Genes

Its only possible to test for the ACTA1 gene as it's the simplest of the 5
genes that cause NM. Our doctor said the other 4 genes are very complex and
finding the marker that indicates NM in those genes is like trying to
identify a single letter in a novel. As such there is no early warning tests
for them as yet. The good news is that if it is the ACTA1 gene causing the
problem they might now be able to test a pregnancy very early on (even
before 12 weeks as is currently the case). Eliza was born through IVF and
there may even be a chance that they can test an embryo pre implantation for
the gene. Our doctors have not given us a guarantee, but they think its
possible (assuming of course it is the ACTA1 gene causing the NM). If this
is the case it certainly makes IVF an interesting option even if you can
conceive naturally.

In terms of lending insight to the inheritance of NM, I think the confusion may
be over the fact that NM can be inherited in at least three different ways. We
inherit two copies of most genes, one from each of our parents. Likewise, we
pass one of each of our genes onto our children. Sometimes a gene can have
a change or a "mutation" which causes it not to work properly.
Nemaline myopathy is generally caused by inheriting one or two mutations
(abnormally functioning genes) involved in muscle functioning. We know of
at least six genes that can cause nemaline myopathy, and there are probably
others that have not yet been identified.

The form of inheritance recently discussed on the NM chatgroup is known as
autosomal recessive inheritance. In this scenario, an individual inherits 2
mutations (2 abnormally functioning copies of a gene), one from each parent.
The parents generally do not have any symptoms of muscle weakness because
they are ?carriers? of the condition. Their second normally functioning copy of
the gene is enough to keep them healthy. A child that inherits both non-working
copies of the gene will have NM.

Other cases of NM are caused by inheriting one mutation. In this scenario,
NM is generally passed directly from from a parent with NM to a child.

NM may also be caused by a new mutation that occurs for the first time in an
individual. In this scenario neither parent is carrying an abnormally functioning
gene that causes NM. Instead, something happens in the egg or sperm that
changes the functioning of the gene, causing the child to have NM.

I hope that this makes sense. Please feel free to ask more questions to clarify
or if you want more details.

Thank you for your email. I know it can be hard to undertand why sequencing
the nebulin gene seems so hard when sequencing the actin gene seems so
simple. Each gene is composed of multiple segments (called exons). Just to
give you an idea, the actin gene has fewer than 10 segments that need to be
sequenced, while the nebulin gene has over 180.

As you stated, many different alterations have been found in the nebulin
gene that results in NM. The reason progress seems to be so slow is that
the gene is so large, it is just not feasible for our labs to sequence every
single individual. That is why our research on the nebulin gene has been
focused on designing a faster and simpler screening method. Our lab, as
well as Dr. Walgren-Peterson's, have been working on this project for
several years, and we have definitely been making significant progress. I am
guessing that it will take at least a couple more years before any technique
is perfected.

Genetic Counceling
To read more about genetic counseling, please visit the National Society of Genetic Counselors (nsgc) web site.
The NSGC also provides contact information of genetic counselors by area.

See details on Dr. Beggs page for contacting a Genetic Councillor in Boston, USA.

Gene	Protein	Dominant	Recessive	Not known
		0	0	0
ACTA1	actin	0	0	1
NEB	nebulin	1	0	1
TPM2	tropomyosin 2	0	0	0
TPM3	tropomyosin 3	0	0	0
TNNT1	troponin T
CFL2	cofilin-2	0	0	0

The following article will be updated by Dr. Beggs team soon.

Genetics. Currently, we know of at least five different genes that are associated with NM. These genes are known by their abbreviations: ACTA1, NEB, TPM2, TPM3, and TNNT1. Each one of these genes carries instructions to make a protein that is important for muscle function. The proteins these genes make are called: actin, nebulin, tropomyosin 2, tropomyosin 3, and troponin T, respectively. A person with NM may have an alteration in any one of these five genes, resulting in a protein that does not work properly. Since there are patients who have nemaline myopathy but no detectable gene alteration, we suspect that there may be other genes that are involved in the cause of this condition. This is why our group is also looking for alterations in other genes as well. Since NM is a condition that arises from gene alterations, it may be passed on from parents to children. There are some families, however, in which NM arises for the first time, with no previous family history of the disorder. We say that in these families NM occurred sporadically. Some families have contacted us to express interest in learning the recurrence chance of NM and how it is passed on in their family. Often, the only way to know this information is through genetic studies.

Information for Patients and Families Boston Children's Hospital We are a group of scientists and doctors studying the genes that may be involved in the cause of muscular disorders. One of our goals is to determine which genes and proteins are involved in nemaline myopathy, a rare muscular disorder. With the generous help of enough candidate families, we may be able to learn information that will hopefully help us understand this disorder, improve diagnosis and develop new treatments. We currently know of five different genes associated with nemaline myopathy. Each of these genes carries instructions to make a protein that is important for muscle function. These proteins are called actin, nebulin, tropomyosin 2, tropomyosin 3, and troponin T. An alteration in any of these genes can result in a non-working protein, causing nemaline myopathy. Some patients do not have an alteration in any of the genes we know about. For this reason, we suspect that there may be additional genes involved in nemaline myopathy yet to be discovered. If you are the parent of a child with nemaline myopathy, or if you yourself are affected, you may be able to make a meaningful difference by helping us find new genes and proteins associated with nemaline myopathy.