 28. Eye testing showed broken pursuits and slow saccades only. She had bilateral upper limb (UL) rigidity and bradykinesia, right more than left associated with similar symptoms in the right lower limb (LL). Rest and postural tremor was noted in the right UL and LL. Her motor unified Parkinson’s disease rating scale score (UPDRS) was 34 with Hoehn and Yahr (H and Y) stage two. She had no non-motor symptoms. So, a diagnosis of early Parkinson’s disease was made and levodopa carbidopa along with trihexyphenidyl (THP) was started with gradual uptitration. After 1 month of levodopa equivalent dose (LED) of 300 mg and THP of 8 mg, her motor score reduced to 15 from 28. Her blood work and magnetic resonance imaging (MRI) brain came out normal. Her L-6-[18F] fluoro-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) scan showed slightly reduced presynaptic dopaminergic uptake in left putamen depicting presynaptic dopaminergic uptake deficit. Genetic testing revealed compound heterozygous variants in the SPG-7 gene: p.Ala510Val, p.Leu78Ter. This missense c.1529C>T (p.Ala510Val) variant in SPG-7 gene has been reported in individuals affected with autosomal recessive SPG but has shown dominant effect in some cases also.[1] SPG-7 is caused by homozygous or compound heterozygous mutation in the paraplegin gene (SPG-7) on chromosome 16q24. This gene encodes paraplegin, which is required for the maintenance of mitochondrial deoxyribonucleic acid (DNA) proteins, so it is postulated that its mutation will lead to mitochondrial dysfunction.[2] In the largest series of patients with SPG-7, the overall clinical phenotype is characterized by slowly progressive spastic paraparesis, variable degrees of cerebellar ataxia, ophthalmoplegia, and optic atrophy contrary to our patient who had only Parkinsonism.[3] SPG type 7 is one of the most common subtypes of autosomal recessive hereditary SPGs, manifesting predominantly in adulthood. Our patient had a compound heterozygous mutation but still manifested with an unusual phenotype mimicking idiopathic Parkinson’s disease. She also had a significant reduction of UPDRS motor score after levodopa. Table 1 describes cases showing levodopa-responsive symmetric Parkinsonism unlike our case with asymmetrical Parkinsonism.Table 1: Other studies showing Parkinsonism associated with other clinical features with SPG-7 gene mutationDeclaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-06-10 | Mobile digital gait analysis captures effects of botulinum toxin in hereditary spastic paraplegia
Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient-reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response. We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters. A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1-month and declining by the 3-month follow-up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response. Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response.
cell therapies
2021-11-25 | Generation of induced pluripotent stem cell line (ZZUi030-A) from a patient with spastic paraplegia type 7.
Spastic paraplegia type 7 is a rare and classical monogenic inherited neurodegenerative disease caused by heterozygous mutations in the SPG7 gene. The principle clinical features include progressive spasms of the lower limbs, scissor gait, and muscle weakness. The disease currently has no effective treatment. In this study, we obtained dermal fibroblasts from a patient, which were successfully transformed into induced pluripotent stem cells (iPSCs) by employing reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our method provides a resource for mechanism exploration, drug research, cell transplantation, and gene therapy.
gene therapies
2026-05-12 | Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families
Abstract Background 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. Results 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. Conclusions 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.
2025-08-09 | Charting the genetic landscape of autosomal recessive hereditary spastic paraplegia: A deep dive into 10 exceptionally rare cases.
Hereditary spastic paraplegias (HSPs) are a genetically and clinically heterogeneous group of neurodegenerative disorders primarily characterized by progressive lower limb spasticity and weakness. Autosomal recessive HSPs (AR HSPs) are rare and account for approximately 30% of cases, with a higher prevalence in populations with increased consanguinity rates. In this study, we investigated 10 patients diagnosed with AR HSPs and identified pathogenic variants in SPART, FA2H, AP4B1, SPG7, SPG11, CYP2U1, and CYP7B1, with three cases harboring novel variants. Clinical presentations ranged from pure spastic paraplegia to complex phenotypes involving intellectual disability, ataxia, dysarthria, joint abnormalities, and systemic features. Exome sequencing and detailed bioinformatics analyses were employed to identify causative variants, which were classified based on ACMG criteria. The study expands the known genetic spectrum of AR HSPs by reporting previously undescribed variants and providing insight into their potential pathogenic mechanisms. The presence of distinct clinical features in patients with the same genetic variant emphasizes the complexity of genotype-phenotype correlations in HSP. Our findings highlight the importance of genetic testing in early diagnosis and clinical management of HSP, enabling more precise prognostic evaluations and potential therapeutic interventions. Given the high consanguinity rates in certain populations, targeted genetic screening may facilitate early detection and personalized treatment strategies. Further functional studies are needed to elucidate the molecular impact of these novel variants and their role in disease progression, potentially paving the way for future gene-based therapies.
2025-08-05 | Decoding Genomic Variants in a Turkish Cohort of Patients with Spasticity
Hereditary spastic paraplegia (HSP) is a complex neurological disorder with significant genetic heterogeneity. Overlapping clinical presentations and population-specific genetic variants pose challenges to differential diagnosis and genetic studies. To identify and characterize genetic variants associated with HSP and related syndromes in a Turkish cohort, emphasizing potential novel findings and inheritance patterns. 45 patients were clinically diagnosed with HSP or related phenotypes and their demographic and clinical details were recorded. Clinical exome sequencing (CES) was employed to identify pathogenic and likely pathogenic variants. Variants were classified using ACMG guidelines and critical variants were confirmed by Sanger sequencing. The cohort included 16 females (35.5%) and 29 males (64.5%), aged 3 months to 72 years. Consanguinity was identified in 70.4% of cases with reported parental data. Pathogenic or likely pathogenic variants were detected in 66.7% of patients. Commonly affected genes included SPAST (17.8%), SPG7 (13.3%), and SPG11 (11.1%). Fifteen novel variants were identified, expanding the known genetic spectrum of HSP. This study highlights the clinical utility of CES in diagnosing HSP and related disorders, identifies novel genetic variants, and provides evidence for complex inheritance mechanisms. These findings enhance the understanding of the genetic landscape of HSP, particularly in the Turkish population.
2025-05-05 | Hereditary Spastic Paraplegia in Alberta: Lessons from a Well-Defined Cohort Including the Indigenous Population.
Hereditary spastic paraplegias (HSP) are rare disorders sharing common features of leg spasticity with gait impairment. Simple and complex forms are recognized; over 50% of cases remain unsolved genetically. Little is known about the genetics of HSP among Indigenous Peoples. To describe clinical, radiological, and genetic features of HSP in Alberta, Canada, and evaluate genetic variability among ethnic groups. Patients with HSP were recruited between 2012 and 2021, and enrolled in an observational study. Genetic testing through research and/or clinical laboratories was performed. 100 patients from 86 Albertan families were enrolled. Overall prevalence was 2.3 per 100,000, with 2.8 per 100,000 in the Indigenous population. Forty-eight families (56%) were found to have pathogenic variants in 17 genes, including SPAST (29.2%), SPG7 (20.8%), SPG11 (8.3%), CAPN1 (6.3%), and SACS (6.3%). 58% of families had complex HSP. 36/66 White (European) families, 5/8 Indigenous families, 4/8 Asian families and 2/3 Middle Eastern families were confirmed with a genetic diagnosis. One Black (African) family was enrolled and tested positive for PI4KA. In Indigenous families, pathogenic variants were found in CTNNB1, SACS, SPG7, and SYNE1. Abnormalities of brain MRI were more frequently observed in patients with SACS, SPG7, SPG11, and ANO10. This study details findings in HSP patients in Alberta and is the first study to examine prevalence and types of HSP in the Indigenous Peoples of Alberta. It highlights the need for familiarity with the phenotypes and genotypes in the different ethnic populations in Alberta.
2025-02-21 | Expanding the Phenotypic Spectrum of SPG7 Rare Damaging Variants: Insights From a Hungarian Cohort.
Mitochondria-associated paraplegin dysfunction is primarily linked to spastic paraplegia; however, genetic alterations in SPG7 have been associated with a broader spectrum of clinical symptoms. To identify disease-causing variants in the SPG7 gene, 437 patients with spastic ataxia, mitochondrial dysfunction-associated symptoms, or motoneuron lesions detected by EMG have been tested. We aimed to assess the clinical spectrum and determine the frequency of damaging variants within patient groups, particularly those less studied. Using ACMG criteria, we identified 10 pathogenic or likely pathogenic variants, 5 variants of uncertain significance with predicted damaging effects, and a probable risk factor variant in 58 patients. We identified 25 biallelic and 33 monoallelic cases. The most common variant was p. Leu78Ter (N = 23), followed by p. Ala510Val (N = 21). The point prevalence of SPG7-associated conditions in Hungary in 2024 is 0.46 per 100 000. In addition to well-characterized cohorts, SPG7 alterations were frequently identified in cohorts with multisystemic mitochondrial disease and lower motoneuron lesions. Multiple mtDNA deletions and histological abnormalities were consistently observed across all groups. In monoallelic cases, no evidence of a digenic effect involving AFG3L2 was found. Both autosomal dominant and recessive inheritance patterns were documented, with monoallelic cases typically presenting with a milder phenotype.
small molecules
2026-06-30 | Berberine improves motor deficits in the spastic paraplegia SPG7 mutant mice
Abstract Hereditary spastic paraplegia type 7 (SPG7) is a neurodegenerative disorder characterized by progressive motor impairment and cerebellar dysfunction. Mutations in the SPG7 gene, encoding the mitochondrial metalloprotease paraplegin, disrupt mitochondrial homeostasis and lead to neuronal vulnerability and deficits in motor coordination. Recent studies have identified defective flickering of the mitochondrial permeability transition pore (mPTP) in SPG7 models, suggesting that altered pore dynamics may represent a functional biomarker of mitochondrial dysfunction. Here, we investigated whether pharmacological modulation of mPTP activity could improve mitochondrial function and motor performance in SPG7 models. Mitochondrial flickering was assessed in vitro , while motor behavior was evaluated in vivo following chronic treatment with berberine, a natural isoquinoline alkaloid known to modulate mitochondrial bioenergetics. Spg7 −/− mice and age-matched Spg7 +/ littermate controls received daily oral berberine administration for several weeks, and motor coordination was assessed using the accelerating rotarod test. Untreated Spg7 −/− mice exhibited reduced rotarod performance compared with controls, indicating impaired motor coordination. Berberine treatment significantly improved motor performance in pre-symptomatic mutant mice. These findings indicate that pharmacological modulation of mitochondrial permeability transition pore dynamics can ameliorate motor dysfunction associated with SPG7 deficiency and highlight mPTP flickering as a functional readout of mitochondrial health.
2026-06-29 | Rescue of mitochondrial and neurite pathology in SPG7 hereditary spastic paraplegia patient-derived cortical neurons.
Biallelic pathogenic variants in SPG7 are a frequent cause of hereditary spastic paraplegia leading to progressive disability due to a length-dependent degeneration of cerebellar and cortical projection neurons. While underlying mechanisms have been linked to impaired mitochondrial function, no disease-modifying therapy is available. We generated induced pluripotent stem cell-derived cortical neurons from SPG7 patients with non-sense or truncating variants and from matched controls. We performed detailed phenotyping of neuronal differentiation, as well as mitochondrial and neuritic morphology and function. We explored the effects of Bz-423, a modulator of the mitochondrial permeability transition pore, as a potential rescue of SPG7-specific cellular phenotypes. We successfully differentiated SPG7 patient-derived neurons, without quantitative differences in differentiation compared with controls. However, we delineate neurite-specific aberrations of mitochondrial morphology and ultrastructure. Moreover, anterograde axonal mitochondrial transport was impaired in SPG7. Exposure to Bz-423 rescued ultrastructural and functional phenotypes. In summary, our data show impaired neuritic mitochondria in a patient-specific human model, and we here demonstrate for the first time beneficial effects of Bz-423 on neuritic ultrastructure and function in a human neuronal SPG7 system. Moreover, we identify the mitochondrial permeability transition pore as a molecular target to rescue phenotypes also in carriers of non-sense or truncating SPG7 variants.
2026-01-26 | Pharmacological Restoration of Mitochondrial Permeability Transition Pore Flickering by High-Content Drug Repurposing
Abstract The mitochondrial permeability transition pore (mPTP) is a voltage- and calcium-regulated channel located in the inner mitochondrial membrane whose activity critically influences cellular fate. While prolonged pore opening leads to mitochondrial depolarization, matrix swelling, and cell death, brief and reversible opening events, referred to as flickering, enable controlled release of calcium and reactive oxygen species and serve essential physiological functions. Emerging evidence indicates that restoring physiological mPTP flickering, rather than suppressing pore activity, may be beneficial in disorders characterized by impaired pore dynamics, including hereditary spastic paraplegia type 7 (SPG7). However, no approved therapies are currently available to promote controlled mPTP pore opening. To identify pharmacological modulators of flickering, we performed a high-content screening of 2,000 FDA and EMA-approved compounds using a validated fluorescence-based assay coupled with automated image analysis. Thirteen compounds increased both the frequency and the area of flickering events while preserving cellular and mitochondrial integrity. Validation in fibroblasts derived from two SPG7 patients and healthy controls confirmed reproducible activity across distinct genetic backgrounds. Among the prioritized candidates, berberine emerged as the most robust modulator, consistently enhancing mPTP flickering independently of SPG7 mutation status. Notably, berberine selectively increased the proportion of small-size flickering events, indicative of physiological pore activity. These findings identify berberine as a promising modulator of mPTP dynamics and support pharmacological restoration of physiological flickering as a potential therapeutic strategy for SPG7 and other disorders associated with impaired mitochondrial permeability transition pore regulation.
2025-04-16 | Broadening the Horizons of Mitochondrial Parkinsonism
Sir, Spastic paraplegia 7 (SPG-7) is characterized by insidiously progressive spastic paraparesis with diminished vibration sense. Additional features including ataxia, spastic dysarthria, dysphagia, pale optic discs, nystagmus, strabismus, ptosis, hearing loss, neuropathy, amyotrophy, skeletal abnormalities, and urinary disturbances may also be seen. However, literature has also shown the presence of Parkinsonism. Our case manifested as pure Parkinsonian syndrome disguising the actual pathology. A 45-year-old female, born to non-consanguineous parents, a homemaker, came to us with a slowness of activities of daily living for 1 year followed by right-hand tremor and change of speech. She never sustained any fall. There was no history of heavy metal or farming exposure with non-contributory family history. She exhibited hypomimia with hypophonic speech. Her mini-mental status examination score (MMSE) was 28. Eye testing showed broken pursuits and slow saccades only. She had bilateral upper limb (UL) rigidity and bradykinesia, right more than left associated with similar symptoms in the right lower limb (LL). Rest and postural tremor was noted in the right UL and LL. Her motor unified Parkinson’s disease rating scale score (UPDRS) was 34 with Hoehn and Yahr (H and Y) stage two. She had no non-motor symptoms. So, a diagnosis of early Parkinson’s disease was made and levodopa carbidopa along with trihexyphenidyl (THP) was started with gradual uptitration. After 1 month of levodopa equivalent dose (LED) of 300 mg and THP of 8 mg, her motor score reduced to 15 from 28. Her blood work and magnetic resonance imaging (MRI) brain came out normal. Her L-6-[18F] fluoro-3,4-dihydroxyphenylalanine positron emission tomography (18F-DOPA PET) scan showed slightly reduced presynaptic dopaminergic uptake in left putamen depicting presynaptic dopaminergic uptake deficit. Genetic testing revealed compound heterozygous variants in the SPG-7 gene: p.Ala510Val, p.Leu78Ter. This missense c.1529C>T (p.Ala510Val) variant in SPG-7 gene has been reported in individuals affected with autosomal recessive SPG but has shown dominant effect in some cases also.[1] SPG-7 is caused by homozygous or compound heterozygous mutation in the paraplegin gene (SPG-7) on chromosome 16q24. This gene encodes paraplegin, which is required for the maintenance of mitochondrial deoxyribonucleic acid (DNA) proteins, so it is postulated that its mutation will lead to mitochondrial dysfunction.[2] In the largest series of patients with SPG-7, the overall clinical phenotype is characterized by slowly progressive spastic paraparesis, variable degrees of cerebellar ataxia, ophthalmoplegia, and optic atrophy contrary to our patient who had only Parkinsonism.[3] SPG type 7 is one of the most common subtypes of autosomal recessive hereditary SPGs, manifesting predominantly in adulthood. Our patient had a compound heterozygous mutation but still manifested with an unusual phenotype mimicking idiopathic Parkinson’s disease. She also had a significant reduction of UPDRS motor score after levodopa. Table 1 describes cases showing levodopa-responsive symmetric Parkinsonism unlike our case with asymmetrical Parkinsonism.Table 1: Other studies showing Parkinsonism associated with other clinical features with SPG-7 gene mutationDeclaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
2024-06-10 | Mobile digital gait analysis captures effects of botulinum toxin in hereditary spastic paraplegia
Hereditary spastic paraplegias (HSPs) comprise a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness. Botulinum toxin has been approved for lower limb spasticity following stroke and cerebral palsy, but its effects in HSPs remain underexplored. We aimed to characterize the effects of botulinum toxin on clinical, gait, and patient-reported outcomes in HSP patients and explore the potential of mobile digital gait analysis to monitor treatment effects and predict treatment response. We conducted a prospective, observational, multicenter study involving ambulatory HSP patients treated with botulinum toxin tailored to individual goals. Comparing data at baseline, after 1 month, and after 3 months, treatment response was assessed using clinical parameters, goal attainment scaling, and mobile digital gait analysis. Machine learning algorithms were used for predicting individual goal attainment based on baseline parameters. A total of 56 patients were enrolled. Despite the heterogeneity of treatment goals and targeted muscles, botulinum toxin led to a significant improvement in specific clinical parameters and an improvement in specific gait characteristics, peaking at the 1-month and declining by the 3-month follow-up. Significant correlations were identified between gait parameters and clinical scores. With a mean balanced accuracy of 66%, machine learning algorithms identified important denominators to predict treatment response. Our study provides evidence supporting the beneficial effects of botulinum toxin in HSP when applied according to individual treatment goals. The use of mobile digital gait analysis and machine learning represents a novel approach for monitoring treatment effects and predicting treatment response.
cell therapies
2021-11-25 | Generation of induced pluripotent stem cell line (ZZUi030-A) from a patient with spastic paraplegia type 7.
Spastic paraplegia type 7 is a rare and classical monogenic inherited neurodegenerative disease caused by heterozygous mutations in the SPG7 gene. The principle clinical features include progressive spasms of the lower limbs, scissor gait, and muscle weakness. The disease currently has no effective treatment. In this study, we obtained dermal fibroblasts from a patient, which were successfully transformed into induced pluripotent stem cells (iPSCs) by employing reprogramming plasmids expressing OCT3/4, SOX2, KLF4, LIN28, and L-MYC. Our method provides a resource for mechanism exploration, drug research, cell transplantation, and gene therapy.
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