Interview with Dr. Gail Herman
From August 1996
Gail Herman, M.D., PhD. is a genetics researcher interested in
X-Linked Myotubular Myopathy. We asked her about the recent announcement of a responsible
gene as well as some questions about her research.
Q. Researchers in Europe have recently announced that they have
found a gene responsible for XMTM. Is this the only gene responsible for this disease or
are there others?
A. We don't know yet. In the original published paper, mutations
(changes in the gene which cause the disease) were found in only a small number of MTM1
patients. However, the researchers did not look through the whole gene because they are
missing a piece of it and they concentrated on changes which were eaiser to spot. There is
a second very similar gene close to the one in which they did find some mutations. So far,
no mutations have been found in this second gene but we and other researchers will check
this one too in the near future. There are at least two other genes related to the MTM1
gene located on chromosomes other than the X. These may be involved some autosomal or
milder MTM cases. Until we can analyze the entire MTM1 gene in a good number of cases
which are clearly X-linked (multiple affected males inherited through the mother's
family), we won't know for sure if this is the only gene involved in X-linked MTM.
Q. In their article, the researchers said that the gene they
discovered is responsible for a protein called myotubularin. What is the role of
myotubularin in muscle development?
A. Again we don't know yet. They "invented" this name for the
new protein which is common when there is something new whose function is not known. There
are some parts of the gene and protein that suggest it plays a role in transmitting
signals - specifically, it may remove phosphate molecules attached to some protein or
proteins. This is not proven yet and is an area where researchers are actively involved:
to determine if it does remove phosphates and if so from what proteins and in which
Q. What are the implications of all this concerning a possible
A. It is too soon to have a good idea about whether treatment will be
possible in the near or even distant future. If the protein is found in the blood and
gives signals to muscle cells, it might be possible to give that protein signal and
improve the muscle cells. In most cases, this is not possible and the protein must get
into each muscle cell. If timing is critical (it needs to be present before the baby is
born), it would be even harder!
Q. Does this make pre-natal testing or the identification of
possible carriers more reliable?
A. In general, YES! This is the first and usually easiest benefit from
having the gene. In the best of cases, the mutation or change is the same in all patients
or very easy to find; in the worst, it is always different and very difficult to find. It
appears that MTM1 will be somewhere in the middle. The gene is not too big but the changes
are very small and differ (we think) in most patients. We and others are looking for these
changes or mutations on a research basis now. In the future, whether such testing will be
available on a fee for service basis is not clear, but hopefully, a few labs in the world
will take it on.
For now, once a change is found in an affected boy, we can test other
family members, in particular, a mother of a sporadic case to see if she is a carrier.
Then one could do other carrier testing or prenatal diagnosis. In some cases, it may be
easier to use the linkage type of testing which was done before the gene was isolated, but
families would know who was at risk. Until a mutation is found in a family, no new type of
testing is possible. We and others will likely analyze some number of families to gather
information....so if a family wants to be included they need to contact a group working on
the disease as soon as possible to be included. We, for example, may not accept many more
sporadic cases but are interested in families with more than 1 affected, milder families
which may not be X-linked, or families with other associated medical problems in addition
Q. You've been looking into the relationship between XMTM and
several blood disorders. What can you tell us about that?
A. As boys with MTM1 receive better care and live longer, we are
becoming aware that some of them have other medical problems. Virutally all of the boys
have undescended testes at birth. Rarely there can be other genital problems. Some boys
have larger than normal fluid spaces in the brain (hydrocephalus). Some boys have problems
with blood clotting abnormally and have had bleeding or require vitamin K (which helps
blood clot normally). Two boys (that we know of) have abnormally shaped red blood cells
(called spherocytosis). Luckily this is mild but can cause mild anemia, elevated bilirubin
(yellow jaundice) and even gallstones. Sometimes the bleeding has taken the form of ulcers
or hemorrhage after a procedure, like a liver biopsy. Dr. Herman is very interested in
understanding better what these problems are, who is at risk, and how to screen for them
(see below). For now, we do not understand these questions but believe they are part of
MTM1 since we know the gene works in all cells not just muscle.
Q. There are a number of research groups around the world looking
into Myotubular Myopathies. Do you know what plans there are to continue with this work?
A. A large MTM meeting will be held in Europe in mid September, like
last year. Workers are trying to gather clinical data and information about mutations to
share at the meeting. Different groups are tackling different aspects of the new questions
about what MTM1 does, what the other related genes do, how best to diagnose it, can we
envision a treatment, etc. Research will continue and likely intensify now that we have
some idea about where to focus.
Q. At times you have recommended an osmotic fragility test (for
spheroctytosis) and a liver function test be performed on affected kids. Under what
circumstances do you recommend these tests?
A. I think for now until we know more about who is at risk and when, I
would recommend a CBC and Chem20 every year on all MTM1 boys. I think all boys should have
an osmotic fragility test by age 6-12 months. If spherocytosis is found, then physicians
should not worry about a mild increase in bilirubin. If other liver tests are abnormal,
they should be followed but there should be great care exercised before doing procedures
such as liver biopsy until we know more.