Nerve Conduction Abnormalities and Neuromyotonia in Genetically Engineered Mouse Models of Human Hereditary...

We performed electrophysiological studies in myelin protein mutant mice in order to characterize nerve conduction changes. We performed neurographic studies on the facial and sciatic nerves and needle electromyography (EMG). Mice homozygously deficient for the peripheral myelin protein 22 gene (Pmp22-/-) exhibited increased motor latencies, reduced nerve conduction velocities, and polyphasia of the M-response, which are the typical electrophysiological signs of dysmyelination. PMP22 +/- mice developed only mild conduction slowing at an old age and a mild reduction of the M-amplitude, which indicates mild axonal dysfunction. Mice overexpressing Pmp22 developed severe electrophysiological signs of dysmyelination. In myelin protein zero-deficient mice (P₀-/-), we found alterations similar to those found in Pmp22-/- mice, whereas P₀+/- mice developed mildly increased sciatic nerve F-wave latencies only late in life, which indicates only mild dysmyelination. Connexin 32-deficient mice showed electrophysiological evidence of mild axonal damage. By EMG, we found the clinical and electrophysiological signs of neuromyotonia, that is, continuous spontaneous motor unit discharges, often in rhythmic patterns (myokymia), in P₀-/-, Pmp22-/-, Trembler, Trembler-J, and Pmp22-overexpressing mice. This indicates abnormal impulse generation in these dysmyelinated nerves. In summary, our studies demonstrate nerve conduction changes in mice with myelin protein gene defects that are similar to those found in patients with Charcot-Marie-Tooth disorders. In addition, we identified new mouse models of hereditary neuromyotonia.