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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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X-Linked Centronuclear Myopathy

Synonyms: X-Linked Myotubular Myopathy, XLCNM, XLMTM

, PhD, , MD, PhD, and , MD, PhD.

Author Information
, PhD
Department of Human Genetics
University of Chicago
Chicago, Illinois
, MD, PhD
Division of Pediatric Neurology
University of Michigan
Ann Arbor, Michigan
, MD, PhD
The Research Institute at Nationwide Children’s Hospital
Columbus, Ohio

Initial Posting: ; Last Update: October 6, 2011.

Summary

Disease characteristics. X-linked centronuclear myopathy (XLCNM) (also known as myotubular myopathy [MTM]) is characterized by muscle weakness that ranges from severe to mild. Severe (classic) XLCNM presents prenatally with polyhydramnios and decreased fetal movement and in newborns with weakness, hypotonia and respiratory distress. Affected males have significantly delayed motor milestones and most fail to achieve independent ambulation. Weakness is profound and often involves facial and extraocular muscles. Respiratory failure is nearly uniform, with most affected individuals requiring 24-hour ventilatory assistance. A minority of males with severe XLCNM die in infancy. Males with moderate XLCNM achieve motor milestones more quickly than males with the severe form; about 40% require no ventilator support or intermittent support. Males with mild XLCNM may require ventilatory support only in the newborn period; they have minimally delayed motor milestones, are able to walk, and may lack myopathic facies. The muscle disease of XLCNM is not obviously progressive. Female carriers of XLCNM are generally asymptomatic, although rare manifesting heterozygotes have been described.

Diagnosis/testing. The diagnosis of XLCNM relies upon identification of characteristic histopathologic changes in muscle samples from males with a consistent clinical picture and supporting genetic testing. In some individuals there is also a family history consistent with X-linked inheritance. MTM1 is the only gene in which mutation is known to cause XLCNM. Molecular genetic testing of MTM1 detects mutations in 60%-98% of affected.

Management. Treatment of manifestations: Treatment is symptomatic. Management optimally involves a team of specialists with expertise in the long-term care of children with neuromuscular disorders, often including a pulmonologist, neurologist, physical therapist and/or rehabilitation medicine specialist, and medical geneticist. Tracheostomy, G-tube feeding, and assistive communication devices are often required. Ophthalmologists and orthopedists specializing in scoliosis management and orthodontists should address specific medical complications.

Prevention of secondary complications: Evaluation of clotting parameters is indicated prior to any surgical procedure.

Surveillance: Annual pulmonary assessment; polysomnography every one to three years; routine examination for signs of scoliosis; annual ophthalmologic examinations to evaluate for ophthalmoplegia, ptosis, and myopia; routine assessment for dental malocclusion.

Genetic counseling. XLCNM is inherited in an X-linked manner. The risk to sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, each sib has a 50% chance of inheriting the MTM1 mutation. Males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will generally not be affected. In simplex cases (i.e., a single occurrence in a family), there is a probability of 80%-90% that a woman is a carrier if her son has a confirmed MTM1 mutation. Thus, about 10%-20% of males who represent simplex cases have a de novo disease-causing mutation in MTM1 and a mother who is not a carrier. Germline mosaicism has been reported. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at risk are possible if the disease-causing MTM1 mutation has been identified in an affected male relative.

Diagnosis

Clinical Diagnosis

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:

  • 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)

Testing

Muscle Biopsy

Affected 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 Females

An 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 Testing

Gene. MTM1 is the only gene in which mutations are known to cause XLCNM [Wallgren-Pettersson 2000].

Testing

Table 1. Summary of Molecular Genetic Testing Used in X-Linked Centronuclear Myopathy

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
MalesHeterozygous Females
MTM1Sequence analysis / mutation scanning 2Sequence variants 360%-98% 4, 553%-98% 6
Deletion / 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 gene

2. 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 Strategy

To 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 by
  • Genetic 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

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.

Clinical Description

Natural History

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.

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

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:

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

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]:

Penetrance

Penetrance is thought to be 100% in affected males. To date all males with a mutation in MTM1 have shown findings of the disease, although disease severity can range from mild to severe.

Carrier females are generally asymptomatic; 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].

Anticipation

XLCNM is generally not associated with anticipation. However, in two families the maternal grandfather had adult-onset disorder of very mild disease, whereas their affected grandsons had severe hypotonia and respiratory insufficiency at birth requiring ventilatory assistance [Biancalana et al 2003, Hoffjan et al 2006].

Nomenclature

Myotubular myopathy (or X-linked centronuclear myopathy [XLCNM]) is considered a subtype of centronuclear myopathy based on the centrally located nuclei of muscle fibers on histologic examination. Autosomal dominant and autosomal recessive centronuclear myopathy should not be referred to as myotubular myopathy.

Males with XLCNM with identifiable mutations in MTM1 are said to have myotubular myopathy (MTM). This term should only be used to refer to individuals with documented or presumed MTM1 mutations.

Prevalence

It has been estimated that XLCNM affects approximately one in 50,000 newborn males [Laporte et al 2001a]; careful, large studies attempting complete ascertainment have not been published.

Differential Diagnosis

Congenital 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations 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 Manifestations

Management 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 Complications

Because 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.)

Surveillance

Appropriate 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:

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked centronuclear myopathy (XLCNM) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • The risk to sibs of a male proband depends on the carrier status of the mother.
  • If the mother is a carrier, there is a 50% chance of transmitting the MTM1 mutation in each pregnancy. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will generally not be affected.
  • Because of the possibility of germline mosaicism, sibs of a proband are at risk even if the MTM1 mutation found in the proband is not detected in DNA extracted from the mother's leukocytes.

Offspring of a proband. In general, affected males do not reproduce. However, Biancalana et al [2003] reported an affected male with mild disease detected at age 20 who fathered two unaffected daughters, both of whom had affected sons. Affected males who do reproduce will pass the disease-causing mutation to all of their daughters and none of their sons.

Other family members. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the disease-causing mutation has been identified in the proband.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers. The usual procedure is to determine fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY and if the disease-causing mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation. Penetrance appears to be 100% in affected males; disease severity is usually similar in affected sibs.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Several instances of germline mosaicism for MTM1 mutations have been described [Vincent et al 1998, Hane et al 1999, Laporte et al 2000]. Thus, it is important to discuss the option of prenatal testing in a male fetus even in instances in which the disease-causing mutation is not identified in DNA extracted from the mother's leukocytes.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Joshua Frase Foundation
    PO Box 2041
    Ponte Vedra Beach FL 32004
    Phone: 904-607-1358
    Fax: 904-273-9818
    Email: info@joshuafrase.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Congenital Muscle Disease International Registry (CMDIR)
    The CMD International Registry is a patient self-report registry with the goal to register the global congenital muscle disease population which includes congenital myopathy and congenital muscular dystrophy.
    1712 Pelican Avenue
    San Pedro CA 90732
    Phone: 800-363-2630
    Fax: 310-872-5374
    Email: counselor@cmdir.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
MTM1Xq28MyotubularinMTM1 homepage - Leiden Muscular Dystrophy pagesMTM1

Data 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)

300415MYOTUBULARIN; MTM1
310400MYOPATHY, CENTRONUCLEAR, X-LINKED; CNMX

Normal 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 Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
Normalc.1260+3G>ANANM_000252​.2
NP_000243​.1
Pathologicc.109C>Tp.Arg37X
c.142G>Tp.Glu48X
c.205C>Tp.Arg69Cys
c.141_144delAGAA p.Glu48Leufs*24
c.614C>Tp.Pro205Leu
c.674T>Cp.Ile225Thr
c.721C>Tp.Arg241Cys
c.1261C>Tp.Arg421X
c.1262G>Ap.Arg421Gln
c.1261-10A>GNA

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

Normal 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

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Suggested Reading

  1. Claeys KG, Maisonobe T, Böhm J, Laporte J, Hezode M, Romero NB, Brochier G, Bitoun M, Carlier RY, Stojkovic T. Phenotype of a patient with recessive centronuclear myopathy and a novel BIN1 mutation. Neurology. 2010;74:519–21. [PubMed: 20142620]
  2. Jungbluth H, Wallgren-Pettersson C, Laporte JF. Centronuclear; Naarden, The Netherlands. Neuromuscul Disord. 2009;19:721–9. [PubMed: 19683444]
  3. Jungbluth H, Wallgren-Petersson C, Laporte J. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis. 2008;3:26. [PMC free article: PMC2572588] [PubMed: 18817572]

Chapter Notes

Author History

Soma Das, PhD (2002-present)
James Dowling, MD, PhD (2011-present)
Gail Ellen Herman, MD, PhD; Nationwide Children’s Hospital, Columbus (2002-2011)
Christopher R Pierson, MD, PhD (2011-present)

Revision History

  • 6 October 2011 (me) Comprehensive update posted live
  • 5 October 2006 (me) Comprehensive update posted to live Web site
  • 3 May 2004 (me) Comprehensive update posted to live Web site
  • 25 February 2002 (me) Review posted to live Web site
  • 2 October 2001 (gh) Original submission
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