Neuromuscular disorders with evidence of both neuropathic and myopathic phenotype.

Abstract

The landscape of genetic research in neuromuscular diseases is revealing an increasing number of genes capable of manifesting both neuropathic and myopathic phenotypes, sometimes in the same patient. While including these genes in broader next-generation sequencing panels addresses the clinical and neurophysiological challenges posed by overlapping or atypical features, it also introduces complexities in the interpretation of their results. In this review, we examine genes that can present with a mixed phenotype, classifying them into categories of clinical utility, and propose a clinical-neurophysiological grid algorithm to guide clinicians toward diagnosis. To better understand the molecular and functional connections of the described genes, we conducted a gene set enrichment analysis, which highlighted proteostasis, autophagy, and mitochondrial function as key biological processes shared between neuropathy and myopathy. Our aim is to provide a structured framework for interpreting these dual presentations, highlighting the convergence of pathogenic pathways, and emphasizing the importance of a comprehensive, multifaceted approach in managing such cases.