NORD gratefully acknowledges James J. Dowling, MD, PhD, Assistant Professor, Eisenberg Emerging Taubman Scholar, Departments of Pediatrics, Neurology, and Neuroscience, Director, Pediatric Neuromuscular Program, University of Michigan Medical Center, for assistance in the preparation of this report.
X-linked myotubular myopathy (XLMTM) is a rare genetic neuromuscular disorder that is characterized by muscle weakness that can range from mild to profound. Symptoms are often present at birth, but may first develop during infancy or early childhood. In rare cases, symptoms may not develop until later, even adulthood. Common symptoms include mild to profound muscle weakness, diminished muscle tone (hypotonia or "floppiness"), feeding difficulties, and potentially severe breathing complications (respiratory distress). Feeding difficulties and respiratory distress develop because of weakness of the muscles that are involved in swallowing and breathing. The overall severity of the disorder can range from mildly affected individuals to individuals who develop severe, life-threatening complications during infancy and early childhood. Most affected individuals have a severe form of the disorder and respiratory failure is an almost uniform occurrence. XLMTM is caused by mutations to the myotubularin (MTM1) gene. The disorder is inherited as an X-linked recessive condition. The disorder predominantly affects males, but female carriers can develop mild symptoms. In rare specific cases, females can develop a severe form similar to that seen in males.
XLMTM belongs to a larger group of disorders known as the centronuclear myopathies. In addition to XLMTM, there are forms of centronuclear myopathy that are inherited as autosomal dominant or autosomal recessive conditions. Generally, the autosomal forms are less severe than XLMTM, however, in rare cases, individuals with an autosomal form can develop severe complications that are similar to those seen in XLMTM. Centronuclear myopathies derive their name from the abnormal location of the nucleus in the center of the muscle fiber (muscle cell) rather than its normal position on the edge. Additional pathologic features include disorganized perinuclear organelles and abnormalities in oxidative staining patterns. Centronuclear myopathies can be further classified into the larger, broader category of congenital myopathy, a group of genetic muscle disorders that are present at birth.
In the medical literature, centronuclear myopathy is generally used for the autosomal forms of the disorder and myotubular myopathy is generally used for the X-linked form. Distinguishing between the X-linked (myotubular) form and the autosomal forms is essential as the symptoms are usually more severe in the X-linked form. NORD has a separate report on centronuclear myopathy that describes the autosomal forms in greater detail. This report specifically deals with X-linked centronuclear (myotubular) myopathy.
The specific symptoms and severity of XLMTM can vary greatly from one person to another. Some individuals may only develop mild symptoms; others develop serious life-threatening complications early during life. The disorder can prove fatal during infancy or childhood. Because of the variable nature of XLMTM, parents should talk to their child’s physician and medical team about their specific case, associated symptoms and overall prognosis.
One classification subdivides XLMTM into a severe (classic) form, a moderate form and a mild form. Most affected individuals have the severe (classic) form of XLMTM. Moderate and mild forms of XLMTM are far less common. In the severe form, affected male infants exhibit extreme muscle weakness and hypotonia at or shortly after birth. Weakness of the muscles used to breathe and swallow can cause respiratory distress and feeding difficulties during infancy often noticeable within the first few days or weeks of life. Respiratory distress can be present at birth and can cause affected infants to require constant, prolonged ventilation during infancy. Affected infants may be unable to suck, swallow or breathe on their own. In the U.S., the initial hospital stay for surviving infants is approximately 90 days.
Long-term ventilation during infancy carries risks including recurrent infection, inadequate shallow breathing (hypoventilation), and lack of oxygen in the blood (hypoxia). Some cases of XLMTM will prove fatal during the first few months or years of life. However, in other cases, individuals will become independent of a ventilator or only require periodic assisted ventilation such as during sleep. A proportion of affected individuals will survive into the teen-age years and beyond.
Muscle weakness and poor muscle development can also cause delays in the attainment of motor milestones. Most affected individuals are unable to walk (non-ambulatory). Muscle weakness associated with XLMTM is not believed to be progressive, but this has not been definitely confirmed. Individuals with XLMTM often grow tired more easily than normal.
Affected infants often have distinctive facial features including a high forehead, underdevelopment of the middle of the face (midface hypoplasia), weakness of facial muscles, and a disproportionately long and narrow head (dolichocephaly) with a long face. Some infants have a narrow, high-arched roof of the mouth (palate) and later on develop severe misalignment of the teeth (malocclusion). Partial or complete paralysis of one or more of the muscles that control the movements of the eye (ophthalmoparesis) is also common. Drooping of the upper eyelid (ptosis) and nearsightedness (myopia) may also occur.
In some individuals, growth parameters may be abnormal. In general, head circumference is larger than would be expected based on age and gender (macrocephaly). Affected infants may be in the 90th percentile for length at birth. Weakness of the facial muscles is often striking.
Additional symptoms may occur including abnormally long fingers and toes, absence of reflexes (areflexia), and shortening or hardening of tissue that causes deformity and restricts movements of affected areas, especially the joints (contractures). Failure of the testes to descend into the scrotum (cryptorchidism) may also occur. As affected individuals grow older more symptoms can occur including fractures of the long bones, malformation of the hip (hip dysplasia) and abnormal side-to-side curvature of the spine (scoliosis). Scoliosis can worsen respiratory problems and cause individuals who no longer require assisted ventilation to go back onto ventilator support. In some cases, advanced bone age and premature production of sex hormones called androgens (premature adrenarche) has also been reported.
Many long-term survivors with severe XLMTM require a wheelchair and need assistance for normal daily activities. A wide variety of additional complications have been reported in long-term survivors. Such complications include narrowing of the outlet that connects the stomach to the small intestine (pyloric stenosis), gallstones, kidney stones, mild anemia due to the formation of abnormal red blood cells (spherocytosis), bleeding abnormalities, and liver dysfunction. Some individuals developed peliosis hepatitis, a liver condition characterized by randomly located, multiple blood-filled cavities throughout the liver. This condition can cause life-threatening bleeding (hemorrhaging) episodes.
Cognitive development and intelligence are usually unaffected, except in extremely rare cases or in individuals who suffer a significant hypoxic episode, in which the brain is deprived of oxygen.
Mild and Moderate Myotubular Myopathy
Some individuals may have milder forms of the disorder. The moderate form of XLMTM is generally characterized by similar signs and symptoms to the severe form. However, individuals will have longer periods of time where the need for ventilator support is decreased. In addition, affected individuals will attain motor milestones faster than individuals with the severe form.
Individuals with the mild form of XLMTM only experience slight delays in attaining motor milestones and most achieve the ability to walk. These individuals may only require ventilator support in the newborn period. Some individuals with the mild form do not have the characteristic facial features that are seen in the severe form of XLMTM.
Individuals with mild or moderate XLMTM are at risk for breathing problems including especially nocturnal hypoventilation and sleep apnea. In addition, respiratory decompensation can develop when dealing with an unrelated illness. This may require a return to or an increase in ventilator support.
At least three multigenerational families have been described in the medical literature with male family members who developed mild cases of XLMTM, sometimes not developing symptoms until adulthood.
XLMTM is caused by a mutation in the myotubularin (MTM1) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
XLMTM is inherited as an X-linked recessive trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. This is a normal process known as random X-chromosome inactivation. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because the X chromosome with the abnormal gene that is “turned off” in approximately 50% of the cells of the body. A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In a minority of cases, a mutation in the MTM1 gene that causes the disorder occurs randomly for no apparent reason (de novo mutation). In these cases, the mother is not a carrier and the risk of recurrence of the mutation in a subsequent pregnancy is extremely low.
As a result of random X-chromosome inactivation, most females with a MTM1 mutation do not develop symptoms, although some females will exhibit mild symptoms such as mild weakness of certain muscles. In extremely rare cases, females can develop a severe form of XLMTM similar to the one seen in males. This may be due to unfavorable random X-chromosome inactivation in which too many cells have an active disease gene.
In a few cases recently reported in the medical literature, male children with XLMTM developed the disorder not because of a mutation, but because of a duplication involving the MTM1 gene. A duplication is a structural chromosomal abnormality in which a portion of the X chromosome appears three times in the cells of the body instead of twice. Researchers believe that some cases in which individuals have XLMTM but do not have a mutation of the MTM1 gene are caused by a duplication of the X chromosome involving the MTM1 gene.
Investigators have determined that the MTM1 gene is located on the long arm (q) of the X chromosome X (Xq28). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The MTM1 gene creates (encodes) a protein known as myotubularin. This protein is believed to be critical for the proper development, maintenance, and function of muscle tissue. The exact, specific functions of this protein are not fully understood, though recent work has suggested in plays a role in maintaining aspects of muscle structure including the part of the muscle fiber responsible for excitation-contraction coupling, which is a normal process involved in skeletal muscle contraction. A mutation in the MTM1 gene leads to low levels of functional myotubularin.
XLMTM primarily affects males. Some carrier females may develop mild symptoms associated with the disorder. The exact incidence of the disorder is unknown, but one estimate places it at 1 in every 50,000 male births in the general population. It is the most common form of centronuclear myopathy.
XLMTM should be suspected in newborns with hypotonia and muscle weakness and older male children with weakness in the arms and legs and diminished muscle bulk. A diagnosis is based upon identification of additional characteristic symptoms (e.g. cryptorchidism, long fingers and toes, macrocephaly), a detailed family history, a thorough clinical evaluation, and a variety of specialized tests.
Clinical Testing and Workup
A muscle biopsy may be performed to aid in obtaining a diagnosis. A biopsy involves surgical removal a small sample of affected muscle tissue and examining the sample under a microscope. This allows physicians to note the characteristic, microscopic changes to muscle tissue, specifically the presence of the nucleus in the center of the muscle fiber (muscle cell) rather than toward the edge.
A diagnosis of XLMTM can be confirmed through molecular genetic testing, which can detect the MTM1 gene mutation that causes the disorder. Molecular genetic testing can detect a mutation in approximately 60%-98% of affected individuals and is available on a clinical basis.
The treatment of XLMTM is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists with expertise in treating neuromuscular disorders. Pediatricians, pulmonologists, neurologists, orthopedists, eye specialists, dental specialists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling will be of benefit for affected individuals and their families.
The treatment of affected individuals usually requires intensive medical intervention. Some affected individuals will require prolonged, constant ventilation support. There are different methods for ventilation including noninvasive and invasive techniques. The decision about the duration of respiratory support is best made by the family in careful consultation with the patient’s physicians and other members of the healthcare team based upon the specifics of their case.
In some individuals feeding difficulties will require the insertion of a feeding tube (gastrostomy). This procedure involves inserted a tube directly into the stomach through a smalls surgical opening in the abdominal wall.
Physical and occupational therapy is recommended to improve muscle strength and prevent contractures. Special measures may be necessary to allow ventilator-dependent individuals to communicate. Additional therapies are symptomatic and supportive. For example, scoliosis may require surgical intervention.
Gene therapy is being studied as an approach to therapy for XLMTM. With the discovery of the MTM1 gene in 2008 has enabled researchers to explore this potential therapy. Animal studies are currently ongoing. If researchers can demonstrate success in animal trials, they can seek approval from the U.S. Food and Drug Administration (FDA) to begin human trials. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach.
Another consideration is protein replacement therapy. Studies utilizing the mouse model of MTM have demonstrated that system injection of a genetically engineered (recombinant) MTM1 protein can prevent disease onset and progression in this model.
Studies are underway to determine whether treatments aimed at the neuromuscular junction – the point where nerve cells and muscle cells meet – can help individuals with XLMTM. Researchers are studying the use of drugs that target proteins of the neuromuscular junction. Initial studies on zebrafish and mice (murine) models have shown significant improvement in fatigable weakness. Much more research, including human trials, are required to determine whether this potential therapy has a role in the treatment of individuals with XLMTM.
Currently, there is an ongoing prospective natural history study of individuals with XLMTM. This study is designed to elucidate and define specific features of the disease over time and to help identify potential outcome measures for future interventional trials. Also, there is patient registry for all congenital muscle disease (called the CMDIR) which includes XLMTM. Patients and families are encouraged to register through the CMDIR:
Congenital Muscular Dystrophy International Registry (CMDIR)
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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