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07.14.2014

Myotubular myopathy

Myotubular myopathy (also called centronuclear myopathy) is a family of rare, inherited diseases. Manifesting itself as a defect in the cell structure of voluntary muscles, it causes low muscle tone and, in most forms, is usually apparent at birth. Affected children have diminished respiratory capacity and are often partially or totally ventilator dependent.

Overview of myotubular myopathy
by: Gail E. Herman, MD, Ph.D.

Myotubular myopathy is a group of inherited muscle disorders for which we do not presently know the cause. These disorders are defined by the presence of centrally located nuclei in muscle biopsy specimens. During the development of a baby in the womb, our muscles go through a complicated series of changes. In myotubular myopathy, it appears that the muscle cells are stopped or arrested at a middle stage.

There are three types of myotubular myopathy based on the pattern of inheritance and clinical severity -- X-linked, autosomal dominant and autosomal recessive. X-linked myotubular myopathy (MTM1) is the most severe form, generally presenting at birth in affected males. In the past, virtually all boys with this condition died shortly after birth or in the first year of life. With better diagnosis and treatment, including preventative tracheostomy and G-tube placement, more of these children are surviving longer. From this we know that the condition is not progressive and the muscles get slowly, very slowly, stronger over time. We also know that intelligence is normal if there has not been a lack of oxygen in the newborn period. Recently, we have become aware of that some boys with presumed X-linked MTM have associated medical problems including hydrocephalus, liver dysfunction, bleeding and hematologic problems, and genitourinary abnormalities in addition to undescended testes. We don't understand the cause for these problems but physicians caring for MTM patients should be aware of their possible occurrence.

Less is known about the autosomal forms of MTM and the symptoms can be quite variable. In general, patients with autosomal dominant MTM, where it is passed on from generation to generation, first have problems in late childhood or even as adults. This condition seems to progress or get worse over time. The autosomal recessive form can begin at birth but is often less severe than the X-linked. Both autosomal forms affect boys and girls equally.

Although the clinical features may distinguish the three types somewhat, there is overlap and it can be impossible to tell in an isolated affected boy what the pattern of inheritance is. Unfortunately, that is the most common situation in the families we see. There is no absolute biochemical, DNA or pathology test which can tell conclusively the pattern of inheritance in an isolated case. This becomes extremely important to help predict how a child with MTM will do and what the chance of having another affected child is within a family.

To better understand how MTM occurs, it is necessary to review a bit of basic genetics: All of our genetic information is organized in structural units called genes which are made of DNA. The genes are organized on larger structures called chromosomes, which occur in pairs. Each cell in our body contains 23 pairs of chromosomes, 44 non-sex chromosomes and two sex chromosomes. Women have a pair of X chromosomes, one received from their mother and one received from their father. Boys have only one X chromosome which they receive from their mother. They receive a Y chromosome, determining maleness, from their father. Thus we have two copies of all of our genes, except boys have only one copy of any gene located on the X chromosome.

All of us have occasional errors in the genes and DNA that we contain, In most cases, since we have a pair of genes, if one gene is not functioning properly, the other can compensate and the individual has no problem. This would be the case for a woman who has an abnormal gene for myotubular myopathy (MTM) on one of her tow X chromosomes. However, if she passed that abnormal X onto her son, there would be no good copy of the gene and he would have a genetic disorder. There are two ways a boy can have an X-linked genetic disease. More than half the time, the mother carries an abnormal MTM gene. Sometimes there may be other affected males in the family which is a clue to the pattern of inheritance. The other way this can occur is what we call a new mutation. In this case, no one in the family carries an abnormal gene, but there has been a change (a MUTATION) in the genetic material on the x chromosome that forms the affected boy. Statistically, there is about a two thirds chance of a mother of an isolated male being a carrier. This person would have a 50% (1 in 2) risk of each male child being affected. We would expect that if a female inherited the abnormal gene she would be the carrier and not have any physical problems. This would also be a 50% chance with each girl conceived if the mother is also a carrier. Sometimes, a muscle biopsy on a mother can show abnormal muscle cells, but a normal muscle biopsy does not rule out the possibility of being a carrier. Special stains of muscle biopsies may help distinguish the X-linked form from other forms of MTM, but these are still relatively new technologies.

For autosomal dominant MTM, it takes only one abnormal copy of a gene on a non-sex chromosome to have the disease . In autosomal recessive MTM, both copies of a non-sex chromosome gene are abnormal in an affected child. Each parent in this form carries on normal and one abnormal copy, but have no muscle problems themselves. In this case, the single normal copy is protective. As you can see, this can be very complicated and indicates that different genes and proteins in the body must function in very different ways. Sometimes having a problems with one-half of a protein causes disease and sometimes all of the protein must be abnormal.

The X-linked MTM1 gene has been localized to the bottom of the human X chromosome and sometimes, it is possible to track the disease in a family where more than a single boy has been affected (called LINKAGE ANALYSIS). If geneticists can track the disease in a family, prenatal diagnosis is possible. I also expect that the gene for X-linked MTM should be isolated in the very near future, and it is a focus of intense research. Once the disease is found, it should (hopefully) rapidly lead to better diagnosis of cases and the ability to tell for sure if a case is the X-linked form. Unfortunately, finding ways for better treatment could take much longer.

We do not know at all where the genes of the autosomal forms of MTM map. It impossible that once the gene for the X-linked form is found, it will provide clues about likely genes which might cause the other forms.

I would like to stress that it is likely that all of us carry several mutated or abnormal genes. Many of the changes produced by these genes are so mild that they may go unnoticed. One should not feel unusual, then, for having a child with a genetic condition. Approximately 3% of all children are born with some recognizable birth defect, and probably all of would have some defect or abnormal gene if we looked hard enough.

Medical reference: Wallgren-Peterson et al. J. Med Genet. 32:673-679, 1995.

Frequently asked questions (FAQs) about myotubular myopathy

Please remember that none of these questions or answers should be used as a replacement for proper genetic counselling.

(1) What is the outcome for kids diagnosed with MTM shortly after birth?
This depends largely on the severity of the disorder and on the interventions taken. Contrary to what is said in much of the available literature, MTM expresses itself in a range of severities. In some cases, it is only slightly noticeable, in some cases it is quite severe.

In the milder cases, it is often managed symptomatically. The kids have more difficulty breathing at first and are very susceptible to the flu, pneumonia and other respiratory diseases. In these cases, the muscles are weaker than they would be if unaffected but are still strong enough to enable many everyday functions. For example, some of these kids are able to walk.

In the more severe cases, long-term survival is unlikely without a tracheotomy and mechanical ventilation. In these cases the patients are usually wheelchair bound and require significant assistance for daily living.

Much of the literature indicates very high mortality rates (as high as 90%) for kids born with MTM. Our experience is different. While mortality in the first year is still very, very high when compared to the general population, with appropriate interventions it nowhere approaches the virtual certainties implied in the literature. Data on this is tough to get and tougher to verify, so we are unable to give any validated statistics supporting our position. However, our experience in discussions with over 200 families is that, with the proper interventions, approximately two-thirds of kids with MTM survive past the first year.

(2) Is there a cure for myotubular myopathy?
Unfortunately, at this time, no. The root cause of MTM is genetic. A problem in a person's genes cause, for reasons still unknown, a structural defect in the skeletal muscles.

(3) I started developing symptoms and was diagnosed with MTM later in life. What does this mean?
We think this is not seen with the X-linked form. All X-linked patients we know of presented at birth or within a few months of life. It could be autosomal recessive or dominant. Again, we think the dominant is milder and might be more likely to present later in life. However, until the autosomal genes are isolated this is only a guess, unless there is a clear history in the family that tells us what type of autosomal MTM this is.

(4) Is there a test to see if I'm a carrier for MTM?
• In the past, doctors have performed muscle biopsies on mothers of isolated males with MTM1. The biopsy can detect some abnormal muscle cells in 50-70% of carrier females. A normal test, however, does not rule out being a carrier.

• If a research group finds a mutation (change in the MTM1 gene itself), then the mother can usually be tested for the presence of this mutation. This is the best way to determine if a woman is a carrier.

• In some families with more than one male affected with MTM1, an indirect molecular test, called linkage analysis can be used to determine if someone is carrier. This usually involved testing several people in the family rather than just one affected male and the potential carrier female.

• This mutation test is now available as a fee for service through the University of Chicago (888-UC-GENES is the phone number). It is our understanding that the success rate at detecting a mutation is ~80%. For more information see the university of Chicago genetic clinical services website.

Studies from Dr. Herman's laboratory on a relatively small sample of sporadic cases (~20) suggest that at least 90% of mothers of affected boys are carriers. This is significantly higher than the predicted 2/3 (66%) from theoretical calculations.

(5) Is pre-natal testing for MTM available?
Just as in carrier testing, there is no easy, simple standard prenatal test for MTM. If a mutation has been found in a family, a pregnancy can be tested for the presence of that mutation. A few specialized diagnostic laboratories are willing to do this sort of prenatal test. It is extremely important to already know the mutation prior to undertaking another pregnancy since there may not be sufficient time to first find a mutation and then test a pregnancy. For cases with more than one affected in a family, linkage testing can be performed without knowing an exact mutation. For many affected pregnancies, there is decreased fetal movement and accumulation of too much fluid, but this may occur too late to be helpful in prenatal testing. Again, please consult your geneticist or genetics counselor.

(6) What type of MTM does my child have?
There are 3 types of MTM based on their pattern of inheritance: X-linked, autosomal dominant, and autosomal recessive.

X-linked appears to be the most common and is seen in boys almost exclusively. Typically, males are severely affected at birth with decreased tone and problems breathing. However, our mutation and clinical studies have shown that a few boys with X-linked disease have a much milder course.

The autosomal recessive form can affect males and females equally. It may start after birth and become worse over time. The gene for this (and the dominant form) has not been identified as yet.

The autosomal dominant form also affects males and females and can be transmitted from a parent to a child. It may be the mildest of the 3 forms and begin in childhood, again becoming worse with age.

The best way to tell if someone has MTM at all is still through a muscle biopsy. Once the pathologic diagnosis is made, molecular testing to see if this is the X-linked form would be the next best step in a male. If no mutations are found, this may be one of the autosomal forms, or perhaps, still X-linked where the exact change was not found or missed. Experience from Dr Herman's lab as well as others suggest that ~80% of boys suspected of having X-linked MTM will have mutations found in this gene.

(7) I've already had a child with MTM. Will my next child be affected?
If MTM is known to exist within a family, the chances that any particular child will be affected depend on the form of MTM present and, if the form is x-linked, the sex of the child. The inheritance of the MTM gene in any single child is an event independent of what happened in any other child with the same parents. In other words, whether earlier children were affected or not does not have any bearing on the odds that the next child will be affected.

If a mother is known to be a carrier of MTM (either through previous children or through carrier testing) and the form of MTM is known, then the chart below describes the probabilities of any particular child being affected.

Sex of Child
Male Female
Autosomal Dominant
(same parents for each pregnancy)
1 in 2 1 in 2
Autosomal Recessive 1 in 4 1 in 4
X-Linked 1 in 2 zero
Note: This table should not be used as a replacement for proper genetic counselling.

If the mother is not a carrier then the risk of another affected child is on the order of 1-3%.

These different risks underscore the value of DNA mutation testing and the need to seek appropriate genetic counseling any time a child is diagnosed with MTM. It also explains why it is so important to find the other autosomal MTM genes so we can, hopefully, identify which type of MTM it is in all patients.

(8) Are there other disorders that accompany MTM?
There are a few other disorders that seem to accompany x-linked MTM. There have not been any additional disorders associated with the other forms of MTM.

A number of kids with confirmed XMTM also have shown a variety of other disorders, most notably hydrocephalus, liver dysfunction, blood disorders (often in the form of spherocytosis), gall stones and genitourinary abnormalities in addition to undescended testes. These other disorders accompany MTM far too frequently to be unrelated. Physicians caring for MTM patients should be aware of their possible occurrence.

An article describing these other disorders and their relationship to MTM has just been published. See the Myotubular Myopathy Resource Group page on research for more details.

(9) Is there any research being done on MTM?
Yes. Research is underway at several centers in the USA and in Europe. See the Myotubular Myopathy Resource Group page on research for more details.

Special thanks to Gail Herman, PhD, MD for supplying answers to many of these questions and to our good friend, Jerome McCombs, PhD, for reviewing these FAQs.

This information was developed by the Myotubular Myopathy Resource Group and is herewith used with permission.

Myotubular Myopathy Resource Group. Frequently Asked Questions (FAQs) about Myotubular Myopathy. Available at: https://www.mtmrg.org/faqs.html. Last accessed February 24, 2014.

The information in this document is for general educational purposes only. It is not intended to substitute for personalized professional advice. Although the information was obtained from sources believed to be reliable, MedLink Corporation, its representatives, and the providers of the information do not guarantee its accuracy and disclaim responsibility for adverse consequences resulting from its use. For further information, consult a physician and the organization referred to herein.

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