VP.05 Innervation defect: new pathomechanism of centronuclear myopathy?

Abstract

Mutations in <i>DNM2, BIN1</i> and <i>MTM1</i> cause centronuclear myopathy (CNM). T-tubule malformation and its resultant defects in excitation-contraction coupling has been suggested to be the pathomechanism of this disease. Recently, in biopsied skeletal muscles from some CNM patients, we noticed the circumferential localization of acetylcholinesterase (AChE) on the sarcolemma on histochemical stain for AChE, which may well be due to the failure of AChE clustering in neuromuscular junction (NMJ). In support of our notion, NMJ anomalies were recently described in <i>Dnm2</i>-mutant animals. To check whether circumferential AChE expression on the sarcolemma is associated with CNM, and if so, to know whether NMJ is structurally and electrophysiologically abnormal in patients with CNM. We re-reviewed muscle pathology slides of the 40 patients with genetically-confirmed CNM (34 <i>DNM2, 1BIN1</i>, and 5 <i>MTM1</i>) and evaluated the localization of AChE. We also analyzed the morphology of NMJ in CNM by electron microscopy (EM). We collected the data of repetitive nerve stimulation (RNS) study and the effects of administration of AChE inhibitors (AChE-I) in CNM patients from the physicians. Circumferential AChE activity on the sarcolemma was observed in all patients with CNM. The frequency of the fibers with circumferential AChE was 100% in all CNM_DNM2, CNM_BIN1 and CNM_MTM1. On EM, postsynaptic structure of NMJ was abnormal in CNM_DNM2 muscles. Decremental response was seen on RNS in all three patients with CNM_DNM2 who received RNS, indicating the presence of myasthenic feature in CNM. One of two patients who received AChE-I showed improvement in muscle manual testing. Abnormal NMJ formation and a failure in AChE clustering indicate defects in NMJ transmission in CNM skeletal muscles. Decremental muscle action potential amplitudes and effective AChE-I suggest that myasthenic features in CNM contribute to muscle weakness in this disease. NMJ transmission defect due to postsynaptic structural abnormality is a new pathomechanism of CNM.