Charcot-Marie-Tooth Disease with Myelin Protein Zero Mutation Presenting as Painful, Predominant Small-Fiber Neuropathy

Abstract

Charcot-Marie-Tooth disease (CMT) rarely presents with painful symptoms, which mainly occur in association with myelin protein zero (MPZ) gene mutations. We aimed to further characterize the features of painful neuropathic phenotypes in MPZ-related CMT. We report on a 58-year-old woman with a longstanding history of intermittent migrant pain and dysesthesias. Examination showed minimal clinical signs of neuropathy along with mild changes upon electroneurographic examination, consistent with an intermediate pattern, and small-fiber loss upon skin biopsy. Genetic testing identified the heterozygous variant p.Trp101Ter in MPZ. We identified another 20 CMT patients in the literature who presented with neuropathic pain as a main feature in association with MPZ mutations, mostly in the extracellular MPZ domain; the majority of these patients showed late onset (14/20), with motor-nerve-conduction velocities predominantly in the intermediate range (12/20). It is hypothesized that some MPZ mutations could manifest with, or predispose to, neuropathic pain. However, the mechanisms linking MPZ mutations and pain-generating nerve changes are unclear, as are the possible role of modifier factors. This peculiar CMT presentation may be diagnostically misleading, as it is suggestive of an acquired pain syndrome rather than of an inherited neuropathy.

Keywords: Charcot–Marie–Tooth disease; myelin protein zero; neuropathic pain; skin biopsy.

Figure 1

Bright-field immunohistochemistry of 50 μm thick sections of the skin biopsy immunostained with protein gene product 9.5 (PGP 9.5). There are long epidermal areas devoid of intraepidermal nerve fibers at the thigh (upper) and at the ankle (lower). The few remaining PGP 9.5-positive nerve fibers crossing the dermal–epidermal junction are indicated by arrowheads.

Figure 2

MPZ protein representation displaying variants associated with painful neuropathy. The numbers within the circles correspond to probands mentioned in the 20 literature-based cases plus the present case report, which share identical constitutional variants. Circle colors are indicative of the variant type (missense, nonsense, and splicing), while protein-domain regions are depicted using distinct colors.