About x-linked congenital recessive muscle hyp...
What is x-linked congenital recessive muscle hyp...?
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.
What are the symptoms for x-linked congenital recessive muscle hyp...?
The specific symptoms and severity of XLMTM can vary greatly from one person to another, though the majority of individuals with MTM have a severe presentation. While the disorder may be fatal during infancy or childhood, some affected individuals will only develop mild to moderate symptoms. 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 (floppiness) 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.
Some children with XLMTM will die during the first few months or years of life. Other individuals will survive this initial period but require 24 hour ventilator, feeding, and wheelchair support. However, other 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 teenage years and beyond. Of note, long-term ventilation during infancy carries risks including recurrent infection, inadequate shallow breathing (hypoventilation), and lack of oxygen in the blood (hypoxia).
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 their peers.
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 eyelids (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 very obvious.
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 variety of additional low incidence 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 develop 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, and often also have eye movement paralysis.
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.
What are the causes for x-linked congenital recessive muscle hyp...?
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 genetic disorder. X-linked genetic disorders are conditions caused by a gene change 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 change 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 change 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 change, he will develop the disease. Males with X-linked disorders pass the disease gene change 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 a skewing of the inactivation of the X-chromosome without the gene change; therefore the majority of the instructions for the myotubularin protein come from the X-chromosome with the gene change.
In a few children 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. There is also now evidence for changes/mutations at the MTM1 gene locus that occur outside of the protein making region but that impact the processing of the MTM1 RNA.
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.
What are the treatments for x-linked congenital recessive muscle hyp...?
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.
What are the risk factors for x-linked congenital recessive muscle hyp...?
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.
Is there a cure/medications for x-linked congenital recessive muscle hyp...?
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 small 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.