Intermediate Charcot-Marie-Tooth disease due to a novel Trp101Stop myelin protein zero mutation associated with debilitating neuropathic pain

Abstract

We report an English kindred affected across 4 generations with a hereditary neuropathy associated with debilitating neuropathic pain as the main clinical feature. The principal finding on clinical examination was sensory loss, and there was variable motor dysfunction. Electrophysiological studies revealed mild features of demyelination with median conduction velocity in the intermediate range. There was an autosomal-dominant pattern of inheritance, and genetic testing revealed a novel heterozygous Trp101X mutation in exon 3 coding for a portion of the extracellular domain of myelin protein zero. This is predicted to lead to premature termination of translation. Myelin protein zero is a key structural component of compact myelin, and over 100 mutations in this protein have been reported, which can give rise to neuropathies with either axonal, demyelinating, or intermediate features encompassing a wide range of severity. Chronic pain is an increasingly recognised sequela of certain hereditary neuropathies and may be musculoskeletal or neuropathic in origin. In this kindred, the neuropathy was relatively mild in severity, however, neuropathic pain was an important and disabling outcome.

Fig. 1

Family pedigree. Roman numerals represent the 1st to the 4th generation. Square, man; Circle, woman; Shaded symbol represents affected patients; Arrow points to the index case. Numbered subjects were seen by their health care team and are described in this report. Patients 5 and 2 were consented and entered the Pain in Neuropathy Study in which quantitative sensory testing was performed.

Fig. 2

Quantitative sensory testing comparison of the lower limbs using z scores. (a) Patient 5. (b) Patient 2. Paradoxical heat sensations on Patient 5 were seen bilaterally (3 on each side); pain ratings did not show evidence of dynamic mechanical allodynia. CDT, cold-detection threshold; WDT, warm-detection threshold; TSL, thermal sensory limen; CPT, cold-pain threshold; HPT, heat-pain threshold; PPT, pressure-pain threshold; MPT, mechanical-pain threshold; MPS, mechanical-pain sensitivity; WUR, wind-up ratio; MDT, mechanical-detection threshold; VDT, vibration-detection threshold.

Fig. 3

Immunohistochemistry. A maximum intensity projection of a confocal image of a lower-limb skin biopsy from a control subject (a) and Patient 5 (b) immunostained for protein gene product (PGP) 9.5 (red) to demonstrate axons and collagen type 4 (green) to show the basement membrane of the epidermis. There is no difference in the number of intraepidermal nerve fibres (arrows). (c-h) Confocal images of the dermis immunostained for PGP 9.5 [(c, f) red] and myelin basic protein [(d, g) MBP, green]. In Patient 5 (f, g, h), although numerous axons can be seen, there are no myelinated internodes, while in a control subject (c, d, e), numerous myelinated internodes were observed. Scale Bar: 50 μm.