CENTRONUCLEAR AND MYOTUBULAR MYOPATHY INFORMATION POINT
United Kingdom
Established March 2001
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What is Centronuclear / Myotubular Myopathy
(A Report Written by Gail E. Herman, MD/PhD, Professor and Director, Center for Molecular and Human Genetics, Columbus Children's Research Institute and Dept of Pediatrics, The Ohio State University, Columbus, OH)
Centronuclear or 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 Centronuclear / Myotubular Myopathy, it appears that ther muscle cells are stopped or arrested at a middle stage.
There are three types of myotubular myopathy based in the pattern of inheritance and clinical severity:
1. x-linked
2. autosomal dominant
3. autosomal recessive
X-Linked
This is the most severe form, generally presenting at birth in affected males. In the past, virtually all the 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 and the muscles get slowly, very slowly, stronger with 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 that some boys with presumed x-linked 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 problenms but physicians caring for these patients should be aware of their possible occurence.
Autosomal
Less is known about the autosomal forms of this condition and the symptons can be quite variable. In general, patients with autosomal dominant, where it is passed 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 it 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, this is probably the most common situation in families that we see. There is also 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 this condition will do and what the chance of having another affected child is in a family.
To better understand how this condition occurs, it is necessary to review a bit of basic genetics: All our genetic information is organised in structural units called genes which are made of DNA. The genes are organised on larger structures, called chromosomes, which occur in pairs. Each cell in our body contains 23 pairs of chromsomes, 44 non-sex chromosomes and two sex chromosomes. Women have a pair of X chromsome, one received from their mother and one from their father. Boys have only one X chromosome which they receive from their mother. They receive a Y chromosome, determining malesness, from their father. Thus, we have two copies of all of our genes, except boys only have 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 funtioning properly, the other can compensate and the individual has no problem. Thus would be the case for a woman who had an abnormal gene for MTM on one of her two 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 that a boy can have an X linked disease. More than half of 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 mutuation. In this case, no none 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 with x linked MTM being a carrier and having a 50% (1 in 2) risk of each male child being affected. We would expect that if a female inherited the abnormal MTM gene, they would be a carrier and usually not have any physical problems. This would also be a 50% chance with each girl conceived if the mother is a carrier. Sometimes, a muscle biopsy on a mother can show abnormal muscle cells but a normal biopsy does not rule out the possibility of being a carrier. Special strains of muscle biopsies may help distinguish the x linked from other forms of MTM but these sre 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 abonormal in an affect child. Each parent in this form carries one normal and one abnormal copy but have no muscle problems themselves. In this case, the single normal copy is prptective. As you can see, this can be very complicated and indicates that differenct genes and proteins in the body must function in very differnt ways. Sometimes having a problem with one half of a protein causes disease and sometimes all of the protein must be abnormal.
The x-linked mtm1 gene has been localised to the bottom of the human x chromosome and sometines, 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, parental 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 reasearch. Once the gene is found it should (hopefully) rapidly lead to a better diagnosis of cases and an 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 for the autosomal forms of MTM map. It is possible 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 is likely that all of us carry several mutuated or abnormal genes. May of the changes produced by these genes are so mild they may go unoticed. One should not feel unusual then for having a child with a genetic condition, approximately 3% of all childern are born with some recognisable birth defect and probably, all of us would have some defect or abnormal gene if we looked hard enough.
CENTRONUCLEAR AND MYOTUBULAR MYOPATHY INFORMATION POINT
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