X-Linked Myotubular Myopathy

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of X-MTM, molecular genetic testing approaches can include a multigene panel or single-gene testing:

• A multigene panel that includes MTM1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing. Rarely, single-gene testing can be considered under the appropriate circumstances. These include: (a) a male child with weakness and a positive family history of X-MTM; or (b) a severely affected male infant with physical features consistent with X-MTM, including diffuse weakness, ophthalmoparesis, and length and head circumference >90th centile. Sequence analysis of MTM1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by myopathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Severe/Classic X-MTM

In males with the severe/classic phenotype, polyhydramnios and decreased fetal movement are frequently reported. Premature delivery is described in approximately one third of males [Beggs et al 2018]. Hypotonia, extremity weakness, and respiratory distress are present during the newborn period. Ventilatory support is required due to respiratory failure [Amburgey et al 2017, Beggs et al 2018]. Hypoxic events may occur, leading to an acquired hypoxic ischemic encephalopathy. Prolonged ventilator dependence leads to an increased risk of respiratory infection, hypoventilation, and hypoxia.

Affected infants often have typical myopathic facies with dolichocephaly, high forehead, long face with midface retrusion, prominent eyes, narrow high-arched palate, and severe malocclusion. Ophthalmoparesis is also frequently observed. Additional features include length greater than the 90th centile with a proportionately lower weight (60% of infants), long fingers and/toes (43%), cryptorchidism and/or undescended testicle (>50%), contractures including clubfeet (30%), and areflexia (60%).

Most infants require lengthy NICU hospitalizations, with approximately 30%-50% of the first year spent in the hospital. Many infants with severe/classic X-MTM succumb to complications of the disorder. The percentage of infants that do not survive the first year of life has been difficult to determine. The reported causes of death are multifactorial, and include removal of ventilatory support. Approximately 25% of male infants die in the first year of life.

Most surviving males are discharged home on 24-hour ventilatory support via tracheostomy and gastrostomy tube feedings. In one study including all forms of X-MTM, 85% of individuals required ventilatory and G-tube support, and nearly all needed wheelchair support for ambulation [Amburgey et al 2017]. The estimated rate of mortality is 10% per year after age one, with few individuals surviving to adulthood. The cause of death is usually related to respiratory failure, though very rarely may be associated with hepatic peliosis.

The muscle disease may not be progressive. A prospective study of the ventilatory support requirements of 33 individuals over one year showed little change. Prospective analysis of muscle function in a small pilot group also detected no large changes over a one-year period [Amburgey et al 2017].

Interestingly, and despite the severe disability and technology dependence of the disease, the annual rate of nonelective hospitalization after the first year of life is not as high as would be expected. In a prospective study of 33 individuals, the rate was 1.1 emergency room visits per year [Amburgey et al 2017]. The rate of hospitalization is higher in very young individuals (age 1-2 years) [Amburgey et al 2017, Beggs et al 2018].

Additional features of the underlying myopathy are ophthalmoplegia, ptosis, and severe myopia. Dental malocclusion (requiring orthodontic care) may occur. Constipation is common. Scoliosis often develops in later childhood (75% of individuals in one study) and may require surgical intervention, though scoliosis surgery is documented in only a minority of individuals (≤10%). 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 long bone fractures [Cahill et al 2007].

Hepatic peliosis. Liver hemorrhage due to hepatic peliosis is perhaps the most serious non-muscle-related complication in X-MTM. Several individuals have died following prolonged liver hemorrhage or hemorrhage into the peritoneal cavity due to hepatic peliosis, a rare vascular lesion characterized by the presence of multiple blood-filled cysts within the liver [Motoki et al 2013]. This complication may occur in up to 5% of individuals.

Growth and pubertal development. Despite chronic illness and prolonged ventilator dependence, many individuals with X-MTM have linear growth above the 50th centile, with some individuals achieving greater than the 90th centile for height. Advanced bone age and/or premature adrenarche have been documented in several young males. However, endocrinologic studies performed on several individuals have been normal. Puberty has occurred normally in the few males who have reached adulthood.

Cognition. A recent natural history study identified that many children require special education for learning/cognitive impairments [Amburgey et al 2017]. This may be due to comorbid hypoxic ischemic encephalopathy, and there are rare individuals with central nervous system complications [McCrea et al 2009]. However, determination of whether there is a primary cognitive component to the disorder awaits further study.

Other. Several medical problems unrelated to the muscle disorder have been reported at low frequency. It is not entirely clear if these are due to MTM1 pathogenic variants or unrelated comorbidities. They include pyloric stenosis (~5%), gastroesophageal reflux (10%), cardiac arrhthymias (10%; severity is unclear), gallstones (9%), kidney stones (10%), and elevated liver function tests (20%). Herman et al [1999] also identified some individuals with a mild form of spherocytosis and a vitamin K-responsive bleeding diathesis. These have not been recently reported and their presence in this population is unknown.

Mild and Moderate X-MTM

At least three reports of multigenerational families with MTM1 pathogenic variants and a much milder phenotype have been described [Barth & Dubowitz 1998, Biancalana et al 2003, Yu et al 2003, Hoffjan et al 2006]. In the recent natural history study, 13% of study subjects could walk independently and were thus considered in the mild/moderate category; 2% required no support for ambulation, ventilation, or feeding.

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 X-MTM [Herman et al 1999]. Most still require some respiratory support (which may be noninvasive), and typically also require feeding assistance.

There are several case reports describing adult males with mild disease and pathogenic variants in MTM1. These include two individuals in their 60s at the time of publication who first manifested limb girdle weakness after childhood (first symptoms age 18 and 52 years, respectively) [Biancalana et al 2003, Hoffjan et al 2006]. At least one of these males had facial weakness and ophthalmoparesis. Yu et al [2003] described two males with a pathogenic variant 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.

Heterozygous females are generally asymptomatic, although symptomatic heterozygote females have been described [Savarese et al 2016, Biancalana et al 2017, Felice et al 2018]. Severity is variable, and some present with severe infantile weakness resembling that seen in affected males. More commonly, symptoms include mild/moderate asymmetric limb weakness and asymmetric reduction of muscle bulk in the correspondingly affected limbs. Facial weakness, ptosis, and ophthalmoparesis are often present. Respiratory failure is not uncommon, and can be unrecognized at the time of presentation.

Histopathologic features [Lawlor et al 2016]

• The characteristic muscle biopsy demonstrates numerous small, rounded myofibers with varying percentages of centrally located nuclei. The myofiber size may be uniform throughout the tissue, which may lead to underestimation of the decreased myofiber size (as there may be no appropriately sized fibers for comparison). 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 [Pierson et al 2007]. The combination of small myofiber size and central nucleation may result in the central nuclei comprising the majority of the cross-sectional area in some myofibers, which is not specific for X-MTM but is characteristic of severe centronuclear myopathies in very young individuals.
• 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, reflecting (respectively) maldistribution of glycogen and mitochondria/sarcotubular organelles [Romero 2010]. In some cases, a particularly striking subsarcolemmal halo will be seen around these aggregates.
• 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]. All fiber types tend to show some degree of decreased myofiber size in most biopsies, however, and appropriately sized or large fibers may be rare or absent. In some biopsies, ATPase staining demonstrates myofibers with central clearing that results from a focal absence of myofibrils [Romero 2010].
• The histopathologic findings listed are not specific to X-MTM and may be encountered in congenital myotonic dystrophy type 1 (see Differential Diagnosis) and in early-onset autosomal forms of centronuclear myopathy. X-MTM 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) X-MTM, whereas the latter are usually eccentrically situated within the myofiber and may alternatively be associated with other centronuclear myopathies or with chronic myofiber regeneration. (2) Necklace fibers are a distinctive feature that has been described in males with sporadic late-onset X-MTM as well as in manifesting heterozygous females [Biancalana et al 2017]. 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. 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 X-MTM 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 described in X-MTM [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]. Levels of both proteins are also diminished, as demonstrated by western blot analysis [Bachmann et al 2017]. Since other centronuclear myopathies also have T-tubule defects, the specific diagnostic utility of this finding may be limited [Toussaint et al 2011].

Electron microscopy. Ultrastructurally, X-MTM is characterized by the disorganization or decreased number of triads (interfaces between the sarcotubular reticulum and T-tubules) in longitudinal sections. This has been well demonstrated in human patients and animal models of disease [Al-Qusairi et al 2009, Dowling et al 2009, Childers et al 2014], and quantitative studies have been performed in some animal treatment studies to assist in the evaluation of therapeutic efficacy [Lawlor et al 2013, Lawlor et al 2016, Mack et al 2017]. These quantitative studies have been highly controlled in the collection and processing of the tissue, however, and quantification of triads or sarcotubular elements in the clinical diagnostic setting is not feasible.

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 pathogenic variants, including some missense variants, no myotubularin was detected on western blot. One out of five boys with suspected X-MTM in whom no pathogenic variant 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 pathogenic variants; one individual had no detectable protein and an intermediate phenotype, but no MTM1 pathogenic variant was detected. While immunologic testing may be helpful in some individuals with suspected X-MTM in whom no pathogenic variant is found, such analysis is not routine, and adequate antibodies to myotubularin are not widely available.