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 ... 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.
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 ... 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.
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 ... 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 (CXORF6; 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.
The diagnosis of X-linked centronuclear myopathy (XLCNM) (also known as myotubular myopathy [MTM]) should be considered in any male with significant neonatal hypotonia and muscle weakness or in older males with diminished muscle bulk and extremity weakness particularly if any of the following are present:...
DiagnosisClinical DiagnosisThe diagnosis of X-linked centronuclear myopathy (XLCNM) (also known as myotubular myopathy [MTM]) should be considered in any male with significant neonatal hypotonia and muscle weakness or in older males with diminished muscle bulk and extremity weakness particularly if any of the following are present:A positive family history suggestive of X-linked inheritance (found in approximately 30% of reported individuals) Length and head circumference greater than the 90th centile, cryptorchidism, and/or long fingers and toes Involvement of the extraocular muscles (i.e. ophthalmoparesis)TestingMuscle BiopsyAffected Males Histopathologic findings:The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. No diagnostic threshold of central nuclei has been established, as the percentage may increase over time. In rare instances, centrally located nuclei may be absent [de Goede et al 2005, Pierson et al 2007]. Periodic acid-Schiff (PAS) and nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase histochemical staining often demonstrate an accumulation of staining product in the center of the small myofibers, which reflects maldistribution of glycogen and mitochondria, respectively [Pierson et al 2005, Romero 2010]. ATPase histochemical staining may show type 1 myofiber predominance or small type 1 and type 2A fibers alongside relatively larger type 2B fibers [Pierson et al 2005]. In some biopsies ATPase staining demonstrates myofibers with central clearing that results from a focal absence of myofibrils [Pierson et al 2005, Romero 2010]. The histopathologic findings listed are not specific to XLCNM and may be encountered in congenital myotonic dystrophy type 1 (see Differential Diagnosis) and in early onset autosomal forms of centronuclear myopathy. XLCNM with a low percentage of central nuclei and type 1 fiber predominance can also resemble congenital fiber type disproportion [Pierson et al 2005]. Note: (1) The clinical and histopathologic features of MTM1-associated myopathies are broad, requiring that a distinction be made between central and internal nuclei [Romero 2010]. The former occur at (or very near) the exact center of a myofiber and are typical of (although not specific for) XLCNM, whereas the latter are eccentrically situated within the myofiber. (2) Necklace fibers are a distinctive feature that has been described in sporadic late-onset MTM1-related XLCNM. Necklace fibers appear on hematoxylin-eosin stained sections as a basophilic ring-like deposit that follows the contour of the myofiber and aligns with internal myonuclei [Bevilacqua et al 2009]. They can also be visualized with succinate dehydrogenase histochemical staining [Bevilacqua et al 2009]. Necklace fibers may be accompanied by muscle hypotrophy and type 1 fiber predominance. The percentage of myofibers with internal nuclei frequently exceeds the percentage of fibers with central nuclei and both tend to increase with age. (3) Biopsies from older individuals may feature increased connective and adipose tissues. Immunohistochemical stains on most (not all) muscle samples from individuals with XLCNM demonstrate persistence of fetal-specific muscle proteins or isoforms such as desmin, vimentin, and fetal myosin [Sarnat 1990, Sewry 1998]. Variation in the immunohistochemical expression of NCAM, utrophin, laminin, alpha 5, and HLA1 antigen has also been described [Helliwell et al 1998]. The clinical utility of these immunostains has not been systematically studied. T-tubule disorganization visualized through immunohistochemistry has been recently described in XLCNM [Al-Qusairi et al 2009, Dowling et al 2009]. DHPRa1, a T-tubule protein, and RyR1, a sarcoplasmic recticulum protein, are abnormally distributed in myofibers with increased immunoreactivity appearing in the center of small fibers [Dowling et al 2009]. Since other centronuclear myopathies also have T-tubule defects the diagnostic utility of this finding may be limited [Toussaint et al 2011]. Immunologic testing using antibodies specific for myotubularin, the protein encoded by MTM1 [Laporte et al 2001b], can detect the presence or absence of myotubularin in cell lines from affected individuals. In 21/24 males with known mutations, including some missense mutations, no myotubularin was detected on western blot. One out of five boys with suspected XLCNM in whom no mutation was identified also had no detectable protein by western analysis. Tosch et al [2010] demonstrated the absence of detectable protein in eight affected individuals with severe to intermediate phenotypes and a decreased amount of protein in an individual with a mild phenotype. Eight of nine individuals had confirmed MTM1 mutations; one individual had no detectable protein and an intermediate phenotype, but no MTM1 mutation was detected. While immunologic testing may be helpful in some individuals with suspected XLCNM in whom no mutation is found, such analysis is not routine, and adequate antibodies to myotubularin are not widely available. Carrier FemalesAn abnormal muscle biopsy is found in 50%-70% of obligate carrier females [Wallgren-Pettersson et al 1995]; thus, muscle biopsy studies are not sensitive enough for carrier testing. Molecular Genetic TestingGene. MTM1 is the only gene in which mutations are known to cause XLCNM [Wallgren-Pettersson 2000].TestingSequence analysis of the 15 coding exons and flanking intron sequence [de Gouyon et al 1997, Laporte et al 1997] is available clinically. In several series, mutations were detected in 60%-90% of individuals with XLCNM [de Gouyon et al 1997, Laporte et al 1997, Herman et al 2002, Tsai et al 2005]. In individuals with mild XLCNM, fewer than 20% of mutations are identified [Bertini et al 2004] and may reflect the involvement of additional genes. Mutation scanning techniques generally yield a mutation detection rate of 60%-90% [Wallgren-Pettersson 1998, Tanner et al 1999b, Flex et al 2002]. Tanner et al [1999b] reported a mutation detection rate of 97%-98% using heteroduplex analysis. Their higher detection rate may reflect a more stringent selection of affected individuals as well as screening for non-coding mutations. Deletion/duplication analysis. Approximately 7% of mutations are large deletions of one or more exons of MTM1 [Laporte et al 2000]. Gene sequencing and mutation scanning methods may detect such deletions in males (Table 1, footnote 4); however, these methods cannot detect deletions in female carriers. Methods such as real-time quantitative PCR or targeted array CGH can be used to detect specific deletions in carrier females or in rare affected females once the deletion is identified in an affected male relative. The occurrence of at least one deep intronic mutation detected by cDNA and protein analysis has been described [Tosch et al 2010]. Complementary DNA and protein analysis can be performed to detect intronic and non-coding mutations.Table 1. Summary of Molecular Genetic Testing Used in X-Linked Centronuclear MyopathyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesHeterozygous FemalesMTM1Sequence analysis / mutation scanning 2Sequence variants 360%-98% 4, 553%-98% 6ClinicalDeletion / duplication analysis 7Deletion / duplication of one or more exons or the whole gene7%7%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.4. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. 5. Includes the mutation detection frequency using deletion/duplication analysis.6. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.If no mutation is found in a male proband, the diagnosis of XLCNM cannot be completely excluded. The failure to detect mutations in approximately 10%-40% of males in whom the diagnosis of XLCNM was suspected, including several males with pedigrees consistent with an X-linked pattern of inheritance [Tanner et al 1999b, Copley et al 2002, Herman et al 2002, Bertini et al 2004, Tsai et al 2005], could reflect one of the following:Misdiagnosis Autosomal dominant or autosomal recessive centronuclear myopathy Presence of mutations in MTM1 regulatory or intronic sequences that may have been missed by the mutation detection protocols used Linkage analysis for families in which no MTM1 mutation has been identified. Normal allelic variants within the gene have been identified (see Molecular Genetics) and can be used for linkage analysis; however, linkage analysis is not the method of choice for genetic testing and should be undertaken with extreme caution for the following reasons: An autosomal form of myotubular myopathy could be present. Even in families with an X-linked pattern of inheritance, it is remotely possible that mutation in another X-linked gene are causative. Testing StrategyTo confirm/establish the diagnosis in a male proband. In males with a “typical” clinical presentation (neonatal hypotonia and weakness), the diagnosis of XLCNM relies on:The observation of characteristic histopathologic changes on muscle biopsy, followed byGenetic testing of MTM1. If MTM1 sequencing is unrevealing, genetic studies for the other known causes of CNM should be undertaken (see Differential Diagnosis). If additional more specific clinical characteristics exist (e.g., large growth parameters and restricted eye movements), molecular genetic testing may precede biopsy, especially if family history is consistent with X-linked inheritance. In infants with a less specific presentation, in older males with mild weakness, and in those individuals without a clear family history, muscle biopsy is considered the test of choice, with molecular genetic testing to follow if the typical biopsy features of centronuclear myopathy are observed. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutation in the family.Carrier females Carrier testing for a large deletion of MTM1 requires deletion/duplication analysis (e.g., real-time quantitative PCR or Southern blot analysis). In families in which the proband is deceased and no DNA from an affected male is available for molecular genetic testing, the mother of the deceased proband can be tested to try to identify the family-specific mutation and, hence, to determine her carrier status. Because of the high probability that the mother of an affected male is a carrier (see Risk to Family Members), the likelihood of identifying an MTM1 mutation is high. However, if no mutation is identified by sequence analysis and deletion/duplication analysis, the presence of either germline mosaicism for an MTM1 mutation or a mutation in a non-coding region remain possibilities. Thus, if an MTM1 mutation is not identified in the mother, prenatal diagnosis by full gene sequencing of MTM1 in a male fetus may still be considered. Note: (1) Carriers are heterozygotes for this X-linked disorder and in rare instances may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, if an affected male is not available for testing, (b) molecular genetic testing usually first by sequence analysis, and then (if no mutation is identified) by methods to detect deletions/duplications.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other phenotype is known to be associated with mutations in MTM1.Contiguous gene deletion. Deletions of the entire MTM1 gene were initially identified in two males [Hu et al 1996] and one female [Dahl et al 1995] who had clinical features in addition to those seen in XLCNM as a result of deletion of adjacent X-linked genes: One of the two males had ambiguous genitalia, the other perineoscrotal hypospadias [Hu et al 1996]. They had overlapping submicroscopic deletions defining a critical region of approximately 430 kb that was expected to contain MTM1 as well as a novel gene implicated in male sexual development. The latter gene was subsequently identified [Laporte et al 1997] and lies 80 kb centromeric to MTM1. Three of four subsequently described males with large deletions involving all of MTM1 and flanking genes had hypogenitalism [Bartsch et al 1999, Biancalana et al 2003, Tsai et al 2005]. The female reported by Dahl et al [1995] had a cytogenetically visible deletion that also included the loci for fragile X syndrome and Hunter syndrome. She had a moderate myopathy as well as intellectual disability. Her symptoms were presumed to result from preferential inactivation of her normal X chromosome, as the deleted X chromosome was active in approximately 80% of her leukocytes.
Two large published clinical series have described, respectively, 37 and 55 males with XLCNM [Wallgren-Pettersson et al 1995, Herman et al 1999]. In the latter series, the X-linked form of CNM was confirmed in all of the reported individuals through direct molecular genetic testing of MTM1. ...
Natural HistoryTwo large published clinical series have described, respectively, 37 and 55 males with XLCNM [Wallgren-Pettersson et al 1995, Herman et al 1999]. In the latter series, the X-linked form of CNM was confirmed in all of the reported individuals through direct molecular genetic testing of MTM1. Following isolation of MTM1 in 1996, Herman et al [1999] described a clinical classification for the broader phenotype. Individuals with MTM1 mutations were classified as having one of the following:Severe (classic) XLCNM. Characteristic facies, chronic ventilator dependence, grossly delayed motor milestones, non-ambulatory, high incidence of death in infancy Moderate XLCNM. Less severely delayed motor milestones than in the severe form, prolonged periods of decreased ventilatory support Mild XLCNM. Ambulatory with minimally delayed motor milestones, chronic ventilatory support not required beyond the newborn period, potential absence of typical myopathic facies Since publication of the phenotypic classification by Herman et al [1999], an adult-onset form has been reported in two males with MTM1 mutations who had no clinical manifestations in infancy but developed a slowly progressive myopathy in adulthood [Biancalana et al 2003, Yu et al 2003, Hoffjan et al 2006]. This phenotype is likely to be very rare. Severe/Classic XLCNM In males with the classic, severe neonatal presentation, polyhydramnios with decreased fetal movement is often present prenatally. Typically, however, the disease presents with hypotonia, extremity weakness, and respiratory distress during the newborn period. Hypotonia and weakness in the neonatal period, while not specific to XLCNM, appear to be universal findings. In addition, in the US series of Herman et al [1999], 80% of affected newborns required endotracheal intubation and ventilatory support at birth. Infants with classic XLCNM have prolonged ventilator dependence with risk of intercurrent respiratory infection, hypoventilation, and hypoxia. Affected infants often have typical myopathic facies with dolicocephaly, high forehead, long face with midface hypoplasia, and narrow high-arched palate with subsequent severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features in the US series included length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism (>50%), contractures including clubfeet (30%), and areflexia (60%). Many infants with XLCNM severe/classic form succumb to complications of the disorder. For surviving infants in the US, the average length of initial hospitalization is approximately 90 days. Most surviving males in the United States are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy (G-tube) feedings.The muscle disease is not thought to be progressive, though this has not been systematically examined.Although the prognosis for this disorder had long been considered grave, 64% of males in the US series survived to at least age one year. Approximately 60% of this group required ventilatory support 24 hrs/day, 20% required support for eight to 18 hrs/day, and 20% did not require or were not receiving any ventilatory support. Long-term survival rates in Europe have been lower and could reflect differences in management and supportive care. The increase in survival rate seen in the US series is thought to be reflective of intensive medical intervention, without which the majority of affected individuals would not survive [McEntagart et al 2002]. Children who survive the first year of life continue to have significant morbidity and early mortality. The cause of death is usually related to respiratory failure.Growth and development. Despite chronic illness and prolonged ventilator dependence, many individuals with XLCNM have linear growth above the 50th centile, with some individuals in the US series achieving greater than the 90th centile for height. Advanced bone age and/or premature adrenarche have been documented in several young males, suggesting some disturbance of endocrine regulation; however, endocrinologic studies performed on several individuals have been normal. Puberty has occurred normally in the few males who have reached adulthood. In the absence of significant hypoxic episodes, cognitive development is normal in the majority of individuals. Rare individuals with central nervous system complications have been reported [McCrea et al 2009].Other findings. Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Scoliosis often develops in later childhood and may require surgical intervention. Scoliosis can exacerbate respiratory insufficiency, in some cases causing ventilator-independent males to become ventilator dependent again as it progresses. Additional orthopedic manifestations include hip dysplasia and, as observed in a small case series, long bone fractures [Cahill et al 2007].Medical problems. With more aggressive supportive care and longer survival of some individuals with XLCNM, medical problems unrelated to the muscle disorder, including pyloric stenosis, a mild form of spherocytosis, gallstones, kidney stones or nephrocalcinosis, a vitamin K-responsive bleeding diathesis, and liver dysfunction manifested by pruritus and elevated serum transaminases, have occurred [Herman et al 1999].Several individuals died following prolonged liver hemorrhage or hemorrhage into the peritoneal cavity. Three individuals had peliosis hepatis, a rare vascular lesion characterized by the presence of multiple blood-filled cysts within the liver [Herman et al 1999, Wang et al 2001]. Several additional boys with XLCNM have had liver dysfunction, peliosis, or hemorrhage into the peritoneum [Herman, personal observation]. The pathogenic mechanisms for these complications are not understood, but their lack of occurrence in other congenital myopathies and similarly severe neuromuscular disorders (including especially spinal muscular atrophy) strongly suggest that they are related to abnormal function of or absence of myotubularin. Those at increased risk for these complications cannot be identified by clinical features or mutation at the present time. In at least one affected individual, findings of peliosis detected on ultrasound examination subsequently resolved. Several families have also reported this feature in their affected children [personal observation]. Mild and Moderate XLCNM At least three reports of multigenerational families with MTM1 mutations and a much milder phenotype have been described [Barth & Dubowitz 1998, Biancalana et al 2003, Yu et al 2003, Hoffjan et al 2006]. Males with moderate or even mild disease are at increased risk for respiratory decompensation with intercurrent illness and may require transient or increased ventilatory support. They are also at risk for some of the same medical complications (including peliosis hepatis) as those with severe XLCNM [Herman et al 1999].The oldest known individuals with mutations in MTM1 are in their sixties [Biancalana et al 2003, Hoffjan et al 2006]. The first is a 67-year-old male who did not have significant respiratory problems or hypotonia in infancy and who first walked at age 18 months [Biancalana et al 2003]. The first symptom was diffuse muscle weakness at age 20 years, resulting in walking difficulties and scapular winging. He needed a tracheotomy to manage bronchopneumonia at age 55 years and now requires respiratory support during the night. He is reported to have a similarly affected 48-year-old brother and two grandsons, ages five and 13 years respectively, both of whom demonstrated hypotonia, respiratory difficulties at birth, some delay in motor development, and muscle weakness; however, both are able to walk and attend regular school. The second is a 68-year-old male who reported no significant delay in his early motor development and had mild hypotonia during childhood. At about age 52 years he developed slowly increasing muscular weakness in his arms and had difficulties climbing stairs. At age 65 years he suffered from a severe pneumonia that was accompanied by an acute exacerbation of muscle weakness. A muscle biopsy at that time demonstrated typical features of centronuclear myopathy. Clinical examination at age 68 years revealed a slightly myopathic facial expression, mild paresis of horizontal eye movements, a high palatal arch, mild scapular winging and prominent wasting and weakness of proximal muscles. This individual was diagnosed after his grandson, who had a severe phenotype including muscular weakness and respiratory problems at birth, was determined to have XLCNM. Yu et al [2003] described two males with a mutation in MTM1, age 55 and 30 years, both of whom live independently. The 30-year-old developed some muscle weakness later in life and had decreased muscle bulk that was improved by diet and weight-lifting exercises.Carrier females. Female carriers of XLCNM are generally asymptomatic, although rare manifesting heterozygotes have been described [Tanner et al 1999a, Tanner et al 1999b, Hammans et al 2000, Wallgren-Pettersson 2000, Sutton et al 2001, Jungbluth et al 2003, Schara et al 2003, Grogan et al 2005, Penisson-Besnier et al 2007]. Manifesting female carriers typically have skewed X-chromosome inactivation [Kristiansen et al 2003].
Genotype-phenotype correlations have been observed in XLCNM, but no definitive pattern exists and exceptions have been reported. Phenotypic variability has been observed in family members with the same mutation [Barth & Dubowitz 1998, Laporte et al 2000] and in unrelated individuals with recurrent mutations [McEntagart et al 2002]. General genotype-phenotype guidelines have emerged nonetheless, but caution is warranted in using genetic testing to predict an individual’s prognosis. ...
Genotype-Phenotype Correlations Genotype-phenotype correlations have been observed in XLCNM, but no definitive pattern exists and exceptions have been reported. Phenotypic variability has been observed in family members with the same mutation [Barth & Dubowitz 1998, Laporte et al 2000] and in unrelated individuals with recurrent mutations [McEntagart et al 2002]. General genotype-phenotype guidelines have emerged nonetheless, but caution is warranted in using genetic testing to predict an individual’s prognosis. Practically all truncating (nonsense and frameshift) mutations and mutations that alter splice sites are associated with severe disease. However, exceptions occur; for example:Recurrent nonsense mutations (e.g., p.Arg37X and p.Glu48X) most often associated with the severe phenotype have been described in individuals with the moderate phenotype [Laporte et al 1997, Buj-Bello et al 1999, Herman et al 1999, Tanner et al 1999b, Laporte et al 2000, Herman et al 2002, McEntagart et al 2002]. Truncating and splicing mutations that affect the 3' end of MTM1, which encodes parts of myotubularin that are distal to the phosphatase active site and SET-interacting domain, may also be associated with the moderate or mild phenotypes [Herman et al 1999, Laporte et al 2000]. Splicing mutations that do not affect the canonical splice donor or acceptor sites and that may result in the production of some normal MTM1 transcript have also been observed in individuals with a milder phenotype [Tsai et al 2005].Deletions have been described in some males with XLCNM who also have abnormal genitalia. These cases likely represent a contiguous gene deletion syndrome in which a gene critical to male genital development was co-deleted with MTM1 [Hu et al 1996, Bartsch et al 1999] (see Genetically Related Disorders). Missense mutations Missense mutations that occur in the phosphatase active site or the SET-interacting domain of myotubularin are associated with a severe phenotype [McEntagart et al 2002].Missense mutations that alter amino acids conserved across species or in human myotubularin-related genes are associated with a severe phenotype [Laporte et al 2001a]. Missense mutations that avoid the phosphatase active site or the SET-interacting domain of myotubularin tend to be associated with less severe phenotype [Herman et al 1999, Laporte et al 2000, Herman et al 2002, McEntagart et al 2002]. Wide phenotypic variation has been observed for some missense mutations (e.g., p.Ile225Thr, p.Arg241Cys, p.Arg421Gln) for which severely and mildly affected individuals are known, and phenotypic variability has even been described within families [Tanner et al 1999b, Buj-Bello et al 1999, de Gouyon et al 1997]. Additional missense mutations that have been found in individuals with both severe and mild phenotypes include p.Pro205Leu and p.Arg69Cys [de Gouyon et al 1997, Laporte et al 1997, Herman et al 2002, Cox et al 2005, Tsai et al 2005]. Seven recurrent mutations account for approximately 25% of all MTM1 mutations [Tanner et al 1999b, Laporte et al 2000, Herman et al 2002, McEntagart et al 2002, Bertini et al 2004, Tsai et al 2005]: The most common is the c.1261-10A>G mutation in intron 11, which produces an in-frame insertion of three amino acids associated with the severe phenotype in all cases. Confirmation of this mutation has been performed by RT-PCR in lymphoblasts [de Gouyon et al 1997] and muscle tissue [Nishino et al 1998, Tanner et al 1998]. The high rate of occurrence of this mutation remains unexplained. The mutations c.141-144delAGAA, p.Arg37X, p.Pro205Leu, p.Arg421Gln, and p.Arg421X are mainly associated with the severe form of the disease; the mutation p.Arg421Cys is associated with a mild or variable phenotype [Bertini et al 2004].
Congenitalmyotonic dystrophy type 1(DM1) is the most likely differential diagnosis for a male with severe XLCNM. Like XLCNM, congenital DM1 may present in utero with polyhydramnios and with weak or infrequent fetal movements. At birth, affected infants are weak, hypotonic, have a myopathic facies, and often require ventilatory support. Hypotonia and myopathy gradually improve, though neonatal mortality as a result of respiratory failure occurs in a significant minority of cases. Children with congenital DM1 may stabilize for many years, but continue to have significant co-morbidities including a high incidence of intellectual disability (50%-60%). Muscle biopsies from infants with congenital DM1 may be indistinguishable from those in infants with XLCNM [Dubowitz & Sewry 2006]. The diagnosis of congenital DM1 is confirmed by identification of more than 1000 CTG repeats in DMPK. The CTG expansion is often more than 2000 repeats in length and, in the severe congenital cases, virtually always inherited from the mother, who may or may not be symptomatic. ...
Differential DiagnosisCongenital myotonic dystrophy type 1(DM1) is the most likely differential diagnosis for a male with severe XLCNM. Like XLCNM, congenital DM1 may present in utero with polyhydramnios and with weak or infrequent fetal movements. At birth, affected infants are weak, hypotonic, have a myopathic facies, and often require ventilatory support. Hypotonia and myopathy gradually improve, though neonatal mortality as a result of respiratory failure occurs in a significant minority of cases. Children with congenital DM1 may stabilize for many years, but continue to have significant co-morbidities including a high incidence of intellectual disability (50%-60%). Muscle biopsies from infants with congenital DM1 may be indistinguishable from those in infants with XLCNM [Dubowitz & Sewry 2006]. The diagnosis of congenital DM1 is confirmed by identification of more than 1000 CTG repeats in DMPK. The CTG expansion is often more than 2000 repeats in length and, in the severe congenital cases, virtually always inherited from the mother, who may or may not be symptomatic. Other centronuclear myopathies. Myotubular myopathy is the most common form of a broader group of myopathies termed centronuclear myopathies (CNMs) [Pierson et al 2005]. Individuals with CNMs share common muscle biopsy features, most particularly the presence of central nuclei in affected skeletal muscle. Individuals with CNM unrelated to MTM1 mutations tend to have less severe clinical symptomatology and do not typically exhibit the abnormal growth parameters seen in males with XLCNM. However, individuals with an “XLCNM-like” presentation and mutations in BIN1, DNM2, or RYR1 have been reported (see following). Thus these genetic causes must be considered in children with the clinical and pathologic picture of XLCNM who do not have mutations in MTM1. Of note, the genetic basis for a fraction of individuals with CNM is as yet unknown. Newly identified CNM-related gene mutations will add to the differential diagnosis of XLCNM in the future. DNM2-related CNM [Bitoun et al 2005, Bitoun et al 2007, Susman et al 2010]. Mutations in DNM2 are the second most common cause of CNM (after MTM1). DNM2 mutations are either de novo (usually in severe cases) or inherited in an autosomal dominant manner. Several children with neonatal onset of hypotonia and weakness (particularly with mutations in the PH domain of DNM2) have been reported [Bitoun et al 2007, Susman et al 2010]. DNM2-related CNM may be distinguished by the presence of “spoke on wheel” changes with oxidative stains on muscle biopsy [Romero 2010]. Of note, progression of weakness has been observed during the teen years and in adulthood in several individuals with DNM2 mutations [Melberg et al 2010, Susman et al 2010].RYR1-related CNM [Wilmshurst et al 2010]. Mutations in the skeletal muscle ryanodine receptor have been reported in individuals with CNM, including in one boy originally diagnosed with XLCNM. Mutations in RYR1 associated with CNM are most often inherited in an autosomal recessive manner and associated with diminished expression of the RyR1 protein. Affected individuals with heterozygous RYR1 mutations have also been identified. Of note, the vast majority of RYR1 mutations are associated with myopathies with cores (central core disease and minicore myopathy).BIN1-related CNM [Nicot et al 2007]. Autosomal recessive mutations in BIN1 have been described in a small group of individuals. The range of clinical severity is broad, though presentation in infancy has been reported [Mejaddam et al 2009].Other congenital myopathies (for a review, see Sewry et al [2008]). Myotubular myopathy falls into the broad clinical classification of congenital myopathies. In general, each subtype of congenital myopathy is distinguished by characteristic features on muscle biopsy. However, initial biopsies in individuals with congenital myopathies, especially if taken in the first year of life, may not show the signature changes and may instead have nonspecific changes. Therefore, particularly in infancy, other congenital myopathies, including especially nemaline myopathy and the subset of individuals with minicore myopathy who have ophthalmoparesis, must be considered on the differential diagnosis. Clinical features that are helpful for distinguishing XLCNM from other congenital myopathies include ophthalmoparesis, length greater than 90th percentile, and elongated features (facial and hands/feet). Congenital myasthenic syndromes (CMS) (for review, see Engel [2008] and Palace & Beeson [2008]). Though rare, it is important to consider congenital myasthenic syndromes in boys being evaluated for myotubular myopathy; many infants with CMS will respond to medications that improve neuromuscular junction function.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with X-linked centronuclear myopathy (XLCNM), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with X-linked centronuclear myopathy (XLCNM), the following evaluations are recommended:Assessment of pulmonary function for long-term ventilatory management, either during initial hospitalization (if presentation at birth) or after the diagnosis has been established. Ophthalmologic evaluation, either during initial hospitalization (if presentation at birth), or after the diagnosis has been established In individuals with hemolysis or unexplained anemia, osmotic fragility test to detect spherocytosis In the presence of infantile vomiting, investigation for pyloric stenosis Baseline abdominal ultrasound examination to detect peliosis hepatis (although the specific risk for subsequent bleeding if peliosis is detected is not known) Treatment of ManifestationsManagement of individuals with XLCNM is based on supportive care measures and in large part is similar to that for other neuromuscular disorders. The management of an individual with XLCNM optimally involves a team of specialists with expertise in the long-term care of individuals with neuromuscular disorders. Such teams often include a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and medical geneticist. Of note, standard of care measures for all congenital myopathies are currently being developed. Once the specific diagnosis of XLCNM is confirmed, management may be guided by family decisions regarding continued ventilatory support for the affected family member. Families may benefit from the involvement of professionals familiar with the data concerning the overall prognosis for XLCNM. Talking with other families who have children with the disorder can be extremely helpful (see Resources).Because of the risks for aspiration pneumonia and respiratory failure in infants with moderate or severe disease, tracheostomy and G-tube feeding should be seriously considered. Even individuals with mild disease are at risk for significant morbidity and mortality from intercurrent respiratory infection and hypoventilation.For ventilator-dependent individuals, communication incorporates speech with a capped tracheostomy or Passy-Muir valve, sign language, and/or communication devices such as writing boards.Affected individuals older than age five years attend school, usually assisted by a dedicated nurse or aide, or have home-based teachers to limit exposure to infectious agents.Ophthalmologists, orthopedists specializing in scoliosis management, and orthodontists should address specific medical complications related to the underlying myopathy.Children with XLCNM and an unexpected decline in motor skills should be evaluated for a potential abnormality in neuromuscular junction function. A recent study from Robb et al [2011] identified one individual with mild XLCNM and unexplained decline in motor skills (i.e., lost ambulation) consistent with a disorder of neuromuscular junction transmission. On evaluation this individual was found to have the electrodiagnostic features of neuromuscular junction disease (electrodecrement with repetitive stimulation and jitter with single fiber EMG) but no laboratory evidence to support a co-occurring diagnosis of myasthenia gravis. Subsequent treatment with pyridostigmine resulted in rapid recovery of ambulation. Prevention of Secondary ComplicationsBecause of the risks for bleeding during or following surgery, clotting parameters should be examined prior to any surgical procedures. (Note, however, that clotting studies in two individuals were normal prior to a lethal bleeding event associated with surgery.)SurveillanceAppropriate surveillance includes:Annual pulmonary assessment, including pulmonary function testing if able to be performed;Polysomnography every one to three years unless symptoms of sleep-disordered breathing are present on history;Spinal examination for signs of scoliosis, particularly in late childhood and adolescence; Annual ophthalmologic exams for ophthalmoplegia, ptosis, and myopia; Assessment for dental malocclusion, with referral for orthodontia if indicated. Currently, the risk for non-neurologic events including bleeding diatheses and gastrointestinal complications is uncertain. Furthermore, the benefit of screening tests for such abnormalities has yet to be determined or systematically studied. Potential screening tests include the following:Annual blood counts [Herman et al 1999] Annual liver function test and abdominal ultrasound to address the potential risk of peliosis hepatis [Herman et al 1999] Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Centronuclear Myopathy, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDMTM1Xq28MyotubularinMTM1 homepage - Leiden Muscular Dystrophy pagesMTM1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Centronuclear Myopathy, X-Linked (View All in OMIM) View in own window 300415MYOTUBULARIN; MTM1 310400MYOPATHY, CENTRONUCLEAR, X-LINKED; CNMXNormal allelic variants. MTM1 is approximately 90 kb in size and comprises 15 exons. The first exon is non-coding and encompasses the putative promoter region of the gene. The start codon is present in exon 2. The gene is ubiquitously expressed and shows a muscle-specific alternative transcript because of the use of a different polyadenylation signal [Laporte et al 1996]. To date, approximately 20-23 different normal allelic variants have been identified in MTM1 [Laporte et al 2000; Herman et al 2002; Das, personal communication]. The polymorphic changes that have been identified are thought not to be disease causing, as they have been found either in individuals in whom a clearly deleterious mutation is also present or in individuals without the disease. The majority of changes identified represent rare variants, with the exception of c.1260+3G>A, which occurs at a frequency of approximately 50% [Laporte et al 2000]. Pathologic allelic variants. Approximately 230 different mutations that cause X-linked centronuclear myopathy have been described [Laporte et al 2000, Herman et al 2002, Biancalana et al 2003, Bertini et al 2004, Tsai et al 2005, Human Gene Mutation Database (HGMD)]. Mutations are evenly distributed throughout the gene with no hot spots. While some mutations appear to be recurrent, no predominant common mutation has been identified in any population. Table 2. Selected MTM1 Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change Reference SequencesNormalc.1260+3G>ANANM_000252.2 NP_000243.1Pathologicc.109C>Tp.Arg37Xc.142G>Tp.Glu48Xc.205C>Tp.Arg69Cysc.141_144delAGAA p.Glu48Leufs*24c.614C>Tp.Pro205Leuc.674T>Cp.Ile225Thrc.721C>Tp.Arg241Cysc.1261C>Tp.Arg421Xc.1262G>Ap.Arg421Glnc.1261-10A>GNASee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). NA = not applicableNormal gene product. MTM1 encodes myotubularin, a protein of 603 amino acids [Laporte et al 1996, Laporte et al 1998b]. Myotubularin was originally characterized as a protein tyrosine phosphatase [Laporte et al 1998a], but was subsequently found instead to function primarily as a lipid phosphatase [Taylor et al 2000], specifically acting to remove phosphates from the 3-position of phosphoinositides. Studies using both cell-free biochemical assays and forced exogenous expression in cell culture have shown that myotubularin converts phosphoinositide-3-phosphate (PI3P) to phosphoinositide phosphate (PIP) and phosphoinositide-3,5-bisphosphate (PI3,5P2) to phosphoinositide-5-phosphate (PI5P) [Taylor et al 2000, Chaussade et al 2003, Robinson & Dixon 2006]. Myotubularin’s cellular function is inferred in part from the known roles of the phosphoinositides (PIs) upon which it acts [Dowling et al 2008]. Based on the localization and function of PI3P and PI3,5P2, myotubularin is presumed to be a critical regulator of endosomal dynamics [Clague & Lorenzo 2005]. Support for this role comes from a series of in vitro studies. Using both anti-myotubularin antibodies and expression-tagged myotubularin constructs, studies have found that the protein localizes to endosomes in a variety of cell types [Laporte et al 2002, Tsujita et al 2004, Cao et al 2007]. Overexpression or siRNA knockdown of myotubularin results in altered PI3P levels and interruption of the normal traffic between endosomes and lysosomes. It also causes abnormalities in the recycling of internalized receptors. The prevailing hypothesis concerning myotubularin function is that the protein helps control the flow of membranes through the endosomal compartment by rapidly removing PI3P and PI3,5P2 and altering the profile of bound effector molecules on the relevant membrane subdomains [Dowling et al 2008]. How this function relates to the role of MTM1 in skeletal muscle is currently unknown.Myotubularin likely has roles in other cellular processes as well. Much of the protein does not localize to endosomes, but is instead at steady state in a dense cytoplasmic network and can be found transiently at Rac-induced membrane ruffles [Laporte et al 2002]. It has been recently shown to interact with the intermediate filament network and specifically with desmin [Hnia et al 2011]. This interaction may both mediate myotubularin localization and also enable myotubularin to participate as a regulator of mitochondrial dynamics.Myotubularin was the first described member of a large group of homologous, evolutionarily conserved proteins. To date, 14 myotubularin-related (or MTMR) proteins have been characterized [Robinson & Dixon 2006]. Eight of the 14 have dual specificity phosphatase activity identical to myotubularin. The remaining six have non-functional phosphatase domains, and are thought to act as co-activators or regulators of the enzymatically active members of the family. For example, myotubularin interacts directly with the non-catalytic MTMR12 [Lorenzo et al 2006]. Like myotubularin, several MTMRs are critical for mammalian development and human neurologic disease. MTMR2 and SBF2 (formerly MTMR13) mutations cause Charcot-Marie-Tooth disease type 4B1 and type 4B2 [Bolino et al 2000, Azzedine et al 2003, Senderek et al 2003, Bolis et al 2007], a demyelinating peripheral neuropathy, and sequence variants in MTMR14 are associated with autosomal recessive centronuclear myopathy [Tosch et al 2006]. Abnormal gene product. Mutations in MTM1 result in loss of function or absence of the myotubularin protein. Disease is mediated at least in part by loss of myotubularin’s phosphatase activity, as missense mutations that impair myotubularin’s enzymatic activity are associated with the severe/classic phenotype. Mutations that do not affect the enzymatic domain support the hypothesis that myotubularin has functions in addition to phosphatase activity. The mechanism(s) whereby lack or dysfunction of myotubularin produces the disease phenotype seen in XLCNM have recently come into focus. This knowledge has been particularly advanced by the recent development of model organisms (specifically in Drosophila [Ribeiro et al 2011], zebrafish [Dowling et al 2009], mouse [Buj-Bello et al 2002, Al-Qusairi et al 2009], and dog [Beggs et al 2010]) that accurately reflect the genetic and pathophysiologic aspects of the disease. Based on data from these models, the weakness in myotubular myopathy is caused, at least in part, by defective excitation-contraction (E-C) coupling. E-C coupling is the process by which electrical stimuli at the neuromuscular junction are translated into muscle contraction. It is mediated by the triad, a structure composed of the T-tubule and the terminal sarcoplasmic reticulum; the triad is responsible for regulated calcium release. Loss of myotubularin results in abnormalities in the structure of the triad as well as impaired stimulus-dependent calcium release. These abnormalities are observed early in the disease process in all model systems examined, and are thus likely an early pathogenic event in humans with XLCNM. Interestingly, abnormalities in the E-C coupling apparatus have been observed in the genetically determined autosomal forms of centronuclear myopathy, thus suggesting a common pathogenic mechanism for all types of CNM [Toussaint et al 2011].Loss of myotubularin likely affects other aspects of muscle function as well. In the zebrafish model of XLCNM, disorganization of the neuromuscular junction has been reported [Robb et al 2011]. In the mouse model and in cells derived from biopsies of affected persons, abnormal mitochondrial function has been described [Hnia et al 2011]. The specific contribution(s) to the disease phenotype of these changes remain to be determined.