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.
Highlights
Centronuclear myopathy (CNM) is a rare, clinically heterogeneous, structural congenital myopathy characterized by the presence of centralized nuclei in the majority of muscle fibers in muscle biopsies that are not linked to excessive regeneration (Zanoteli et al, 1998)
Three inheritance patterns are described: (i) X-linked recessive, which gives rise to a form referred to as myotubular myopathy (MIM #310400), with a severe neonatal presentation marked by profound hypotonia and respiratory failure; this pattern is associated with the MTM1 gene (MIM *300415) (Laporte et al, 1996); (ii) autosomal dominant, causing a milder, neonatal to adult-onset muscle involvement (MIM #160150); this is related with mutations in the DNM2 gene (MIM *602378) (Bitoun et al, 2005); and (iii) autosomal recessive, with intermediate severity compared to the other forms (MIM #255200); the latter is caused by mutations in the genes BIN1 (MIM *601248) (Nicot et al, 2007) or
A majority of rounded fibers with clusters of centralized nuclei is suggestive of involvement of the BIN1 gene, while the presence of areas of myofibrillar disorganization devoid of mitochondria, such as moth-eaten or core-like structures, points to the RYR1 gene
Summary
Centronuclear myopathy (CNM) is a rare, clinically heterogeneous, structural congenital myopathy characterized by the presence of centralized nuclei in the majority of muscle fibers in muscle biopsies that are not linked to excessive regeneration (Zanoteli et al, 1998). Three inheritance patterns are described: (i) X-linked recessive, which gives rise to a form referred to as myotubular myopathy (MIM #310400), with a severe neonatal presentation marked by profound hypotonia and respiratory failure; this pattern is associated with the MTM1 gene (MIM *300415) (Laporte et al, 1996); (ii) autosomal dominant, causing a milder, neonatal to adult-onset muscle involvement (MIM #160150); this is related with mutations in the DNM2 gene (MIM *602378) (Bitoun et al, 2005); and (iii) autosomal recessive, with intermediate severity compared to the other forms (MIM #255200); the latter is caused by mutations in the genes BIN1 (MIM *601248) (Nicot et al, 2007) or
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