Beggs Laboratory

Nemaline Myopathy

Nemaline myopathy (NM) is a rare neuromuscular disease that is associated with a broad range of special medical needs, such as weakness of the respiratory muscles and those in the face, arms, legs and the trunk as well as low muscle tone. Diagnosis is based on the presence of rod-like structures known as "nemaline bodies" in a patient's muscle biopsy.

The clinical presentation of nemaline myopathy can be quite variable. Some patients have a few findings while others may have numerous issues that require constant medical attention. Most patients have symptoms at birth or start developing symptoms during the first year of life. When nemaline myopathy is present at birth, the disease outcome is usually more severe. Patients with this form of NM show distinct muscle weakness and low muscle tone. These patients tend to have serious, life-threatening breathing problems due to respiratory muscle weakness. There are also later-onset forms of nemaline myopathy, with milder symptoms appearing in childhood or adulthood.

For more information, read the Review Article on NM.

Our laboratory is interested in studying DNA and muscle tissue samples of these individuals since it would provide insight into the genetic cause of their muscular condition. Identification of these genes could have direct clinical benefit to patients and their families by allowing for specific diagnostic testing such as carrier detection and prenatal diagnosis for those who wish. Furthermore, understanding the genetic cause(s) of nemaline myopathy will increase our understanding of muscle biology and provide insights into future development of specific treatments and therapies.

Genetics

Nemaline myopathy may be passed on from parents to children in some families, while in others, it may arise for the first time, with no previous family history of the disorder. When a genetic change occurs for the first time in an individual, it is known as sporadic. On the other hand, when NM is inherited, it can be passed on in an autosomal dominant or in an autosomal recessive form.

Microscopic structures called thin filaments, are in part responsible for the formation of skeletal muscle fibers. The thin filaments are in turn formed by different kinds of muscle-specific proteins, many of which are altered in NM. Currently, we know of five proteins that when altered, can cause NM. These proteins are called actin, tropomyosin 2, tropomyosin 3, troponin T, and nebulin. The figure shown below illustrates how these proteins get together to form the skeletal muscle thin filaments:

All proteins are made by genes. Genes are individual units of information that tell the body all the necessary instructions for development and function. The DNA, also known as the genetic material, is the chemical structure that harbors all of our genes. Sometimes genes acquire mutations. Mutations are DNA changes that have an impact on our health. As the figure above shows, the genes that make actin, tropomyosin 2, tropomyosin 3, troponin T, and nebulin are called:

• ACTA1
• TPM2
• TPM3
• NEB
• TNNT1

Recently we discovered mututation in a sixth gene for NM called CFL2.

A person with NM may have an alteration in one of these five genes, resulting in a protein that does not work properly. Some patients that have been diagnosed with NM, when tested, have no detectable alteration in any of the known genes. This why it is suspected that there may be additional genes involved in the cause of this condition that have not been discovered yet.

Although there is no clinical diagnostic genetic testing for TPM2, TPM3, NEB or TNNT1, GeneDx offers clinical testing for ACTA1 mutations. As you read above, ACTA1 mutations are responsible for approximately 15 % (15 in 100) cases of NM. This means that a negative ACTA1 test does not rule out the possibility of passing NM to a child.

Research

In the Beggs laboratory, one of our goals is to determine which additional genes and proteins are involved in nemaline myopathy. If you are the parent of a child with nemaline myopathy, if you yourself are affected, or if you are the healthcare provider of a patient with nemaline myopathy, you may be able to help us find new genes and proteins associated with nemaline myopathy. With the generous help of enough candidate families, we may be able to learn information that will hopefully help us to better understand this disorder, improve diagnosis and develop new treatments and therapeutic methods.