What causes congenital muscular dystrophy (CMD)?

It isn’t known why the CMDs cause muscle weakness earlier than other types of muscular dystrophy. One possibility is that the muscle proteins affected in CMD are required early in the development of an infant’s muscle, while muscle proteins linked to other muscular dystrophies don’t become important until the muscles begin to get a lot of use as a child grows.

It’s important to note that just because the muscle weakness in CMD starts earlier, CMD isn’t automatically more severe than other forms of muscular dystrophy. The degree and rate of progression of muscle weakness varies with different forms of CMD and from one child to the next.

In the mid-1990s, researchers found that a deficiency of a protein then called merosin and now more often called laminin 2 was the underlying cause of at least some cases of CMD. Merosin normally anchors muscle cells to a structure that encases them (like the skin on a hot dog) called the basal lamina.

Doctors began to classify CMD as either “merosin-deficient” or “merosin-positive.” The gene for merosin is on chromosome 6.

Then, in 1998, researchers identified mutations in the gene for integrin as another cause of CMD. Integrin, which surrounds and supports each muscle fiber, connects laminin 2 with proteins inside the cells.

As the 20th century ended, researchers began to suspect that Ullrich’s disease, now known as Ullrich CMD, was caused by a lack of collagen 6, a ropelike protein located in the area where laminin 2 is found.

Collagen 6, which helps support the muscle fiber, probably affects muscle cells via its connection to laminin 2. Laminin 2, in turn, connects to muscle cells via either of two other proteins: integrin or dystroglycan.

Dystroglycan links the outer surface of muscle cells with structures outside them via branches, made of sugar molecules, that protrude from its surface and stick to laminin.

The branch structure explains why mutations in diverse genes all appear to cause CMD. Each of these proteins contributes in a different way to the process of “sugar coating” (glycosylating) dystroglycan. Several forms of CMD that affect not only the muscles but the eyes and brain — Fukuyama CMD (seen mainly in Japan), muscle-eye-brain disease and Walker-Warburg syndrome — arise from defects in these glycosylation proteins.

The illustration below shows the physical relationships among these proteins.

Most forms of congenital muscular dystrophy stem from loss of firm connections between muscle fibers and their surroundings (extracellular matrix).

In 2001, researchers identified mutations in the gene for selenoprotein N1 as a cause of CMD with a rigid spine and sometimes frozen joints at the elbows, hips, ankles or knees. This protein is believed to play a role in muscle development early in life.

What are the inheritance patterns in CMD?

The CMDs are caused by genetic defects that affect important muscle proteins. Most forms of CMD are inherited in an autosomal recessive pattern.

In brief, if a disease is recessive, two copies of the defective gene (one from each parent) are required to produce the disease. Each parent would be a carrier of the gene flaw but wouldn’t usually have the disease.

If a disease is dominant, then only one copy of the genetic defect is needed to cause the disease. Anyone with the gene flaw will have disease symptoms and can pass the disorder to children.

Many times, MD appears to have occurred “out of the blue,” but in reality, one or both parents may be carriers, unknowingly harboring the genetic mutation. Many parents have no idea they’re carriers of a disease until they have a child who has the disease.

A good way to find out more about these risks is to talk to your MDA clinic physician or ask to see the genetic counselor at the MDA clinic. For more, see Facts About Genetics and Neuromuscular Diseases.