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

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/.