MPZ-, GDAP1-, and NEFL-Related Charcot-Marie-Tooth Disease with Diverse Clinical and Electrophysiological Phenotypes

Abstract

Charcot-Marie-Tooth disease (CMT) is a spectrum of clinically and genetically heterogeneous peripheral neuropathies. CMT can be classified into demyelinating, intermediate, or axonal neuropathy based on clinical, histopathological, and electrophysiological findings. Approximately 140 genes have been reported to be associated with CMT. Mutations in the myelin protein zero (MPZ), ganglioside-induced differentiation related protein 1 (GDAP1), and neurofilament light-chain polypeptide gene (NEFL) genes have been reported to cause all three types of CMT, which is noteworthy because most CMT-related genes cause a single type of neuropathy (either demyelinating or axonal). In contrast, it remains unclear why these genes cause several types of CMT. CMT is presently incurable; however, ongoing attempts to treat CMT with various drugs and dietary supplements have increased the importance of an exact genetic diagnosis for precision medicine. Therefore, it is important to identify the causative mutations and compare the associated clinical characteristics. Taken together, a comparison of causative mutations and clinical features of patients with MPZ, GDAP1, and NEFL mutations will be the first step in understanding how different types of CMT are caused, and will enable a molecular genetic diagnosis. In this review, we describe the clinical, electrophysiological, and genetic characteristics of MPZ-, GDAP1-, and NEFL-related CMT.