DNM2 mutations in a cohort of sporadic patients with centronuclear myopathy.
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.
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil ; Department of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology, Collège de France, University of Strasbourg, Illkirch, France.
Osorio
O
Abath Neto
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Cristiane de Araújo
Cde A
Martins
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Mary
M
Carvalho
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Gerson
G
Chadi
Associação de Pais e Amigos dos Excepcionais, Chapecó, SC, Brazil.
Katia Werneck
KW
Seitz
Setor de Doenças Neuromusculares, Departamento de Neurologia, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Acary Souza Bulle
AS
Oliveira
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Umbertina Conti
UC
Reed
Department of Translational Medicine and Neurogenetics, Institute of Genetics and Molecular and Cellular Biology, Collège de France, University of Strasbourg, Illkirch, France.
Jocelyn
J
Laporte
Departamento de Neurologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
Edmar
E
Zanoteli
DNM2; centronuclear myopathy; congenital myopathy; dynamin 2