# 160150

MYOPATHY, CENTRONUCLEAR, 1; CNM1


Alternative titles; symbols

MYOPATHY, CENTRONUCLEAR, AUTOSOMAL DOMINANT
MYOTUBULAR MYOPATHY, AUTOSOMAL DOMINANT


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p25.3 {Centronuclear myopathy, autosomal, modifier of} 160150 AD 3 MTMR14 611089
19p13.2 Centronuclear myopathy 1 160150 AD 3 DNM2 602378
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Facial muscle weakness
Eyes
- Ptosis
- Ophthalmoparesis
SKELETAL
- Contractures
MUSCLE, SOFT TISSUES
- Muscle weakness, primarily proximal
- Distal muscle weakness may occur
- Delayed motor development
- Muscle hypertrophy may occur
- Muscle biopsy shows centralized nuclei
- Atrophy of type 1 fibers
- Type 1 fiber predominance
NEUROLOGIC
Central Nervous System
- Walking difficulties
Peripheral Nervous System
- Areflexia
MISCELLANEOUS
- Variable age of onset (range early childhood to adult)
- Slowly progressive
MOLECULAR BASIS
- Caused by mutation in the dynamin-2 gene (DNM2, 602378.0004).

TEXT

A number sign (#) is used with this entry because of evidence that centronuclear myopathy-1 (CNM1) is caused by heterozygous mutation in the gene encoding dynamin-2 (DNM2; 602378) on chromosome 19p13.


Description

Centronuclear myopathy-1 (CNM1) is an autosomal dominant congenital myopathy characterized by slowly progressive muscular weakness and wasting. 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 (summary by Bitoun et al., 2005).

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) on chromosome Xq28; CNM2 (255200), caused by mutation in the BIN1 gene (601248) on chromosome 2q14; CNM4 (614807), caused by mutation in the CCDC78 gene (614666) on chromosome 16p13; CNM5 (615959), caused by mutation in the SPEG gene (615950) on chromosome 2q35; and CNM6 (617760), caused by mutation in the ZAK gene (609479) on chromosome 2q31.

The mutation in the MYF6 gene that was reported to cause a form of CNM, formerly designated CNM3, has been reclassified as a variant of unknown significance; see 159991.0001.

Some patients with mutation in the RYR1 gene (180901) have findings of centronuclear myopathy on skeletal muscle biopsy (see 255320).


Clinical Features

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.


Inheritance

The transmission pattern of CNM1 in the families reported by Bitoun et al. (2005) was consistent with autosomal dominant inheritance.


Molecular Genetics

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.


Genotype/Phenotype Correlations

Bohm et al. (2012) reported 60 families with genetically confirmed CNM1, including 36 families with mutations in the MID domain of the DNM2 gene, 22 with mutations in the PH domain, and 2 with mutations in the PH-GED linker domain. Combined with previous reports, the most common mutation in CNM1 in the MID domain is R465W (602378.0006), followed by E368K (602378.0007), R369W (602378.0005), and R369Q (602378.0004). The most common mutations in the PH domain are R522H and S619L (602378.0010). Mutations in the PH-GED domain are rare. The phenotype displayed marked inter- and intrafamilial variability, but in general, there were 3 major classes, ranging from the most severe with onset of symptoms in infancy to the least severe with onset in adulthood. At a minimum, all patients had areflexia or hyporeflexia, muscle weakness, and hypotrophic fibers with centralized nuclei on muscle biopsy. S619L was associated with a severe neonatal phenotype with hypotonia and delayed motor milestones, E368K with early onset and severe muscle weakness at birth with partial improvement over time, and R552H with a mild phenotype. Functional studies of the variants were not performed.


Pathogenesis

Although the myofibers in centronuclear myopathy do not share all the histologic features of embryonic myotubes, the centrally placed nuclei have suggested to many investigators that the primary pathology in this disorder is an arrest of muscle fiber maturation at the myotube stage (Banker, 1986). Mora et al. (1994) suggested that there is only a partial arrest of fiber maturation because they found an intracytoplasmic distribution of dystrophin and beta-spectrin (see 182790), an immature pattern, but no evidence of fetal myosin overexpression as is found in immature myotubes. None of these specimens originated from patients with X-linked centronuclear myopathy, although several may have had the autosomal recessive form.

The DNM2 gene is mutant in some cases of autosomal dominant centronuclear myopathy. To investigate the ability of DNM2 mutant proteins to localize to the centrosome, Bitoun et al. (2005) prepared green fluorescent protein (GFP) chimeras using wildtype and mutant DNM2 constructs. Transfected mutants showed reduced labeling in the centrosomes of human fibroblasts, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.


REFERENCES

  1. Banker, B. Q. The congenital myopathies. In: Engel, A. G.; Banker, B. Q.: Myology: Basic and Clinical. New York: McGraw-Hill (pub.) 1986. Pp. 1527-1581.

  2. Bitoun, M., Bevilacqua, J. A., Eymard, B., Prudhon, B., Fardeau, M., Guicheney, P., Romero, N. B. A new centronuclear myopathy phenotype due to a novel dynamin 2 mutation. Neurology 72: 93-95, 2009. [PubMed: 19122038, related citations] [Full Text]

  3. Bitoun, M., Bevilacqua, J. A., Prudhon, B., Maugenre, S., Taratuto, A. L., Monges, S., Lubieniecki, F., Cances, C., Uro-Coste, E., Mayer, M., Fardeau, M., Romero, N. B., Guicheney, P. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann. Neurol. 62: 666-670, 2007. [PubMed: 17932957, related citations] [Full Text]

  4. Bitoun, M., Maugenre, S., Jeannet, P.-Y., Lacene, E., Ferrer, X., Laforet, P., Martin, J.-J., Laporte, J., Lochmuller, H., Beggs, A. H., Fardeau, M., Eymard, B., Romero, N. B., Guicheney, P. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nature Genet. 37: 1207-1209, 2005. [PubMed: 16227997, related citations] [Full Text]

  5. Bohm, J., Biancalana, V., DeChene, E. T., Bitoun, M., Pierson, C. R., Schaefer, E., Karasoy, H., Dempsey, M. A., Klein, F., Dondaine, N., Kretz, C., Haumesser, N., and 56 others. Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Hum. Mutat. 33: 949-959, 2012. [PubMed: 22396310, images, related citations] [Full Text]

  6. Karpati, G., Carpenter, S., Nelson, R. F. Type I muscle fibre atrophy and central nuclei: a rare familial neuromuscular disease. J. Neurol. Sci. 10: 489-500, 1970. [PubMed: 4910660, related citations] [Full Text]

  7. McLeod, J. G., Baker, W. de C., Lethlean, A. K., Shorey, C. D. Centronuclear myopathy with autosomal dominant inheritance. J. Neurol. Sci. 15: 375-388, 1972. [PubMed: 5016690, related citations] [Full Text]

  8. Mora, M., Morandi, L., Merlini, L., Vita, G., Baradello, A., Barresi, R., Di Blasi, C., Blasevich, F., Gebbia, M., Daniel, S., Cornelio, F. Fetus-like dystrophin expression and other cytoskeletal protein abnormalities in centronuclear myopathies. Muscle Nerve 17: 1176-1184, 1994. [PubMed: 7935525, related citations] [Full Text]

  9. Mortier, W., Michaelis, E., Becker, J., Gerhard, L. Centronucleare Myopathie mit autosomal dominatem Erbgang. Humangenetik 27: 199-215, 1975. [PubMed: 1150240, related citations] [Full Text]

  10. Spiro, A. J., Shy, G. M., Gonatas, N. K. Myotubular myopathy. Arch. Neurol. 14: 1-14, 1966. [PubMed: 4954227, related citations] [Full Text]

  11. Tosch, V., Rohde, H. M., Tronchere, H., Zanoteli, E., Monroy, N., Kretz, C., Dondaine, N., Payrastre, B., Mandel, J.-L., Laporte, J. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum. Molec. Genet. 15: 3098-3106, 2006. [PubMed: 17008356, related citations] [Full Text]

  12. 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, related citations] [Full Text]


Cassandra L. Kniffin - updated : 11/6/2017
Cassandra L. Kniffin - updated : 5/20/2015
Cassandra L. Kniffin - updated : 12/22/2011
Cassandra L. Kniffin - updated : 3/16/2009
Cassandra L. Kniffin - updated : 3/31/2008
Victor A. McKusick - updated : 11/1/2005
Victor A. McKusick - updated : 8/28/2003
Victor A. McKusick - updated : 11/29/2000
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 01/06/2023
carol : 03/28/2022
carol : 02/15/2019
carol : 02/14/2019
carol : 02/11/2019
carol : 11/07/2017
ckniffin : 11/06/2017
carol : 06/05/2017
alopez : 05/21/2015
mcolton : 5/21/2015
ckniffin : 5/20/2015
carol : 8/26/2014
ckniffin : 8/25/2014
carol : 8/16/2013
carol : 9/12/2012
ckniffin : 9/12/2012
joanna : 6/14/2012
carol : 12/29/2011
ckniffin : 12/22/2011
wwang : 3/10/2011
ckniffin : 2/16/2011
ckniffin : 3/12/2010
wwang : 3/25/2009
ckniffin : 3/16/2009
wwang : 4/4/2008
ckniffin : 3/31/2008
alopez : 7/19/2007
ckniffin : 7/19/2006
alopez : 11/3/2005
terry : 11/1/2005
tkritzer : 9/2/2003
tkritzer : 8/29/2003
tkritzer : 8/28/2003
alopez : 3/13/2002
mcapotos : 12/18/2000
mcapotos : 12/14/2000
terry : 11/29/2000
mark : 10/20/1995
carol : 1/26/1995
mimadm : 12/2/1994
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989

# 160150

MYOPATHY, CENTRONUCLEAR, 1; CNM1


Alternative titles; symbols

MYOPATHY, CENTRONUCLEAR, AUTOSOMAL DOMINANT
MYOTUBULAR MYOPATHY, AUTOSOMAL DOMINANT


SNOMEDCT: 716696006;   ICD10CM: G71.228;   ORPHA: 169189;   DO: 0111223;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p25.3 {Centronuclear myopathy, autosomal, modifier of} 160150 Autosomal dominant 3 MTMR14 611089
19p13.2 Centronuclear myopathy 1 160150 Autosomal dominant 3 DNM2 602378

TEXT

A number sign (#) is used with this entry because of evidence that centronuclear myopathy-1 (CNM1) is caused by heterozygous mutation in the gene encoding dynamin-2 (DNM2; 602378) on chromosome 19p13.


Description

Centronuclear myopathy-1 (CNM1) is an autosomal dominant congenital myopathy characterized by slowly progressive muscular weakness and wasting. 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 (summary by Bitoun et al., 2005).

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) on chromosome Xq28; CNM2 (255200), caused by mutation in the BIN1 gene (601248) on chromosome 2q14; CNM4 (614807), caused by mutation in the CCDC78 gene (614666) on chromosome 16p13; CNM5 (615959), caused by mutation in the SPEG gene (615950) on chromosome 2q35; and CNM6 (617760), caused by mutation in the ZAK gene (609479) on chromosome 2q31.

The mutation in the MYF6 gene that was reported to cause a form of CNM, formerly designated CNM3, has been reclassified as a variant of unknown significance; see 159991.0001.

Some patients with mutation in the RYR1 gene (180901) have findings of centronuclear myopathy on skeletal muscle biopsy (see 255320).


Clinical Features

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.


Inheritance

The transmission pattern of CNM1 in the families reported by Bitoun et al. (2005) was consistent with autosomal dominant inheritance.


Molecular Genetics

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.


Genotype/Phenotype Correlations

Bohm et al. (2012) reported 60 families with genetically confirmed CNM1, including 36 families with mutations in the MID domain of the DNM2 gene, 22 with mutations in the PH domain, and 2 with mutations in the PH-GED linker domain. Combined with previous reports, the most common mutation in CNM1 in the MID domain is R465W (602378.0006), followed by E368K (602378.0007), R369W (602378.0005), and R369Q (602378.0004). The most common mutations in the PH domain are R522H and S619L (602378.0010). Mutations in the PH-GED domain are rare. The phenotype displayed marked inter- and intrafamilial variability, but in general, there were 3 major classes, ranging from the most severe with onset of symptoms in infancy to the least severe with onset in adulthood. At a minimum, all patients had areflexia or hyporeflexia, muscle weakness, and hypotrophic fibers with centralized nuclei on muscle biopsy. S619L was associated with a severe neonatal phenotype with hypotonia and delayed motor milestones, E368K with early onset and severe muscle weakness at birth with partial improvement over time, and R552H with a mild phenotype. Functional studies of the variants were not performed.


Pathogenesis

Although the myofibers in centronuclear myopathy do not share all the histologic features of embryonic myotubes, the centrally placed nuclei have suggested to many investigators that the primary pathology in this disorder is an arrest of muscle fiber maturation at the myotube stage (Banker, 1986). Mora et al. (1994) suggested that there is only a partial arrest of fiber maturation because they found an intracytoplasmic distribution of dystrophin and beta-spectrin (see 182790), an immature pattern, but no evidence of fetal myosin overexpression as is found in immature myotubes. None of these specimens originated from patients with X-linked centronuclear myopathy, although several may have had the autosomal recessive form.

The DNM2 gene is mutant in some cases of autosomal dominant centronuclear myopathy. To investigate the ability of DNM2 mutant proteins to localize to the centrosome, Bitoun et al. (2005) prepared green fluorescent protein (GFP) chimeras using wildtype and mutant DNM2 constructs. Transfected mutants showed reduced labeling in the centrosomes of human fibroblasts, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.


REFERENCES

  1. Banker, B. Q. The congenital myopathies. In: Engel, A. G.; Banker, B. Q.: Myology: Basic and Clinical. New York: McGraw-Hill (pub.) 1986. Pp. 1527-1581.

  2. Bitoun, M., Bevilacqua, J. A., Eymard, B., Prudhon, B., Fardeau, M., Guicheney, P., Romero, N. B. A new centronuclear myopathy phenotype due to a novel dynamin 2 mutation. Neurology 72: 93-95, 2009. [PubMed: 19122038] [Full Text: https://doi.org/10.1212/01.wnl.0000338624.25852.12]

  3. Bitoun, M., Bevilacqua, J. A., Prudhon, B., Maugenre, S., Taratuto, A. L., Monges, S., Lubieniecki, F., Cances, C., Uro-Coste, E., Mayer, M., Fardeau, M., Romero, N. B., Guicheney, P. Dynamin 2 mutations cause sporadic centronuclear myopathy with neonatal onset. Ann. Neurol. 62: 666-670, 2007. [PubMed: 17932957] [Full Text: https://doi.org/10.1002/ana.21235]

  4. Bitoun, M., Maugenre, S., Jeannet, P.-Y., Lacene, E., Ferrer, X., Laforet, P., Martin, J.-J., Laporte, J., Lochmuller, H., Beggs, A. H., Fardeau, M., Eymard, B., Romero, N. B., Guicheney, P. Mutations in dynamin 2 cause dominant centronuclear myopathy. Nature Genet. 37: 1207-1209, 2005. [PubMed: 16227997] [Full Text: https://doi.org/10.1038/ng1657]

  5. Bohm, J., Biancalana, V., DeChene, E. T., Bitoun, M., Pierson, C. R., Schaefer, E., Karasoy, H., Dempsey, M. A., Klein, F., Dondaine, N., Kretz, C., Haumesser, N., and 56 others. Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy. Hum. Mutat. 33: 949-959, 2012. [PubMed: 22396310] [Full Text: https://doi.org/10.1002/humu.22067]

  6. Karpati, G., Carpenter, S., Nelson, R. F. Type I muscle fibre atrophy and central nuclei: a rare familial neuromuscular disease. J. Neurol. Sci. 10: 489-500, 1970. [PubMed: 4910660] [Full Text: https://doi.org/10.1016/0022-510x(70)90027-4]

  7. McLeod, J. G., Baker, W. de C., Lethlean, A. K., Shorey, C. D. Centronuclear myopathy with autosomal dominant inheritance. J. Neurol. Sci. 15: 375-388, 1972. [PubMed: 5016690] [Full Text: https://doi.org/10.1016/0022-510x(72)90166-9]

  8. Mora, M., Morandi, L., Merlini, L., Vita, G., Baradello, A., Barresi, R., Di Blasi, C., Blasevich, F., Gebbia, M., Daniel, S., Cornelio, F. Fetus-like dystrophin expression and other cytoskeletal protein abnormalities in centronuclear myopathies. Muscle Nerve 17: 1176-1184, 1994. [PubMed: 7935525] [Full Text: https://doi.org/10.1002/mus.880171008]

  9. Mortier, W., Michaelis, E., Becker, J., Gerhard, L. Centronucleare Myopathie mit autosomal dominatem Erbgang. Humangenetik 27: 199-215, 1975. [PubMed: 1150240] [Full Text: https://doi.org/10.1007/BF00278346]

  10. Spiro, A. J., Shy, G. M., Gonatas, N. K. Myotubular myopathy. Arch. Neurol. 14: 1-14, 1966. [PubMed: 4954227] [Full Text: https://doi.org/10.1001/archneur.1966.00470070005001]

  11. Tosch, V., Rohde, H. M., Tronchere, H., Zanoteli, E., Monroy, N., Kretz, C., Dondaine, N., Payrastre, B., Mandel, J.-L., Laporte, J. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum. Molec. Genet. 15: 3098-3106, 2006. [PubMed: 17008356] [Full Text: https://doi.org/10.1093/hmg/ddl250]

  12. 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]


Contributors:
Cassandra L. Kniffin - updated : 11/6/2017
Cassandra L. Kniffin - updated : 5/20/2015
Cassandra L. Kniffin - updated : 12/22/2011
Cassandra L. Kniffin - updated : 3/16/2009
Cassandra L. Kniffin - updated : 3/31/2008
Victor A. McKusick - updated : 11/1/2005
Victor A. McKusick - updated : 8/28/2003
Victor A. McKusick - updated : 11/29/2000

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 01/06/2023
carol : 03/28/2022
carol : 02/15/2019
carol : 02/14/2019
carol : 02/11/2019
carol : 11/07/2017
ckniffin : 11/06/2017
carol : 06/05/2017
alopez : 05/21/2015
mcolton : 5/21/2015
ckniffin : 5/20/2015
carol : 8/26/2014
ckniffin : 8/25/2014
carol : 8/16/2013
carol : 9/12/2012
ckniffin : 9/12/2012
joanna : 6/14/2012
carol : 12/29/2011
ckniffin : 12/22/2011
wwang : 3/10/2011
ckniffin : 2/16/2011
ckniffin : 3/12/2010
wwang : 3/25/2009
ckniffin : 3/16/2009
wwang : 4/4/2008
ckniffin : 3/31/2008
alopez : 7/19/2007
ckniffin : 7/19/2006
alopez : 11/3/2005
terry : 11/1/2005
tkritzer : 9/2/2003
tkritzer : 8/29/2003
tkritzer : 8/28/2003
alopez : 3/13/2002
mcapotos : 12/18/2000
mcapotos : 12/14/2000
terry : 11/29/2000
mark : 10/20/1995
carol : 1/26/1995
mimadm : 12/2/1994
supermim : 3/16/1992
supermim : 3/20/1990
ddp : 10/27/1989