A Case Report of a Novel Myelin Protein Zero (MPZ) Pathogenic Variant in Charcot-Marie-Tooth Disease Combined With...

Charcot-Marie-Tooth (CMT) disease is the collective term for the most common inherited peripheral neuropathies, affecting both motor and sensory nerves. A typical CMT patient presents with slowly progressive distal muscle weakness and atrophy that primarily involves the small foot muscles, peroneal muscles, and, often later, the muscles of the hands and forearms. Foot deformities, most commonly pes cavus and claw toes, are common and can lead to gait impairments. In this paper, we report a patient with an intermediate CMT (CMT-Int) type carrying a novel pathogenic variant in the MPZ gene combined with type 2 diabetes. The patient's initial symptoms included a gradual onset of muscle wasting, weakness, and sensory impairment in the lower limbs. Electrophysiological findings suggested widespread peripheral nerve damage affecting both sensory and motor fibers, with a predominant demyelinating pattern accompanied by axonal damage. Genetic testing identified a previously unreported heterozygous mutation in the MPZ gene, specifically c.548G > A, p.Trp183∗. This alteration results in the replacement of the 183rd amino acid (tryptophan) by a stop codon. This premature stop codon is predicted to escape nonsense-mediated mRNA decay, resulting in a C-terminally truncated protein that may exert a dominant-negative effect. Although a different variant affecting the same codon (c.549G > A, p.Trp183∗, VCV000917145.1) has been documented, this particular pathogenic mutation has not been previously recorded. After being diagnosed with CMT, the patient developed type 2 diabetes following pancreatic cyst surgery in September 2022. The presence of both conditions exposed her peripheral nerves to congenital structural abnormalities combined with the metabolic consequences of chronic hyperglycemia and local ischemia, thereby exacerbating nerve injury.