Genetic analysis of a family with skeletal muscle ion channelopathy and hereditary spastic paraplegia type 7 caused by SCN4A and SPG7 double mutations

Abstract

Hereditary spastic paraplegia (HSP) is a rare and genetically heterogeneous neurodegenerative disorder, primarily defined by progressive lower-limb spasticity and weakness. Among the numerous genes implicated, pathogenic variants in the spastic paraplegia 7 (SPG7) gene represent one of the most common causes of HSP, whereas mutations in SCN4A, a skeletal muscle ion channel gene, are typically associated with a diverse spectrum of phenotypes, including hyperkalemic and hypokalemic periodic paralysis, potassium-aggravated myotonia, and congenital paramyotonia. To date, however, the coexistence of pathogenic variants in SPG7 and SCN4A within the same pedigree, and their potential pathogenic interplay, has not been documented.

In this study, we performed comprehensive genetic profiling, including whole-exome sequencing, mitochondrial genome analysis, dynamic mutation screening, copy number variation assessment, and Sanger sequencing. We identified a novel heterozygous SPG7 variant (c.578A>G; p.E193G) alongside a known pathogenic SCN4A missense mutation (c.2111C>T; p.T704M). Remarkably, individuals harboring both variants presented with highly complex phenotypes that combined classical HSP manifestations with ion channel dysfunctions, such as congenital paramyotonia and hypokalemic periodic paralysis.

These findings provide the first evidence of a possible genetic interaction between SPG7 and SCN4A, expanding the recognized clinical and molecular spectrum of HSP. Our results underscore the diagnostic value of multi-gene testing in patients with atypical or overlapping neuromuscular symptoms and highlight the importance of considering potential polygenic contributions when interpreting the clinical heterogeneity of HSP.