DNM2 mutations in a cohort of sporadic patients with centronuclear myopathy

Abstract

Centronuclear myopathy (CNM) is a rare congenital muscle disease characterized by fibers with prominent centralized nuclei in muscle biopsies. The disease is clinically heterogeneous, ranging from severe neonatal hypotonic phenotypes to adult-onset mild muscle weakness, and can have multiple modes of inheritance in association with various genes, including MTM1, DNM2, BIN1 and RYR1. Here we analyzed 18 sporadic patients with clinical and histological diagnosis of CNM and sequenced the DNM2 gene, which codes for the dynamin 2 protein. We found DNM2 missense mutations in two patients, both in exon 8, one known (p.E368K) and one novel (p.F372C), which is found in a position of presumed pathogenicity and appeared de novo. The patients had similar phenotypes characterized by neonatal signs followed by improvement and late childhood reemergence of slowly progressive generalized muscle weakness, elongated face with ptosis and ophthalmoparesis, and histology showing fibers with radiating sarcoplasmic strands (RSS). These patients were the only ones in the series to present this histological marker, which together with previous reports in the literature suggest that, when RSS are present, direct sequencing of DNM2 mutation hot spot regions should be the first step in the molecular diagnosis of CNM, even in sporadic cases.

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands

“… 27 Some DNM2 variants have been described to be more frequent in late‐onset phenotypes, 23 however, this was not observed in our cohort. The delay between onset and diagnosis was long (14 ± 14 years), probably related to the late onset, relatively mild symptoms, and slow progression, 9 and the limited diagnostic options before the era of exome sequencing.…”

“…Variable degrees of radial sarcoplasmic strands were present in six patients; both features have been described previously. 9 , 31 …”

“… 6 , 7 , 8 Patients may present within the spectrum of the floppy infant syndrome, or with variable degrees of weakness with delayed gross motor milestones, respiratory and/or bulbar involvement. 7 , 9 , 10 , 11 Presentation is predominantly in infancy and childhood, but some patients do not present until their teens or adolescence with reduced exercise tolerance and mild ptosis, and often remain ambulatory throughout adult life.…”

Uma família brasileira com miopatia centronuclear por mutação no gene DNM2

“…Aqui, relatamos uma família brasileira com fenótipo grave de MCN autossômica dominante, portadores da mutação do DNM2 (c.1393C>T, p.Arg465Trp). Não é do nosso conhecimento a descrição de nenhuma família com mutações no gene DNM2 no Brasil, havendo somente relato de casos esporádicos da doença (mutação de novo) 7…”

A dog model for centronuclear myopathy carrying the most common DNM2 mutation

“…The age of onset and disease severity ranges from severe neonatal hypotonia and respiratory distress to mild adult-onset muscle weakness, and correlates with the position of the mutation. To date, more than 100 families and about 20 different ADCNM-related DNM2 mutations have been reported, essentially clustering in hotspot regions in exons 8, 11, 14, 15 and 16 ( Abath Neto et al, 2015 ; Bohm et al, 2012 ; Werlauff et al, 2015 ). The most common mutation c.1393C>T resides in exon 11, affects approximately 25% of the cases, leads to the amino acid substitution p.ArgR465Trp (R465W) in the MID domain, and most often results in a moderate clinical presentation involving childhood onset and slowly progressive distal muscle weakness ( Bohm et al, 2012 ).…”