MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights

Ce Kang¹, Rajasumi Rajalingam^{2

3}, Zachary Walls⁴, Jana Huang², Christine Sun², Laura I Rudaks^{1

5

6}, Dennis Yeow^{1

5

6

7

8}, Ashar Rasheed², Jenny W Zhang², Moath Hamed⁹, Marianthi Breza¹⁰, Susen Schaake¹¹, Chetan Vekhande¹², Jason Massa¹³, Robyn E Massa¹³, Aakash Shetty¹², Carolyn M Sue^{7

8}, Franca Cambi¹³, Oksana Suchowersky¹², Franca Vulinovic¹¹, Sonja Petkovic¹¹, Christine Klein¹¹, Katja Lohmann¹¹, Connie Marras², Kishore R Kumar^{1

5

6

14}

Affiliations

¹ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
² The Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
³ Department of Psychiatry, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
⁴ Faculty of Engineering and Information Technologies, University of Sydney, Darlington, NSW, Australia.
⁵ ANZAC Research Institute, Department of Neurology and Molecular Medicine Laboratory, Concord Repatriation General Hospital and Sydney Local Health District, Concord, NSW, Australia.
⁶ Translational Neurogenomics Group, Garvan Institute for Medical Research, Darlinghurst, NSW, Australia.
⁷ Neuroscience Research Australia and Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
⁸ Department of Neurology, Prince of Wales Hospital, South Eastern Sydney Local Health District, Sydney, NSW, Australia.
⁹ Department of Neurology, NYP Brooklyn Methodist Hospital, Brooklyn, NY, USA.
¹⁰ Neurogenetics Unit 1st Department of Neurology Eginition Hospital School of Medicine National and Kapodistrian University of Athens, Athens, Greece.
¹¹ Institute of Neurogenetics, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.
¹² Department of Medicine (Neurology) and Medical Genetics, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB, Canada.
¹³ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, St Vincent's Healthcare Clinical Campus, University of New South Wales, Darlinghurst, NSW, Australia.

PMID: 41734945
DOI: 10.1002/mdc3.70559

Review

MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights

Ce Kang et al. Mov Disord Clin Pract. 2026.

. 2026 Feb 24.

doi: 10.1002/mdc3.70559. Online ahead of print.

Authors

Affiliations

¹ Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
² The Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
³ Department of Psychiatry, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
⁴ Faculty of Engineering and Information Technologies, University of Sydney, Darlington, NSW, Australia.
⁵ ANZAC Research Institute, Department of Neurology and Molecular Medicine Laboratory, Concord Repatriation General Hospital and Sydney Local Health District, Concord, NSW, Australia.
⁶ Translational Neurogenomics Group, Garvan Institute for Medical Research, Darlinghurst, NSW, Australia.
⁷ Neuroscience Research Australia and Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
⁸ Department of Neurology, Prince of Wales Hospital, South Eastern Sydney Local Health District, Sydney, NSW, Australia.
⁹ Department of Neurology, NYP Brooklyn Methodist Hospital, Brooklyn, NY, USA.
¹⁰ Neurogenetics Unit 1st Department of Neurology Eginition Hospital School of Medicine National and Kapodistrian University of Athens, Athens, Greece.
¹¹ Institute of Neurogenetics, University of Lübeck and University Hospital Schleswig-Holstein, Lübeck, Germany.
¹² Department of Medicine (Neurology) and Medical Genetics, Faculty of Medicine and Dentistry University of Alberta, Edmonton, AB, Canada.
¹³ Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁴ School of Clinical Medicine, Faculty of Medicine and Health, St Vincent's Healthcare Clinical Campus, University of New South Wales, Darlinghurst, NSW, Australia.

PMID: 41734945
DOI: 10.1002/mdc3.70559

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/.

Keywords: ATL1; atlastin; autosomal dominant; hereditary spastic paraplegia; spast; spastin.

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References

1. Kumar KR, Blair NF, Sue CM. An update on the hereditary spastic paraplegias: new genes and new disease models. Mov Disord Clin Pract 2015;2(3):213–223.
1. Saputra L, Kumar KR. Challenges and controversies in the genetic diagnosis of hereditary spastic paraplegia. Curr Neurol Neurosci Rep 2021;21(4):15.
1. Lange LM, Gonzalez‐Latapi P, Rajalingam R, et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society task force ‐ an update. Mov Disord 2022;37(5):905–935.
1. Lo Giudice T, Lombardi F, Santorelli FM, Kawarai T, Orlacchio A. Hereditary spastic paraplegia: clinical‐genetic characteristics and evolving molecular mechanisms. Exp Neurol 2014;261:518–539.
1. Finsterer J, Loscher W, Quasthoff S, Wanschitz J, Auer‐Grumbach M, Stevanin G. Hereditary spastic paraplegias with autosomal dominant, recessive, X‐linked, or maternal trait of inheritance. J Neurol Sci 2012;318(1–2):1–18.

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MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights

Affiliations

MDSGene Systematic Review of Common Forms of Dominant Hereditary Spastic Paraplegia: Novel Insights

Authors

Affiliations

Abstract

References

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LinkOut - more resources

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