Coexistence of CMT1A and diabetes mellitus in a young woman with a severe and progressive neuropathy and respiratory insufficiency

Most duplicated CMT1A patients have a mild to moderate neuropathy along the spectrum of the peripheral neuropathies. However, phenotypical variability has been recognized even within monozygotic twins, and a few patients may develop an incapacitating disease. Genetic and environmental factors may be involved, and diabetes mellitus (DM) may play a role. We recently saw a 39-year-old woman with CMT1A and DM type 1 who developed a very severe neuropathy. She developed progressive weakness with walking difficulties and frequent falls since the age of 34. She has had uncontrolled DM since the age of 22 but no other co-morbidity. She had pes cavus, distal weakness and atrophy more pronounced in the lower limbs, reduced sensation to pinprick and vibration up to the knees and wrists, and generalized areflexia. On nerve conduction studies there was a diffuse demyelinating neuropathy (median motor nerve: 18.5 m/s and 5.7 mV). Although conduction velocities were uniformly reduced, the median compound muscle action potential (CMAP) was dispersed with proximal stimulation. After informed consent, genetic tests confirmed the PMP2 duplication. Two years later, the motor deficits had worsened, and her CMAP amplitudes were significantly reduced (Median nerve: 17.7 m/s and 0.5 mV). Temporal dispersion was now present in her right median and both ulnar nerves. She was treated with IVIg (2.0 g/kg) with no improvement. Five years after the first evaluation, she was wheelchair bound, and her CMT neuropathy score was 34 of 36, reflecting the severity of the neuropathy. She additionally had facial weakness, dysphagia, and respiratory insufficiency with diaphragmatic weakness. Her distal CMAPs and sensory nerve action potentials were absent, as were both phrenic CMAPs. Axillary, musculocutaneous, and facial nerve CMAPs were dispersed and had prolonged latencies and low amplitudes (Fig. 1, upper division). On needle electrode examination distal, proximal, thoracic (intercostal), and bulbar (genioglossus) muscles displayed a severely reduced number of neurogenic motor unit action potentials in association with electrophysiological evidence of acute denervation (fibrillation potentials and positive sharp waves 2þ to 4þ). Restrictive dysfunction was seen on spirometry (forced vital capacity 1⁄4 51.38%). A sural nerve biopsy revealed severe loss of myelinated fibers, a large number of onion bulbs, thickening of capillary walls FIGURE 1. Upper division: The facial nerve compound muscle action potential (CMAP) has low amplitude, prolonged latency and temporal dispersion; Lower division: A photomicrograph of the sural nerve biopsy shows a myelinated fiber surrounded by an incipient onion bulb formation (arrow), several onion bulb formations deprived of their respective axons (short arrow), thickened capillary walls (arrow heads) and no inflammation. Semithin section. Toluidine blue. Scale bar 1⁄4 100 lm.