The centronuclear myopathies (CNM) are a rare group of hereditary neuromuscular diseases that are both clinically and genetically heterogeneous. Although most patients present with muscle weakness and low muscle tone, onset of symptoms and severity ranges from neonatal onset of severe weakness requiring respiratory and feeding intervention to onset of mild weakness in adulthood requiring assistance with mobility. The clinical presentation can appear similar to congenital or limb girdle muscular dystrophy, but the creatine kinase level is generally not elevated and muscle biopsies do not have significant dystrophic features. Diagnosis of CNM is based on the presence of increased central nuclei on muscle biopsy, without other features of another myopathy or dystrophy.
There are currently four genes known to be associated with centronuclear myopathy: MTM1, DNM2, RYR1, and BIN1. MTM1 mutations cause a form of CNM known as X-linked myotubular myopathy (XLMTM). The disease was named because of the similarity in muscle appearance between these patients and the stage of fetal muscle development when normal muscle fibers (myotubes) have central nuclei. XLMTM is the most common and severe form of CNM, with most boys presenting in infancy with weakness and secondary respiratory and feeding issues that often require support. DNM2-associated CNM is an autosomal dominant disease that most often presents in childhood or adolescence, although recent reports suggest that some patients with DNM2 mutations map present with severe weakness in infancy. Thus far, most mutations that have been identified in the DNM2 gene appear to be recurrent and occur in a limited number of hotspots. Different DNM2 mutations have also been associated with Charcot Marie Tooth Disease.
RYR1 and BIN1 mutations have been associated with recessive congenital myopathy with central nuclei with an extremely variable phenotype that generally presents at birth and ranges from non-ambulatory with feeding and respiratory support to ambulatory with recurrent respiratory infections/insufficiency. RYR1 mutations have also been associated with central core disease, multiminicore disease, congenital fiber type disproportion (CFTD), and core-rod myopathy. Mutations in RYR1 and DNM2 are estimated to account for 15% of cases of CNM each. BIN1 mutations appear to be the least common cause of CNM, accounting for only 5% of cases, and leaving approximately 20% of CNM cases without a molecular diagnosis.
The University of Chicago Genetic Services performs clinical full gene sequencing of MTM1, DNM2, and BIN1. The Beggs laboratory at Children’s Hospital Boston is focused on better understanding the molecular basis of CNM and other congenital myopathies. Patients with and without an identified genetic mutation are welcome to participate by providing a blood/saliva sample, medical records and a tissue sample from previous biopsy when available. For more information, please contact Elizabeth DeChene, MS CGC (edechene@enders.tch.harvard.edu or 617-919-2169) or visit the lab website at www.childrenshospital.org/research/beggs.