[Note: We are deeply grateful for Dr. Herman taking the time to write the following article. This has been retyped, so all typos, mis-spellings, etc. are ours, not hers. Reprinted by permission.]
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 rile 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 ANALYIS). 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.)