Gregorio A Nolasco, Mònica Roldán, Yalda Jamshidi, Ioannis Georvasilis, Rocío Jadraque Rodríguez, Reza Boostani, Ali Shoeibi, Lluís Armengol, Anna Codina, Ehsan Ghayoor Karimiani, Cristina Hernando-Davalillo, Loreto Martorell, María Luisa Ramírez Almaraz, Jordi Muchart, Carlos Ortez, Andrés Nascimento, Roser Urreizti, Daniel Natera-de Benito, Mercedes Serrano
{"title":"扩大遗传性痉挛性截瘫范围:脑瘫模拟的双等位基因SPAST变异。","authors":"Gregorio A Nolasco, Mònica Roldán, Yalda Jamshidi, Ioannis Georvasilis, Rocío Jadraque Rodríguez, Reza Boostani, Ali Shoeibi, Lluís Armengol, Anna Codina, Ehsan Ghayoor Karimiani, Cristina Hernando-Davalillo, Loreto Martorell, María Luisa Ramírez Almaraz, Jordi Muchart, Carlos Ortez, Andrés Nascimento, Roser Urreizti, Daniel Natera-de Benito, Mercedes Serrano","doi":"10.1002/acn3.70206","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST-related disorders and explore the underlying abnormal cellular mechanisms.</p><p><strong>Methods: </strong>We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.</p><p><strong>Results: </strong>Individuals exhibited early-onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole-exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.</p><p><strong>Interpretation: </strong>We provide the first evidence of biallelic inheritance in SPAST-related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate-to-severe early-onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST-related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.\",\"authors\":\"Gregorio A Nolasco, Mònica Roldán, Yalda Jamshidi, Ioannis Georvasilis, Rocío Jadraque Rodríguez, Reza Boostani, Ali Shoeibi, Lluís Armengol, Anna Codina, Ehsan Ghayoor Karimiani, Cristina Hernando-Davalillo, Loreto Martorell, María Luisa Ramírez Almaraz, Jordi Muchart, Carlos Ortez, Andrés Nascimento, Roser Urreizti, Daniel Natera-de Benito, Mercedes Serrano\",\"doi\":\"10.1002/acn3.70206\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST-related disorders and explore the underlying abnormal cellular mechanisms.</p><p><strong>Methods: </strong>We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.</p><p><strong>Results: </strong>Individuals exhibited early-onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole-exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.</p><p><strong>Interpretation: </strong>We provide the first evidence of biallelic inheritance in SPAST-related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate-to-severe early-onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST-related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.</p>\",\"PeriodicalId\":126,\"journal\":{\"name\":\"Annals of Clinical and Translational Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-09-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Clinical and Translational Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/acn3.70206\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Clinical and Translational Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/acn3.70206","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Objective: Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST-related disorders and explore the underlying abnormal cellular mechanisms.
Methods: We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control.
Results: Individuals exhibited early-onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole-exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants.
Interpretation: We provide the first evidence of biallelic inheritance in SPAST-related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate-to-severe early-onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST-related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.
期刊介绍:
Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.