Alternative titles; symbols
SNOMEDCT: 46804001; ICD10CM: G71.220; ORPHA: 596, 604680; DO: 0111225;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Myopathy, centronuclear, X-linked | 310400 | X-linked recessive | 3 | MTM1 | 300415 |
A number sign (#) is used with this entry because X-linked centronuclear myopathy (CNMX), also known as X-linked myotubular myopathy-1, is caused by mutation in the myotubularin gene (MTM1; 300415) on chromosome Xq28.
For a general phenotypic description and a discussion of genetic heterogeneity of centronuclear myopathy, see CNM1 (160150).
See myotubular myopathy with abnormal genital development (300219), a possible contiguous gene syndrome.
Van Wijngaarden et al. (1969) described this disorder in 5 affected males in 4 sibships connected through females who in 2 instances showed partial manifestations on muscle biopsy. The patients were born as floppy infants and had serious respiratory problems early in life; extraocular, facial, and neck muscles were always affected. Meyers et al. (1974) reported affected brothers; both were floppy infants and died at 7 and 18 months of age. The mother showed no abnormality on muscle biopsy or enzyme assay. One of the brothers was previously reported by Engel et al. (1968).
Heckmatt et al. (1985) reported in detail on 8 unrelated children. Facial diplegia and often external ophthalmoplegia were frequent. The newborn cases resemble those of congenital myotonic dystrophy; the distinction can be made by examination of their mother who in the latter situation will invariably show mild facial weakness and clinical or electrical myotonia. Polyhydramnios is a feature of both forms of congenital myopathy, i.e., myotonic dystrophy and X-linked myotubular myopathy. Keppen et al. (1987) noted that there is often a history of polyhydramnios due to decreased fetal swallowing of amniotic fluid.
Moerman et al. (1987) concluded that severe X-linked centronuclear myopathy was responsible for neonatal death from respiratory failure in a case with congenital eventration of the diaphragm which was paper thin and almost transparent. At least 1 other male in the sibship had confirmed X-linked centronuclear myopathy leading to neonatal death. A second patient who died neonatally with congenital eventration of the diaphragm was found by Moerman et al. (1987) to have congenital myotonic dystrophy. In studies through 5 generations of a family, Oldfors et al. (1989) described 8 affected individuals in 4 generations connected through carrier females. Death in the first days of life from asphyxia was common, as was polyhydramnios.
Joseph et al. (1995) reported 10 additional cases distributed in 6 unrelated families. They noted birth length greater than the 90th percentile and large head circumference with or without hydrocephalus in 70% of cases, narrow, elongated face in 80%, and slender, long digits in 60%. There was concordance in the occurrence and severity of hydrocephalus in most sib pairs. The above features in a 'floppy' male infant served as clues for early clinical diagnosis which could then be confirmed by muscle biopsy. Development of polyhydramnios was observed in the third trimester of an at-risk dizygotic twin gestation monitored by serosonography, with confirmation of the diagnosis of myotubular myopathy at birth.
Herman et al. (1999) presented a clinical review of patients with MTM1, using data obtained through medical record review and family interview on 55 male subjects from 49 independent North American families for which a mutation was identified in the MTM1 gene by direct genomic sequencing. Seventy-four percent (26 of 35) over the age of 1 year were living, and 80% remained completely or partially ventilator-dependent. Cognitive development was normal, in the absence of significant hypoxia, and the muscle disorder appeared nonprogressive. Medical complications observed in some long-term survivors included pyloric stenosis, spherocytosis, gallstones, kidney stones or nephrocalcinosis, a vitamin K-responsive bleeding diathesis, and rapid linear growth with advanced bone age. Six patients had biochemical evidence of liver dysfunction, and 2 died after significant liver hemorrhage. The authors suggested that the prognosis for MTM1 may not be as poor as previously reported. They also noted that patients should be carefully monitored for potentially life-threatening medical complications in other (nonmuscle) organ systems.
Pathologic Findings
Askanas et al. (1979) found that muscle cells established from biopsy specimens in 2 patients MTM1 showed an unusual ability to proliferate through numerous passages. Ultrastructurally, the cultured muscle fibers appeared immature even after several weeks. The nuclei were large, the number of ribosomes greatly increased, the myofibrils remained unstriated, and glycogen was accumulated in large lakes. The level of adenylate cyclase in membranes was reduced.
Sarnat et al. (1981) reported the case of an affected infant. At 5 days of age, a muscle biopsy revealed that more than 90% of muscle fibers fulfilled histologic, histochemical, and electron microscopic criteria of fetal myotubules (8 to 15 weeks of gestation). The infant died unexpectedly at 9 months of age of a seemingly unrelated cause, spontaneous rupture of a multifocal cavernous hemangioma of the liver. Postmortem examination revealed that progressive maturation of the fetal muscle had not occurred postnatally, and this maturational arrest was generalized to all striated muscles.
Obligate Female Carriers
Heckmatt et al. (1985) reported mild facial weakness and, on muscle biopsy, increased variability in fiber size in an obligate carrier of the X-linked type. Keppen et al. (1987) found a normal muscle biopsy in a woman who had 2 affected sons by different fathers, indicating that a normal muscle biopsy in the mother cannot exclude X-linked inheritance. Clinical examination of 2 obligatory carriers by Oldfors et al. (1989) showed no muscle weakness, but muscle biopsy showed pathologic changes including greatly increased variability of fiber size and many fibers with central nuclei.
In agreement with recessive inheritance of X-linked myotubular myopathy, heterozygous carriers of MTM1 gene mutations are usually asymptomatic, although mild facial weakness has been reported (Heckmatt et al., 1985; Wallgren-Pettersson et al., 1995). Tanner et al. (1999) reported a 39-year-old Yemenite woman, who was the offspring of first-cousin parents, with a histologic and clinical phenotype consistent with X-linked myotubular myopathy. Gait difficulty was first noted at the age of 5 years. She showed weakness first in the lower and then in the upper extremities and underwent corrective surgery for deformity of the ankles. The patient had a normal intellectual capacity and was still ambulant. She had an elongated face with prognathism. Her speech was dysarthric with a nasal quality. She had marked kyphoscoliosis and bilateral pes equinovarus. There was moderate weakness of her facial muscles and neck flexors and winging of the right scapula. The proximal upper limb muscles and the distal hand muscles were weak and wasted, whereas the forearm muscles showed almost normal strength. In the lower leg, the pattern of weakness was similar with severe pelvic girdle and distal weakness. One of the patient's sisters gave birth to at least 2 boys with established histopathologic features of X-linked myotubular myopathy. The proband was shown to be a carrier of the most common MTM1 gene mutation (300415.0006), which is associated with a severe phenotype in males. The patient was found to have an extremely skewed X-inactivation pattern, thus explaining her abnormal phenotype. The mother, on the other hand, was a nonmanifesting carrier but likewise had an extremely skewed X-inactivation pattern in the opposite direction. The findings indicated a possible inheritance of skewed X inactivation. Linkage analysis excluded involvement of the XIST locus (314670) at Xq13.
Sutton et al. (2001) described a female heterozygous for an R224X mutation of the MTM1 gene (310400.0008) with limb-girdle and facial weakness typical of the cases reported by Tanner et al. (1999) and Hammans et al. (2000). However, in their patient, Sutton et al. (2001) found no skewed X-chromosome inactivation in either lymphocyte or muscle DNA.
Schara et al. (2003) reported a female with prenatal/neonatal onset of clinical symptoms due to myotubular myopathy, who had a heterozygous mutation in the MTM1 gene (300415.0009). During pregnancy, fetal movements were reduced. After birth, she showed severe hypotonia, dyspnea, a weak cry, absent tendon reflexes, a high-arched palate, and a right-sided ptosis. She later had limb-girdle and facial muscle weakness and a waddling gait. Skeletal muscle biopsy showed a wide variation of fiber size and numerous internal nuclei. Schara et al. (2003) noted the more severe clinical course in this female compared to other reported affected females and emphasized the prenatal onset of symptoms.
Grogan et al. (2005) reported 3 sisters with myotubular myopathy confirmed by genetic analysis of the MTM1 gene. All reported unilateral weakness and atrophy of the upper limb since childhood, and the 2 older sisters had onset of gradually progressive generalized weakness in their thirties. X-rays of the hand in 1 patient showed skeletal asymmetry. Two of the sisters had an elevated hemidiaphragm on the ipsilateral side to their upper limb involvement. Five additional asymptomatic female family members carried the same mutation and showed skewed X-inactivation favoring the paternal X chromosome. A fourth unrelated woman with an MTM1 mutation had left facial and left upper and lower limb weakness and atrophy since age 6 years. She developed progressive generalized weakness at age 40 years; x-ray showed elevated left hemidiaphragm. X-inactivation was markedly skewed.
Braga et al. (1990) reported 7 cases from 3 families, calling attention to the prenatal onset and rapid progression of the disorder. They concluded that needle biopsy of muscle, showing an increased number of centrally located nuclei with perinuclear halos, is a 'powerful tool for early diagnosis.'
Sarnat (1990) found by immunohistochemical studies persistence of desmin and vimentin in 2 female carriers of the X-linked form, which they thought might be useful in carrier detection. In 3 mothers of boys with X-linked centronuclear myopathy, one of them an obligate carrier, Breningstall et al. (1991) found abnormalities of nonspecific character on muscle biopsy. They reviewed other experience with muscle biopsy in possible carriers and concluded that a more specific tissue marker is required before muscle biopsy can facilitate carrier identification.
Laporte et al. (2001) found that 87% (21/24) of patients with known MTM1 mutations showed reduced myotubularin levels in a variety of cell lines, as detected by immunoprecipitation followed by Western blot analysis. Four patients were diagnosed by immunoprecipitation before mutations in the MTM1 gene were identified. The authors suggested that this would be a rapid and helpful method for initial diagnosis of XLMTM.
Differential Diagnosis
Heckmatt et al. (1985) reported in detail on 8 unrelated children. They pointed out that the severity, mode of presentation and pedigree pattern permit definition of 3 types: a severe neonatal X-linked recessive type, a less severe infantile or juvenile autosomal recessive type (255200), and a yet milder autosomal dominant type (160150).
Wallgren-Pettersson et al. (1995) reviewed data relevant to the differential diagnosis of the X-linked, autosomal dominant, and autosomal recessive forms of myotubular myopathy. Whereas the X-linked recessive form is well documented, information is scantier on the autosomal dominant and autosomal recessive forms. No clear consensus exists regarding the use of the alternative names myotubular or central nuclear myopathy. Quantitative clinical differences existed between the 3 types, in regard to age at onset, severity of the disease, and prognosis, and also regarding some of the clinical characteristics. The autosomal dominant form had a later onset and milder course than the X-linked form, and the autosomal recessive form was intermediate in both respects. Wallgren-Pettersson et al. (1995) noted that determining the mode of inheritance and prognosis in individual families, especially those with a single male patient, poses a problem.
The families reported by Van Wijngaarden et al. (1969), Bradley et al. (1970), Meyers et al. (1974), Heckmatt et al. (1985), Keppen et al. (1987), Moerman et al. (1987), Oldfors et al. (1989), and Joseph et al. (1995) supported X-linked recessive inheritance.
Torres et al. (1985) reported the cases of 2 brothers with severe neonatal centronuclear myopathy and their mother who had evidence of a skeletal muscle, peripheral nerve, and brain-stem disorder. They suggested that all 3 had the same disorder inherited as an autosomal dominant with variable expressivity. The 2 brothers died at 4 days and 5 years of age. The authors noted that neonatal death or death in infancy occurs with the X-linked recessive form but has not been reported with the autosomal dominant form. McKusick (1985) thought it likely that this family was an instance of the X-linked recessive form with manifestations in a heterozygous female.
Germline mosaicism in the mother of boys with MTM1 was observed by Tanner et al. (1998), Vincent et al. (1998), and Hane et al. (1999). Hane et al. (1999) found that these 3 cases of germline mosaicism represented 23% of a total of 13 new mutations. They cited reports that germline mosaicism had been observed in 14% of new mutations in Duchenne muscular dystrophy (see 310200), 10% of new mutations in retinoblastoma (180200), and 19% of new mutations in facioscapulohumeral muscular dystrophy (see 158900).
In normal muscle, mature myofibers have peripherally placed nuclei, whereas only immature myotubes have nuclei centrally placed. Spiro et al. (1966) had suggested that the pathogenesis of this disorder is a failure of maturation. Additional evidence to support this hypothesis comes from demonstration of persistence of vimentin (193060) in centronuclear myopathy fibers (Sarnat et al., 1981), persistence of prenatal myosin heavy chains (Sawchak et al., 1991), and persistence of the N-CAM cell adhesion molecule (116930; Fidzianska et al., 1994). Sarnat (1990) and Sarnat (1992) demonstrated that both vimentin and desmin (125660) persist in the X-linked form; as a rule, this does not occur in the autosomal dominant form of the disorder.
Torres et al. (1985) reviewed evidence that the central and peripheral nervous systems are involved in this disorder.
Using cDNA microarray analysis, Noguchi et al. (2005) found that skeletal muscle from patients with genetically confirmed MTM1 had upregulation of transcripts for cytoskeletal and extracellular matrix proteins and downregulation of genes involved in energy metabolism, especially those involved in the glycolytic pathway. The authors suggested that increased remodeling of cytoskeletal and extracellular architecture within muscle fibers contributes to fiber atrophy and intracellular organelle disorganization seen in muscle biopsies from affected patients.
Williams et al. (1985) described preliminary family studies with DNA polymorphisms suggesting that the gene for myotubular myopathy is on Xp. From studies using DNA markers in 1 Welsh family and 1 Swiss family, however, the same group (Thomas et al. (1987, 1990)) found no recombination with 4 markers for Xq28, including those for colorblindness and factor VIII (300841). The maximum lod score was 3.74 at theta = 0.00 for one of the markers, and if the information from the other markers was included as a multipoint linkage analysis, the lod score became impressively high. Darnfors et al. (1989, 1990) added data bringing the combined maximum lod score to 5.12 at theta = 0.0. Starr et al. (1990) also found linkage to markers in band Xq28; no recombinants were found. Both Starr et al. (1990) and Thomas et al. (1990) quoted a personal communication from J. L. Mandel indicating the possibility of a second form of X-linked centronuclear myopathy determined by a gene at a site other than Xq26-qter. Liechti-Gallati et al. (1991) likewise mapped this disorder to Xq28 through linkage analysis of 8 families. They placed the gene close to F8C. Lehesjoki et al. (1990) found 1 recombinant, indicating that MTM1 is proximal to F8C.
Janssen et al. (1994) found a maximum 2-point lod score of 4.00 at theta = 0.0 for the marker DXS466. Three recombinations were found with other markers in this region, placing the XLMTM gene in the 8-Mb (11 cM) region between DXS297 and DXS134. Dahl et al. (1994) reported 2 new families with MTM1 that showed recombination with either DXS304 or DXS52. These families and a third, previously described recombinant family were analyzed with 2 highly polymorphic markers in the interval between the above 2 markers. No recombination with MTM1 and the VNTR DXS455 or the microsatellite DXS1684 was found. Together with the mapping of an interstitial X-chromosome deletion in a female patient with moderate signs of myotubular myopathy, these data allowed Dahl et al. (1994) to order the loci as a step toward positional cloning of the gene.
Dahl et al. (1995) provided further information concerning the patient with the interstitial deletion in Xq27-q28. Analysis of inactive X-specific methylation at the androgen receptor gene showed that the deleted X chromosome was active in approximately 80% of leukocytes. Unbalanced inactivation may account for the moderate MTM1 phenotype and the mental retardation that later developed in the patient. Comparison of this deletion with that carried by a male patient with a severe Hunter syndrome (309900) phenotype but no myotubular myopathy, in combination with linkage data on recombinant MTM1 families, led to a positional refinement of the MTM1 locus to a 600-kb region between DXS304 and DXS497.
Samson et al. (1995) reported a family with a single case of myotubular myopathy in which linkage analysis, combined with examination of muscle biopsies in females for a determination of carrier status, led them to 'strongly suggest genetic heterogeneity' of this X-linked disorder. Guiraud-Chaumeil et al. (1997) reanalyzed this family with markers closest to the MTM1 gene on Xq28 and used SSCP analysis on characterized exons to search for mutations in the proband. They identified a missense mutation in the proband (300415.0002) that was not present in his mother or in 3 other females who had been thought to be carriers on the basis of detection of some small fibers with centrally located nuclei in their muscle biopsies.
In a male with X-linked myotubular myopathy, Laporte et al. (1996) identified a missense mutation in the MTM1 gene (300415.0001). This was 1 of 4 missense mutations that, together with 3 frameshift mutations, were found in 7 of 60 MTM1 patients studied. Other mutations in the MTM1 were identified in X-linked MTM patients by de Gouyon et al. (1997), Laporte et al., 1997, Tanner et al. (1998), Buj-Bello et al. (1999), and Laporte et al. (2000).
Laporte et al. (2000) stated that 133 different mutations in the MTM1 gene had been identified as the cause of X-linked myotubular myopathy. They found that most truncating mutations caused a severe and early lethal phenotype, and that some missense mutations were associated with milder forms and prolonged survival, up to 54 years in the first reported family (Van Wijngaarden et al., 1969; Barth and Dubowitz, 1998).
Zanoteli et al. (2005) reported a male infant with a severe form of X-linked myotubular myopathy and a large deletion of the MTM1 gene encompassing exons 4-15. The patient also had deletion of the telomeric MTMR1 gene (300171). Although the authors considered the contiguous gene syndrome associated with abnormal genital development (300219), the patient only had cryptorchidism as an anomaly and showed expression of the F18 gene (MAMLD1; 300120), which is believed to be deleted in that disorder. Zanoteli et al. (2005) concluded that the severe phenotype in this child was due to the large deletion of the MTM1 gene and that the MTMR1 gene is not involved in early sexual development.
X-linked myotubular myopathy was proposed to result from an arrest in myogenesis, as the skeletal muscle from patients contains hypotrophic fibers with centrally located nuclei that resembled fetal myotubes (Spiro et al., 1966; Van Wijngaarden et al., 1969). To understand the pathophysiologic mechanism of XLMTM, Buj-Bello et al. (2002) generated mice lacking myotubularin by homologous recombination. These mice were viable, but their life span was severely reduced. They developed a generalized and progressive myopathy starting at approximately 4 weeks of age, with amyotrophy and accumulation of central nuclei in skeletal muscle fibers leading to death at 6 to 14 weeks of age. Buj-Bello et al. (2002) showed that muscle differentiation in knockout mice occurred normally, contrary to expectations. They provided evidence that fibers with centralized myonuclei originate mainly from a structural maintenance defect affecting myotubularin-deficient muscle rather than a regenerative process. In addition, they demonstrated through a conditional gene-targeting approach that skeletal muscle is the primary target of murine XLMTM pathology.
Dowling et al. (2009) observed that zebrafish with reduced levels of myotubularin had significantly impaired motor function and obvious histopathologic muscle changes, including abnormally shaped and positioned nuclei and myofiber hypotrophy, as observed in the human disease. Loss of myotubularin caused increased phosphatidylinositol 3-phosphate (PI3P) levels in muscle in vivo. Morpholino knockdown of Mtm1 in zebrafish muscle resulted in abnormalities in the T-tubule and sarcoplasmic reticulum network, similar to T-tubule disorganization observed in skeletal muscle biopsies from patients with myotubular myopathy. Expression of the homologous myotubularin-related proteins Mtmr1 (300171) and Mtmr2 (603557) could functionally compensate for the loss of myotubularin in zebrafish. Dowling et al. (2009) suggested that XLMTM may be linked mechanistically by tubuloreticular abnormalities and defective excitation-contraction coupling to myopathies caused by mutations in the RYR1 gene (180901).
Cowling et al. (2014) found a 1.5-fold increase in DNM2 (602378) expression in muscle biopsies isolated from human patients with CNMX and in heterozygous Mtm1 -/y mice compared to controls. Crossing Mtm1 -/y with Dnm2 +/- mice resulted in increased survival and greatly improved muscle strength, suggesting that reduced expression of the Dnm2 gene can rescue the early lethality observed in Mtm1 -/y mice. Skeletal muscle from the double-mutant mice showed decreased or even rescued atrophy compared to Mtm1 -/y mice, and histologic abnormalities such as fiber atrophy and nuclei mispositioning were absent or reduced in the double-mutant mice. Ultrastructural analysis showed improvement of sarcomere organization and triad structures. In addition, muscle-specific reduction of Dnm2, particularly in the diaphragm, was sufficient to rescue the lethal phenotype even after birth and the onset of symptoms. The findings indicated that MTM1 and DNM2 regulate muscle organization and force through a common pathway, and suggested that MTM1 may act as a negative regulator of DNM2. Cowling et al. (2014) concluded that reduction of DNM2 protein levels may provide a therapeutic approach for patients with CNMX.
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