Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands
Stacha F.I. Reumers, Corrie E. Erasmus, Karlijn Bouman, Maartje Pennings, Meyke Schouten, Benno Küsters, Floor A.M. Duijkers, Anneke J. van der Kooi, Bregje Jaeger, Corien C. Verschuuren‐Bemelmans, Catharina G. Faber, Baziel G.M. van Engelen, Erik‐Jan Kamsteeg, Heinz Jungbluth, Nicol C. Voermans
Abstract
Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.