Autosomal dominant centronuclear myopathy is a congenital myopathy characterized by slowly progressive muscular weakness and wasting (Bitoun et al., 2005). The disorder involves mainly limb girdle, trunk, and neck muscles but may also affect distal muscles. Weakness may ... Autosomal dominant centronuclear myopathy is a congenital myopathy characterized by slowly progressive muscular weakness and wasting (Bitoun et al., 2005). The disorder involves mainly limb girdle, trunk, and neck muscles but may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life, and some affected individuals become wheelchair-bound in their fifties. Ptosis and limitation of eye movements occur frequently. The most prominent histopathologic features include high frequency of centrally located nuclei in a large number of extrafusal muscle fibers (which is the basis of the name of the disorder), radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers. - Genetic Heterogeneity of Centronuclear Myopathy Centronuclear myopathy is a genetically heterogeneous disorder. See also X-linked CNM (CNMX; 310400), caused by mutation in the MTM1 gene (300415); CNM2 (255200), caused by mutation in the BIN1 gene (601248) on chromosome 2q14; CNM3 (614408), caused by mutation in the MYF6 gene (159991) on chromosome 12q21; and CNM4 (614807), caused by mutation in the CCDC78 gene (614666) on chromosome 16p13. In addition, some patients with mutation in the RYR1 gene (180901) can have findings of centronuclear myopathy on skeletal muscle biopsy (see 255320).
Spiro et al. (1966) reported an isolated case of what the authors referred to as 'myotubular myopathy.' There was slowly progressive muscle weakness; muscle biopsy showed centrally located nuclei. In the development of skeletal muscle a 'myotubular' stage ... Spiro et al. (1966) reported an isolated case of what the authors referred to as 'myotubular myopathy.' There was slowly progressive muscle weakness; muscle biopsy showed centrally located nuclei. In the development of skeletal muscle a 'myotubular' stage with centrally located nuclei occurs in utero at about 10 weeks of age. Spiro et al. (1966) thought this disease may represent persistence of fetal muscle. McLeod et al. (1972) reported a family that displayed autosomal dominant inheritance. Slowly progressive muscle weakness began between the first and third decades. It was primarily proximal in distribution but sometimes involved the facial musculature. External ophthalmoplegia and pharyngeal weakness were not features. Sixteen members of the family were affected. Karpati et al. (1970) reported affected mother and daughter. Skeletal muscle pathology showed atrophy predominantly of type 1 muscle fibers, with central nuclei and pale central zones with variably staining granules. These changes were indistinguishable from those in the other genetic varieties of centronuclear myopathy. Mortier et al. (1975) described centronuclear myopathy in teenaged brother and sister whose father may have been affected. Symptoms began in the children at 4 or 5 years of age with a 'sleepy facial expression,' clumsy gait, and easy fatigability. The disease progressed in a few years to generalized muscle weakness and atrophy, ptosis, ophthalmoplegia externa, and areflexia. Distal muscles in the lower limbs were severely affected. The father of the children had ptosis from at least age 20 years and generalized muscle atrophy had been noted at age 25. Wallgren-Pettersson et al. (1995) reviewed the differential diagnosis of the X-linked, autosomal dominant, and autosomal recessive forms of myotubular myopathy. They were aware of 13 reported pedigrees of which only 2 included histologically verified male-to-male transmission of MTM. Of 26 histologically verified cases, onset of symptoms was in the first decade in 9, in the second decade in 4, and later in 12. The clinical features are generalized muscle weakness, often predominantly proximal, but some patients show a definite additional distal involvement. A few patients have calf hypertrophy. The facial muscles may also be involved and some patients have ptosis or ophthalmoplegia. Of the 26 patients, 24 were alive at the time of writing of the reports, at ages ranging from 11 months to 68 years (mean 37 years). One patient had died at the age of 57 years of cardiorespiratory failure and another at 5 years. The autosomal dominant form for the most part has a later onset and milder course than the X-linked form but the clinical features do not seem to be qualitatively different. Bitoun et al. (2007) reported 5 unrelated patients with sporadic MTM due to heterozygous mutations in the DNM2 gene (see, e.g., 602378.0010; 602378.0011). Three had a more severe form of the disorder, with onset at birth necessitating ventilation and nasogastric feeding, and delayed development. The other 2 patients had normal motor development but developed a restrictive respiratory syndrome at ages 10 and 7 years, respectively. All patients had generalized muscle weakness most prominent in the distal lower limbs, and EMG showed myopathic changes. Other variable features included open mouth, arched palate, ptosis, pes cavus, scoliosis, contractures, and hyperlaxity. Skeletal muscle biopsies showed hypotrophy of type 1 fibers and centralized nuclei. The 2 older patients, who were also the least affected, developed loss of deep tendon reflexes at age 8 and 7 years, respectively. Bitoun et al. (2007) noted that the phenotype in these sporadic patients showed earlier onset and greater severity in general compared to other patients with DNM2-related MTM. Bitoun et al. (2009) reported a 34-year-old woman from central Africa with MTM confirmed by muscle biopsy and genetic analysis. Onset of symptoms occurred at age 7 years, with difficulty walking and running. She later developed facial weakness, ptosis, and weakness in the paraspinal, upper, and lower limb muscles. Motor nerve conduction velocities were normal. In her teenage years, she had rapid progression, with onset of ophthalmoparesis, dysphagia, and frequent falls. By age 30, she required a wheelchair and showed a progressive restrictive respiratory syndrome.
In affected members of 11 families with centronuclear myopathy, Bitoun et al. (2005) identified recurrent and de novo heterozygous missense mutations in the DNM2 gene (see, e.g., 602378.0004-602378.0007), which encodes a protein involved in endocytosis and membrane trafficking, ... In affected members of 11 families with centronuclear myopathy, Bitoun et al. (2005) identified recurrent and de novo heterozygous missense mutations in the DNM2 gene (see, e.g., 602378.0004-602378.0007), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly, and centrosome cohesion. - Genetic Modifiers Tosch et al. (2006) provided evidence that mutations in the MTMR14 gene (611089) on chromosome 3p25 may act as modifiers of the centronuclear myopathy phenotype. The authors reported patients with sporadic myotubular myopathy in which each proband carried a heterozygous missense mutation in the MTMR14 gene. The first proband and his unaffected father carried an R336Q substitution (611089.0001). A second mutation was not identified. The other proband carried a Y462C substitution in MTMR14 (611089.0002) and an additional missense mutation in DYN2 (E368K; 602378.0007). The Y462C mutation was found in a control individual. Both variants impaired enzymatic function, the R336Q mutation strongly, and the Y462C mutation to a lesser extent. Tosch et al. (2006) remarked that myotubular myopathy patients with other characterized mutations in DYN2 usually have an age of onset in childhood or adulthood, whereas the age of onset in their patient was neonatal. The report raised the possibility of MTMR14 being a modifier of the phenotype in some cases of centronuclear myopathy.