Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.

IF 3.9 2区 医学 Q1 CLINICAL NEUROLOGY
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
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Abstract

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.

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。
目的:遗传性痉挛性截瘫(HSP)是一种罕见的神经退行性疾病,以痉挛和下肢无力为特征。最常见的类型是SPG4,通常是常染色体显性的,由SPAST基因变异引起,通常表现为纯HSP。我们描述了来自三个不相关家庭的5名符合脑瘫临床标准并携带双等位基因SPAST变异的个体。我们的目标是增加对spast相关疾病的临床和遗传学理解,并探索潜在的异常细胞机制。方法:我们进行了全面的表型和遗传分析。利用共聚焦显微镜对双等位SPAST变异、单等位SPAST变异和健康对照的成纤维细胞培养物进行了硅片和功能研究。结果:个体表现出早发性复杂HSP,伴有不同程度的脑病严重程度、痉挛和神经轴突受累,偶尔会导致脑瘫的诊断。全外显子组测序鉴定出纯合子和复合杂合子SPAST变体。功能研究表明,患者来源的成纤维细胞中痉挛蛋白和微管蛋白水平降低,线粒体断裂,丝状足形态异常,支持变异的致病性。解释:我们提供了spast相关疾病双等位基因遗传的首个证据,并得到了功能分析的支持,将临床范围扩大到包括中度至重度早发性脑病。我们的研究结果强调了基因诊断对脑瘫预后、咨询和个性化治疗的重要性。发现的变异揭示了spastin相关疾病的遗传复杂性,并提示spastin水平在表型变异中存在阈值效应。细胞机制,如线粒体动力学和膜形态可能有助于发病,值得进一步研究。
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来源期刊
Annals of Clinical and Translational Neurology
Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)
CiteScore
9.10
自引率
1.90%
发文量
218
审稿时长
8 weeks
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.
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