Phenotype variability and histopathological findings in centronuclear myopathy due to DNM2 mutations.

摘要

Autosomal-dominant centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene (DNM2) is a rare congenital myopathy histopathologically characterized by centrally located nuclei and a radial arrangement of sarcoplasmic strands around the central nuclei. A total of 1,582 consecutive muscle biopsies of adult patients (age >/=18 years) were screened for morphologically characteristic signs of CNM. Patients with CNM were screened for mutations in DNM2. Clinical data and complementary neurophysiologic, respiratory, cardiac, and muscle MRI data in these patients were analyzed. Six index patients had histopathological signs of CNM (0.38%). Three had the heterozygous p.R465W and 2 siblings the heterozygous p.E368K DNM2 mutation. In 2 patients mutational screening for DNM2, BIN1, MTM1, and RYR1 was negative. Apart from the siblings, there was no positive history, parental mutation screening in 2 cases was negative. Both the percentage of muscle fibers with centralized nuclei and the ratio of muscle fibers with centralized to internalized nuclei were higher in DNM2-CNM compared to non-DNM2-CNM (50% vs. 18% and 94% vs. 63%). The onset was already neonatal or in infancy in 3/5 patients with DNM2 mutation. Symptoms in DNM2-CNM included bilateral ptosis (n = 3), paresis of the external ocular muscles (n = 2), axonal neuropathy (n = 4), restrictive ventilatory involvement (n = 5), and contractures (n = 5), including muscular torticollis (n = 1) and masticatory muscles (n = 2). DNM2-CNM patients and non-DNM2-CNM patients could not be distinguished by clinical features. DNM2-CNM often shows de novo mutations. In addition to the feature of radial sarcoplasmic strands, the ratio of centrally to internalized nuclei might help to differentiate DNM2-CNM from other forms of CNM. Other genes than currently known seem to cause the clinical and histopathological phenotype of CNM.