Myotubular myopathy (MTM) belongs to a rare group of developmental disorders of voluntary muscle called congenital myopathies that present as a "floppy baby" syndrome. This is a genetically inherited disorder with various abnormalities in muscle fiber development, muscle tone, and contraction. MTM refers to the pathological finding of muscle fibers with centrally located nuclei resembling the myotubule stage of muscle development.
This condition is also called as centronuclear myopathy (CNM), X-linked MTM (MTM1), pericentronuclear myopathy, or type I fiber hypotrophy with central nuclei. It is primarily caused by defective maturation of the muscle. Spiro first described this disorder in 1966. The myotubularin gene was identified in 1996.
Muscle fibers normally undergo a complicated series of maturational changes before becoming a fully functional normal adult muscle fiber. The myotubule stage is an intermediate state in the fiber maturational process. It is seen normally only in an 8–20-weeks-old fetus and is characterized by central nuclei. In MTM, the maturation is arrested at this stage and the protein machinery of the muscle fiber needed for contraction is not fully formed. Muscles of patients with MTM thus show an overabundance of immature, poorly functional myotubular fibers.
MTM has different modes of inheritance , resulting in a wide variability of symptom onset (birth to early adulthood) and rate of symptom progression. Some researchers classify CNM and MTM as two extreme ends of a spectrum, with CNM being the milder form. Disability arises due to weakness of voluntary muscles and respiratory difficulty, progressing to death.
There are three types of MTM, based on the mode of inheritance.
X-linked MTM (MTM1)
This is the most common form and is inherited usually in an X-linked recessive fashion, although de novo (new) mutations can occur rarely. It is due to a mutation in the myotubularin, or MTM1, gene that occurs on the long arm of the X chromosome at locus Xq28. Another related gene, called MTMR1, is also found on the X chromosome. About 150 types of myotubularin mutations have been identified, and, depending on the type, the severity of disease expression varies. Mutations that truncate the gene lead to severe or lethal disease expression. Mutations that delete part of the gene or cause misreading of the gene cause less severe disease. The gene encoding for the myotubularin protein is widely expressed, not just in the muscle. The relationship between the gene product and the disease is still being investigated.
Each cell has one pair of sex chromosomes. The female has two copies of the X chromosome, one inherited from each parent, while the male has only one X chromosome inherited from the mother and the Y chromosome inherited from the father. A mother that carries one abnormal X chromosome containing the myotubularin mutation has a 50% chance of passing it to each of her offspring. If the daughter inherits the mutation, she may not exhibit any symptoms as she has an extra normal copy; this makes her a carrier. However, a son who inherits the mutation will express the disease, as he cannot compensate for the mutated gene carried on his single X chromosome. If an affected male child has other affected male siblings, about 90% of the time the abnormal gene has been inherited from the mother in an X-linked fashion. If there are no other affected male siblings, then it is most likely a de novo mutation. Father-to-son transmission is not possible in MTM1.
Carriers of X-linked MTM
Carriers are usually females who have an abnormal gene on one of their X chromosomes. They usually do not express the disease due to compensation from the normal copy. Skewed inactivation of the X chromosome containing the normal gene leads to milder disease expression.
Autosomal dominant MTM
In this mode of inheritance, one copy of another myotubularin gene (MTMR2, MTMR3) is abnormal on an autosome, chromosome 12. Each cell has two chromosomes 12 carrying the myotubularin gene, and there are two alternate forms (alleles) in which the gene can exist. Therefore, four possible combinations of alleles can exist for this gene. If a person has one normal and one abnormal allele and expresses the normal allele, the individual will have the autosomal dominant form of MTM. Both males and females are equally affected, and the disease is passed on from generation to generation. There will usually be one affected person in each generation, and each child has a 50% chance of inheriting the abnormal gene. Father-to-son transmission is possible.
Autosomal recessive MTM
This can occur in three ways. The affected person can have two abnormal alleles of the myotubularin gene or can have two different types of abnormal alleles. Finally, the affected person can have one normal and one abnormal allele and expresses the abnormal allele. Males and females are affected equally. Some ethnic predilections occur due to consanguinity where each parent of an affected child is a non-expressing carrier with both a normal and an abnormal allele. Therefore, each of their children has a 25% chance of being affected and a 50% chance of being a nonexpressing carrier.
MTM is a rare condition; accurate estimates are unavailable. Approximate estimates for X-linked MTM range from one 50,000–500,000 newborn males. Unlike other congenital myopathies, there is a relatively high incidence in Africans.
Signs and symptoms
There is a wide spectrum of clinical features seen in MTM depending on the mode of inheritance, but the basic problem arises from poor muscle tone interfering with posture, locomotion, and muscle strength. In general, the earlier the symptoms present, the more severe and progressive is the disorder.
This is the most severe and most studied form, which presents at birth or even prior to birth, typically occurring in males. Mothers who are pregnant with affected boys experience polyhydramnios, which is an excessive amount of amniotic fluid due to decreased fetal swallowing of the fluid. Affected boys also exhibit decreased movements in utero. Fetal cardiac rhythm disturbances can also occur. Newborn males with MTM have a weak cry, are floppy at birth, have difficulty suckling and swallowing, exhibit severe generalized muscle weakness, and have serious respiratory difficulty. Life-threatening difficulties are caused by respiratory and swallowing problems. In very severe cases, the infants succumb to the disease quite early in the absence of adequate respiratory support, and death can occur within a few days of birth. Intermediate form of X-linked MTM occurs in adolescents who develop severe muscle weakness and become non-ambulatory between early and middle life. Mild forms can present in early adulthood with facial weakness, eye muscle weakness, and mild gait difficulty.
Affected boys have a long slender body with long fingers and toes and appear frail. Length is disproportional to body weight as skeletal growth surpasses muscle growth. This is thought to be a result of endocrine dysfunction leading to rapid skeletal growth. The head can be dolicocephalic (elongated) or enlarged due to hydrocephalus . Other facial features, such as high arched palate, dental abnormalities, puffy or droopy eyelids (ptosis) due to eye muscle weakness, and squint, occur. Poor muscle tone leads to decreased blinking during the day and incomplete eye closure during sleep, causing eye irritation. Speech is soft and nasal. The affected children adopt a frog-leg posture due to hypotonia (decreased muscle tone). Skeletal deformities, such as pigeon-chest, scoliosis , and joint dislocations, also occur due to hypotonia. Tendon reflexes are absent. Over time, contractures occur in the hip, knee, and ankle joints, making walking difficult. Swallowing difficulty leads to drooling with aspiration of oral secretions into the lungs that can result in pneumonia. Intelligence and cognitive development is usually normal unless there has been a significant birth injury or respiratory distress with prolonged lack of oxygen.
Other associated medical problems include spherically shaped abnormal red blood cells (spherocytes), anemia, enlarged spleen, and gallstones. Peliosis hepatis is a disorder in which the liver has large blood-filled cysts that can rupture into the abdominal cavity and cause massive bleeding and death. Some have a vitamin K responsive bleeding disorder. Other genital and urinary problems like undescended testes (cryptoorchidism) and kidney stones also occur. Constipation can be a result of poor gut motility or overall physical immobility. Hearing and vision are unaffected.
Autosomal dominant MTM
This is the least severe form and tends to affect males twice as often as females. It presents in late childhood or early adulthood and progresses slowly. It is less common than X-linked MTM. The major problem is proximal muscle weakness in the shoulders and hips with leg cramps. Ptosis, joint contractures, and a mild tremor can also be seen.
Autosomal recessive MTM
This can begin at birth, in late infancy, or in early adulthood, but is much less severe than X-linked MTM. Females are slightly more affected than males. Common features include: weakness of eye muscles and face; thin face with a high, arched palate; hypotonia; mild generalized weakness, including neck, trunk, shoulder, and hip muscles; delayed motor milestones; and respiratory distress. Affected individuals develop a waddling gait due to hip muscle weakness and have lordosis and club-feet. Infants have a slowly progressive paralysis of eye muscles, loss of facial expression, and continuing limb weakness as they grow. Seizures or blackout spells can occur. Intelligence can be normal, or mental deficiency can occur. This condition progresses slowly and eventually leads to loss of ambulation. Many children are never able to run or participate in games with their peers.
These are usually women and they present with mild facial weakness, spinal deformities, such as scoliosis, flat feet, mild muscle weakness, and gait difficulty.
There is a considerable overlap in symptom severity among the three forms of MTM in affected males. Thus, in a family with a single affected male child, reliance on clinical features alone to diagnose the pattern of inheritance, to predict its prognosis, and to counsel the family regarding the chance of having another affected child becomes difficult. Detailed and thorough family history should be obtained to detect other family members with possible MTM. There is no absolute biochemical, DNA , or pathology test that can tell conclusively the pattern of inheritance in an isolated case. A history of spontaneous abortions or death of male infants in the neonatal period is a clue to X-linked transmission.
Creatine kinase (CK) is an enzyme that indicates muscle breakdown and can be normal or slightly increased. Electromyography (EMG), which involves needle testing of muscle activity, can point to a myopathy without being specific for MTM. Muscle biopsy is diagnostic, whereby a piece of muscle from the thigh or arm is taken and studied under the microscope to highlight the typical central plump nuclei in muscle fibers. The diagnosis depends on demonstrating a large number of muscle fibers with centrally placed nuclei. In X-linked MTM, all muscles are equally affected and about 50–80% of the muscle fibers are abnormal. Muscle biopsy can detect 50–70% of female carriers of X-linked MTM, but the biopsy can also be normal.
Genetic testing can be done in specialized laboratories to detect the common types of myotubularin gene mutations . If no mutation is found on the X chromosome, this means that either the mutation is transmitted autosomally or that it is a mutation that cannot be detected by currently available methods. The mother of a child with X-linked MTM can also be tested genetically to see if she is a carrier, as this helps predict the chances of recurrence in a future pregnancy. Testing for X-linked MTM is available on a commercial basis, but testing for autosomal forms is only available through a research study.
Prenatal diagnosis is possible for detecting X-linked MTM by tracing the family history of the disease by a process of linkage analysis, which works only if there is more than one affected male member in the family. This can be done even if the exact type of genetic mutation is not known. Pre-implantation genetic diagnosis (PGD) is a technique whereby testing is done on the embryo and only unaffected embryos are placed back in the uterus for continuation of pregnancy.
Treatment and management
As of 2005, there is no proven treatment to cure or stop progression of MTM, but aggressive supportive measures for swallowing and breathing are warranted to preserve good functional ability as these have been shown to prolong life expectancy. A team approach, including a neurologist, pulmonologist, orthopedic surgeon, physiatrist, physical therapist, occupational therapist, and geneticist, ensures the best possible therapy.
Tracheostomy tubes and ventilators help with breathing. In some cases, the muscles become stronger with time, and the tubes can be removed. Stents can be used to widen and support floppy airways. Lung infections can be treated with antibiotics. Chest physiotherapy helps to periodically clear lung secretions and decrease the incidence of pneumonia. Nutrients can be fed via oral feeding tubes and G-tubes. There are no special ingredients to be incorporated in the diet, as no supplement has been consistently proven to improve muscle strength and build muscle bulk. Caloric intake should be tailored to the requirements of each individual child.
Physical therapy plays a very important part in maintaining and improving muscle strength, joint flexibility, range of motion, and gait. Care should be taken not to overexert and fatigue the already weak muscles and a regular exercise program should be devised. Passive stretching, bracing, and surgical-release procedures are done to prevent tendon and joint contractures. Bracing or surgery may be needed to correct spinal deformities. The occupational therapist can help in devising adaptive equipment for walking and for other daily activities.
Speech therapy is important to overcome problems with speaking due to poor phonation and articulation. Passy-Muir speaking valves can be used in patients who have a tracheostomy tube. Orthodontic services are needed to correct dental malocclusion. Some children can learn to communicate using sign language, communication assist devices, or high-tech computerized devices. Intelligence is not affected, and therefore these children may even be able to attend regular schools. Artificial tears should be used to prevent dry eyes. Yearly blood tests and liver function tests should be done to monitor development anemia and liver malfunction. Folic acid is used when the child has anemia and spherical red blood cells. Appropriate precautions should be taken to avoid bleeding during any major surgery.
Genetic counseling should be sought after a child has been diagnosed with MTM to discuss the prognosis for the child, to help the couple with future reproductive planning, and to help with prenatal diagnosis. The probability of having another affected child varies with the specific mode of inheritance.
Only males are severely affected by X-linked MTM and prognosis has been historically poor due to early respiratory failure. The children lack enough strength and endurance in the respiratory muscles to withstand respiratory complications, such as infections and lung collapse. Death used to occur within one to two years of life, with a mean of five months. Respiratory weakness and frequent pneumonias indicate poor prognosis. Today, with interventions like ventilators and tracheostomy tubes, these complications are delayed and survival is prolonged. Currently, more than two-thirds of children with MTM survive past the first year of life. In X-linked MTM, contrary to prior thinking, the muscle weakness does not appear to be progressive. Children with autosomal recessive MTM usually survive past infancy. Those with autosomal dominant MTM even survive into late adulthood, and the disease is compatible with a normal life expectancy.
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Muscular Dystrophy Association. 3300 East Sunrise Drive, Tucson, AZ 85718-3208. (800) 572 1717. (April 11, 2005.) <http://www.mdausa.org>.
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National Organization for Rare Disorders, Inc. 55 Kenosia Ave, PO Box 1968, Danbury, CT 06813-1968. (800) 999 6673. (April 11, 2005.) <http://www.rarediseases.org>.
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Chitra Venkatasubramanian, MBBS, MD