MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights
Year: 2026
Type: review
Study design: Systematic Review
Abstract: BACKGROUND: Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder characterized by progressive spasticity and lower limb weakness. The most common forms of autosomal dominant HSP are caused by pathogenic variants in SPAST (SPG4 or HSP-SPAST), ATL1 (SPG3A or HSP-ATL1), and REEP1 (SPG31 or HSP-REEP1). OBJECTIVES: We performed an MDSGene Systematic Review to determine in-depth genotype-phenotype associations and to estimate longitudinal progression, to inform prognostication and clinical trial stratification. METHODS: We systematically collected demographic, phenotypic, and genetic data from published reports of individuals affected by these forms of HSP using the MDSGene protocol. RESULTS: We reviewed 2177 affected individuals, including 1670 individuals with HSP-SPAST, 356 with HSP-ATL1 and 151 with HSP-REEP1. HSP-ATL1 was associated with an earlier age at onset compared to HSP-SPAST and HSP-REEP1. Toe-walking was more frequently reported in HSP-ATL1 (10.4%) and HSP-REEP1 (3.3%) than HSP-SPAST (0.3%). Upper limb hyperreflexia and abnormalities of bladder function were more frequent in HSP-SPAST than HSP-ATL1 or HSP-REEP1. Sufficient data was available to estimate disease progression for HSP-SPAST; this showed that Spastic Paraplegia Rating Scale (SPRS) scores increased with increasing age at examination after the age of 40 years. Truncating variants were more frequent in HSP-SPAST and HSP-REEP1 than HSP-ATL1. CONCLUSION: Overall, HSP-ATL1, HSP-SPAST and HSP-REEP1 demonstrated differences in clinical phenotypes. To our knowledge, this is the first systematic review to model longitudinal progression using SPRS scores in HSP. Missing data is a limiting factor in all these comparisons, highlighting the need for uniform data collection. Online resources can be found at https://www.mdsgene.org/.
DOI: 10.1002/mdc3.70559
Authors: Ce Kang, Rajasumi Rajalingam, Zachary Walls, Jana Huang, Christine Sun, Laura I. Rudaks, Dennis Yeow, Ashar Rasheed, Jenny W. Zhang, Moath Hamed, Marianthi Breza, Susen Schaake, Chetan Vekhande, Jason Massa, Robyn E. Massa, Aakash Shetty, Carolyn M. Sue, Franca Cambi, Oksana Suchowersky, Franca Vulinovic, Sonja Petkovic, Christine Klein, Katja Lohmann, Connie Marras, Kishore R. Kumar
Institutions: The University of Sydney, Western Michigan University, University of Toronto, Toronto Western Hospital, Garvan Institute of Medical Research, Concord Repatriation General Hospital, Sydney Local Health District, Anzac Research Institute, UNSW Sydney, Prince of Wales Hospital, South Eastern Sydney Local Health District, Neuroscience Research Australia, NewYork–Presbyterian Brooklyn Methodist Hospital, National and Kapodistrian University of Athens, Eginition Hospital, University Hospital Schleswig-Holstein, University of Lübeck, University of Alberta, University of Pittsburgh
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,400
OpenAlex ID: W7131400166