Alternative titles; symbols
SNOMEDCT: 240081004; ORPHA: 169186; DO: 0111220;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q14.3 | Centronuclear myopathy 2 | 255200 | Autosomal recessive | 3 | BIN1 | 601248 |
A number sign (#) is used with this entry because of evidence that centronuclear myopathy-2 (CNM2) is caused by homozygous or compound heterozygous mutation in the amphiphysin-2 gene (BIN1; 601248) on chromosome 2q14.
For a general phenotypic description and a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
Sher et al. (1967) described 2 black sisters with generalized muscle weakness and wasting. In 80 to 98% of muscle fibers numerous nuclei were situated centrally. Little degenerative change was evident in the muscles. Muscle biopsy from the asymptomatic mother showed a mixture of small, centrally nucleated fibers and normal fibers. Clinically, the myopathy began early in life and progressed slowly, resulting in marked ptosis, generalized muscular atrophy, and scoliosis.
Pearson et al. (1967) described a female patient with evidence of myopathy from birth. The mother, although clinically normal, showed minor histologic abnormalities of skeletal muscle. Bradley et al. (1970) described affected black brothers with onset of weakness at 8 and 15 years of age and death at 34 years of age in both. Bradley et al. (1970) concluded that the disorder is a degeneration rather than a maturation arrest.
Pavone et al. (1980) observed a girl with typical clinical and histologic features of centronuclear myopathy. The electromyogram was of myopathic type. The parents were first cousins once removed. A paternal aunt and uncle and a maternal aunt, all dead, were thought to have also been affected. Curiously, the authors concluded that the pedigree 'suggests autosomal dominant inheritance with low penetrance.' Difficulty walking, noted at the 'end of the third semester of life,' was the first manifestation. She showed severe hypotonia, bilateral ptosis and absence of deep tendon reflexes. At age 10 years, external ophthalmoplegia and facial weakness were also present. Death in the affected relatives had been at ages 2, 5, and 12 years.
Wallgren-Pettersson et al. (1995) reported that at least 11 myotubular myopathy (MTM) families with pedigrees compatible with autosomal recessive inheritance had been reported. A twelfth, Welsh, family was presented in a workshop. In the 12 families, there were 21 patients with a histologically verified diagnosis of MTM. In 6, the onset of the disease was in infancy, in 7 it was in early childhood, and in a further 8 it was between 8 and 30 years. Clinical features commonly included ophthalmoplegia, ptosis, and facial weakness. Feeding difficulties were reported in 6 of the patients, 2 were floppy at birth, and 2 had asphyxia at birth. Muscle weakness was often most pronounced proximally, but some showed an additional distal involvement. In 3 of the families, the parents were consanguineous, and there were also reports of 2 sporadic cases of male patients with consanguineous parents. All but 1 of the 21 patients whose diagnoses had been histologically verified were alive at the time of reporting at ages between 3 and 32 years (mean 18 years). One patient had died from heart failure at the age of 16 years.
Nicot et al. (2007) reported 3 unrelated consanguineous families with autosomal recessive centronuclear myopathy. Onset ranged from birth to childhood. Three of 5 affected individuals were still alive with mild, proximal, slowly progressive muscle weakness. None needed assisted ventilation. Affected members from 1 Indian family showed mild to severe congenital contractures. There was no cognitive impairment. Skeletal muscle biopsies showed numerous fibers with central nuclei.
Claeys et al. (2010) reported a 21-year-old Moroccan man with centronuclear myopathy. He had delayed motor milestones, walked at age 3.5 years, and had difficulties in running and climbing stairs since childhood. He also had mild mental retardation (IQ of 70) with speech development at age 3.5 years. Diffuse muscle atrophy and progressive muscle weakness became apparent at age 11 years. Physical examination at age 21 years showed muscle weakness in axial and upper and lower proximal and distal limb muscles, with scapular winging, Gowers sign, hyperlordosis, and waddling gait. Other features included facial diplegia, vertical ophthalmoparesis, dysphonia, and dysarthria. There was mild dysmorphism, with an elongated face, high-arched palate, retrognathism, and protruding ears. Hands were thin with long small fingers, and feet showed bilateral pes cavus and equinovarus. Laboratory studies showed variable elevation of serum creatine kinase, and exertional dyspnea. Skeletal muscle biopsy showed centralized nuclei, type 1 fiber predominance, myofibrillar disorganization in some fibers, and rare radial sarcoplasmic strands. EMG showed pseudomyotonic and myotonic discharges, fibrillations, and small short polyphasic motor unit potentials. There was a decremental response at repetitive stimulation, suggesting a postsynaptic neuromuscular transmission defect. The disorder was slowly progressive.
Among 18 Spanish patients, 15 of known Roma background, from 13 families with CNM2, Cabrera-Serrano et al. (2018) found that 16 were homozygous for a founder R234C mutation (601248.0005) and 2 were compound heterozygous for R234C and an R145C mutation (601248.0006) in the BIN1 gene. All of the homozygous patients had nearly complete fat replacement of paravertebral cervical and dorsal and lumbar muscles, consistent with the prominent axial muscle involvement seen on clinical examination. Among muscle biopsy specimens from 13 patients available for review, central nuclei were present in 6 to 98% of the fibers. Compound heterozygous patients showed wide clinical variability, ranging from severe early onset to late childhood onset with a mild phenotype. The authors noted that additional patients needed to be studied to determine whether the specific pattern of radiologic muscle pattern in their homozygous R234C patients is specific to that mutation or common to other BIN1 mutations.
Wallgren-Pettersson et al. (1995) noted that the age of onset in the autosomal recessive form is generally later than in the X-linked form and earlier than in the autosomal dominant form. The severity of the disease seemed to be intermediate between that in the other 2 forms.
The transmission pattern of CNM2 in the families reported by Nicot et al. (2007) was consistent with autosomal recessive inheritance.
In affected members of 3 unrelated consanguineous families with autosomal recessive centronuclear myopathy, Nicot et al. (2007) identified homozygous mutations in the BIN1 gene (601248.0001-601248.0003).
In a Moroccan man with autosomal recessive centronuclear myopathy since childhood and mild mental retardation, Claeys et al. (2010) identified a homozygous mutation in the BIN1 gene (R154Q; 601248.0004).
Among 53 patients diagnosed with centronuclear myopathy at 5 major centers in Spain, Cabrera-Serrano et al. (2018) identified 16 who were homozygous for an arg234-to-cys (R234C; 601248.0005) mutation and 2 who were compound heterozygous for R234C and an arg145-to-cys (R145C; 601248.0006) mutation. All 15 of the known Roma patients had the R234C mutation, which was found by haplotype analysis to be a founder mutation; the remaining 3 patients were of unknown ethnic origin and were lost to follow-up.
Bradley, W. G., Price, D. L., Watanabe, C. K. Familial centronuclear myopathy. J. Neurol. Neurosurg. Psychiat. 33: 687-693, 1970. [PubMed: 5478951] [Full Text: https://doi.org/10.1136/jnnp.33.5.687]
Cabrera-Serrano, M., Mavillard, F., Biancalana, V., Rivas, E., Morar, B., Hernandez-Lain, A., Olive, M., Muelas, N., Khan, E., Carvajal, A., Quiroga, P., Diaz-Manera, J., and 10 others. A Roma founder BIN1 mutation causes a novel phenotype of centronuclear myopathy with rigid spine. Neurology 91: e339-e348, 2018. [PubMed: 29950440] [Full Text: https://doi.org/10.1212/WNL.0000000000005862]
Claeys, K. G., Maisonobe, T., Bohm, J., Laporte, J., Hezode, M., Romero, N. B., Brochier, G., Bitoun, M., Carlier, R. Y., Stojkovic, T. Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology 74: 519-521, 2010. [PubMed: 20142620] [Full Text: https://doi.org/10.1212/WNL.0b013e3181cef7f9]
Nicot, A.-S., Toussaint, A., Tosch, V., Kretz, C., Wallgren-Petterson, C., Iwarsson, E., Kingston, H., Garnier, J.-M., Biancalana, V., Oldfors, A., Mandel, J.-L., Laporte, J. Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy. (Letter) Nature Genet. 39: 1134-1139, 2007. [PubMed: 17676042] [Full Text: https://doi.org/10.1038/ng2086]
Pavone, L., Mollica, F., Grasso, A., Pero, G. Familial centronuclear myopathy. Acta Neurol. Scand. 62: 33-40, 1980. [PubMed: 7211157] [Full Text: https://doi.org/10.1111/j.1600-0404.1980.tb03001.x]
Pearson, C. M., Coleman, R. F., Fowler, W. M., Jr., Mommaerts, W. F. H. M., Munsat, T. L., Peter, J. B. Skeletal muscle: basic and clinical aspects and illustrative new diseases. Ann. Intern. Med. 67: 614-650, 1967. [PubMed: 5342815] [Full Text: https://doi.org/10.7326/0003-4819-67-3-614]
Sher, J. H., Rimalovski, A. B., Athanassiades, T. J., Aronson, S. M. Familial centronuclear myopathy: a clinical and pathological study. Neurology 17: 727-742, 1967. [PubMed: 15088533] [Full Text: https://doi.org/10.1212/wnl.17.8.727]
Wallgren-Pettersson, C., Clarke, A., Samson, F., Fardeau, M., Dubowitz, V., Moser, H., Grimm, T., Barohn, R. J., Barth, P. G. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. J. Med. Genet. 32: 673-679, 1995. [PubMed: 8544184] [Full Text: https://doi.org/10.1136/jmg.32.9.673]