Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics
Por:
Nolasco-Tovar GA, Roldan-Molina M, Jamshidi Y, Georvasilis I, Rodríguez RJ, Boostani R, Shoeibi A, Armengol L, Codina-Bergadà A, Karimiani EG, Hernando-Davalillo C, Martorell-Sampol L, Ramírez Almaraz ML, Muchart-Lopez J, Ortez-Gonzalez CI, Nascimento-Osorio A, Urreizti R, Natera-de Benito D and Serrano M
Publicada:
1 ene 2026
Ahead of Print:
1 sep 2025
Resumen:
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.
Filiaciones:
Nolasco-Tovar GA:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Roldan-Molina M:
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Confocal Microscopy and Cellular Imaging Unit, Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Barcelona, Spain
Jamshidi Y:
Genetics Research Centre, St George's, University of London, London, UK
Genetics Centre of Excellence, Novo Nordisk Research Centre Oxford, Oxford, UK
:
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Confocal Microscopy and Cellular Imaging Unit, Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Barcelona, Spain
Rodríguez RJ:
Pediatric Neurology Department, Hospital General Universitario Dr. Balmis, Alicante, Spain
Boostani R:
Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran
Shoeibi A:
Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran
Armengol L:
Quantitative Genomic Medicine Laboratories, qGenomics, Esplugues de Llobregat, Barcelona, Spain
Codina-Bergadà A:
Applied Research in Neuromuscular Diseases, Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Karimiani EG:
Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
Hernando-Davalillo C:
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, Barcelona, Spain
Martorell-Sampol L:
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, Barcelona, Spain
U-703 Center for Biomedical Research Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Ramírez Almaraz ML:
Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, Barcelona, Spain
Muchart-Lopez J:
Diagnostic Imaging Department, Hospital Sant Joan de Déu, Barcelona, Spain
Ortez-Gonzalez CI:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Nascimento-Osorio A:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
U-703 Center for Biomedical Research Network on Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
Urreizti R:
Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, Barcelona, Spain
Natera-de Benito D:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Serrano M:
Pediatric Neurology Department, Hospital Sant Joan de Déu, Barcelona, Spain
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
Genetic and Molecular Medicine Department, Pediatric Institute for Rare Diseases, Hospital Sant Joan de Déu, Barcelona, Spain
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