Childhood-onset hereditary spastic paraplegia: at the crossroads between neurodevelopment and neurodegeneration
In brief
Nearly 6 in 10 genetic variants in childhood HSP involved nonclassic genes
In a Spanish cohort of 91 children with hereditary spastic paraplegia, genetic testing identified a cause in 62%; 58% of the variants were in genes not classically linked to the condition. Developmental delay and gait problems were common, and more than half had complex symptoms. The findings underscore the need for broader genetic testing and better tools to track childhood disease.
- Journal
- European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society (Q1)
- Published
- 29 October 2026
- Study design
- Retrospective cohort
- Evidence level
- Level 3, Low (CEBM 3b)
- Authors
- Natalia Espasandin-Hueter, Ainara Salazar-Villacorta, José-Miguel Escudero, Anna Marcé-Grau, Agustí Rodríguez-Palmero, Agatha Schlüter, et al.
- PMID
- 42976539
- DOI
- 10.1016/j.ejpn.2026.10.002
Why clinicians should know about it
- Picked for Genetics (clinical) (paper of the day, 4 November 2026): Pediatric rare-disease cohort reports exome diagnostic yield
Abstract
OBJECTIVE: To describe the phenotypic and genotypic features in a cohort of childhood-onset hereditary spastic paraplegia (HSP). METHODS: We conducted a multicenter retrospective study of patients with pediatric-onset HSP diagnosed between 2004 and 2024 in several tertiary Spanish centers. Patients included had a clinical diagnosis of HSP after the exclusion of secondary causes of paraparesis; clinical, neuroimaging, neurophysiological and genetic data were retrieved from their respective electronic health records. RESULTS: A total of 91 patients were enrolled from 87 families. The median age at disease onset was 12 months, with global developmental delay and gait abnormalities being the most common presentations. 45% had pure HSP and 55% had complex HSP, with speech impairment and intellectual disability being the most prevalent associated symptoms in the latter. Family history indicated dominant inheritance in 14%, recessive inheritance in 17%, while 69% were isolated cases. 61% of patients had abnormal neuroimaging, predominantly thin corpus callosum and white matter hyperintensities. Genetic diagnosis was achieved in 62%, largely by WES, with the lowest diagnostic yield occurring in isolated pure HSP. SPAST, CTNNB1 and KIF1A were the most frequently involved genes, with 58% variants found in non-classical SPG-related genes. INTERPRETATION: Our data underline the high phenotypic and genotypic heterogeneity in childhood-onset HSP and suggests that some neurodevelopmental disorders featuring progressive spastic paraparesis as presenting or dominant clinical sign, overlap with HSP phenotypes caused by mutations in "classical" SPG genes. While the study further characterized some phenotype-genotype relationships, pediatric-specific assessment scales are urgently needed to better frame the natural history of this group of disorders.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.