ArticleHuman molecular genetics2023
De novo variants cause complex symptoms in HSP-ATL1 (SPG3A) and uncover genotype-phenotype correlations.
Article in Human molecular genetics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 17 citations in OpenAlex.
- Health-Related Quality of Life in Rare Forms of Childhood-Onset Hereditary Spastic Paraplegia.Annals of clinical and translational neurology · 2026Observational
- LXR agonist rescues synaptic dysfunction and degeneration in SPG3A patient-specific iPSC-derived neurons.Acta neuropathologica communications · 2025Article
- The Spastic Paraplegia-Centers of Excellence Research Network (SP-CERN): Clinical Trial Readiness for Hereditary Spastic Paraplegia.Neurology. Genetics · 2025Article
- Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A.Journal of neurology · 2024Article
- Atlastin-1 regulates endosomal tubulation and lysosomal proteolysis in human cortical neurons.Neurobiology of disease · 2024Article
- Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.International journal of molecular sciences · 2024Review
- Plasma Neurofilament Light Chain Is Elevated in Adaptor Protein Complex 4-Related Hereditary Spastic Paraplegia.Movement disorders : official journal of the Movement Disorder Society · 2023Article
- Reply to: Early-Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST.Movement disorders : official journal of the Movement Disorder Society · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Pathogenic variants in ATL1 are a known cause of autosomal-dominantly inherited hereditary spastic paraplegia (HSP-ATL1, SPG3A) with a predominantly 'pure' HSP phenotype. Although a relatively large number of patients have been reported, no genotype-phenotype correlations have been established for specific ATL1 variants. Confronted with five children carrying de novo ATL1 variants showing early, complex and severe symptoms, we systematically investigated the molecular and phenotypic spectrum of HSP-ATL1. Through a cross-sectional analysis of 537 published and novel cases, we delineate a distinct phenotype observed in patients with de novo variants. Guided by this systematic phenotyping approach and structural modelling of disease-associated variants in atlastin-1, we demonstrate that this distinct phenotypic signature is also prevalent in a subgroup of patients with inherited ATL1 variants and is largely explained by variant localization within a three-dimensional mutational cluster. Establishing genotype-phenotype correlations, we find that symptoms that extend well beyond the typical pure HSP phenotype (i.e. neurodevelopmental abnormalities, upper limb spasticity, bulbar symptoms, peripheral neuropathy and brain imaging abnormalities) are prevalent in patients with variants located within this mutational cluster.
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