New genetic test advances detection and diagnosis of muscular dystrophy

Jun 28 2007

A new genetic test targeting the most common types of muscular dystrophy--those caused by mutations in the dystrophin gene--is far quicker with greater accuracy and sensitivity than existing tests.

It can be used to confirm clinical diagnoses, to test female family members who may be carriers, and to perform prenatal testing.

The test was developed by Michael Zwick, PhD, and Madhuri Hegde, PhD, assistant professors in the Department of Human Genetics and the Emory Genetics Laboratory in the Emory University School of Medicine.

Muscular dystrophy includes more than 30 genetic diseases characterized by progressive weakness and degeneration of the skeletal muscles that control movement. Some forms are seen in infancy or childhood, while others may not appear until middle age or later. Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and primarily affects boys. It is caused by absence of dystrophin, an important muscle protein involved in maintaining the strength of muscle fibers.

According to the National Institute of Neurodegenerative Diseases and Stroke (NINDS), DMD onset is between 3 and 5 years, with rapid progression. Most boys are unable to walk by age 12 and later need a respirator to breathe. Girls in these families have a 50 percent chance of inheriting and passing the defective gene to their children. Becker muscular dystrophy, which is similar to Duchenne but less severe, results from faulty or not enough dystrophin.

As currently implemented the new test, called EmArray Dystrophin, detects 99 percent of mutations in the dystrophin gene including deletions, duplications and point mutations.

The EmArray Dystrophin test uses a new kind of microarray technology that contains the entire sequence of the dystrophin gene, the largest known gene in humans, on a chip the size of a microscope slide. The test initially detects deletions and duplications, then microarray-based resequencing is used to rapidly identify subtle genetic variations that may cause muscular dystrophy.

The EmArray Dystrophin test confirms clinical diagnosis of Duchenne and Becker muscular dystrophy in a male and characterizes the type and size of the mutation. Women with a family history of Duchenne or Becker who are at risk to be carriers can be tested, then, if found to be carriers, can have prenatal testing.

"Previously, access to prenatal testing was limited for some women when the affected male relative was not available for testing. The EmArray Dystrophin test greatly improves access to prenatal and carrier testing for women without the need to test a male relative, in a rapid timeframe," according to Vanessa Rangel Miller, MS. In addition to improved testing, the Emory Genetics Laboratory, Parent Project Muscular Dystrophy, leading researchers and clinicians are working together to develop a database for mutations and clinical data.

"Our new genetic test, along with new therapies currently in clinical trials, is a very positive development for muscular dystrophy patients and their families," says Dr. Hegde.

In the last five years DMD research has accelerated, resulting in more knowledge about the role of the dystrophin gene and an increased understanding about what happens to a muscle cell lacking the dystrophin protein. Researchers around the world are investigating a number of different treatment strategies, all with the goal of slowing or stopping muscle degeneration. Several clinical trials are underway and many others are in development, including testing of an oral medication intended to circumvent mutations in the dystrophin gene and increase normal gene expression.

According to Dr. Hegde, about 13 percent of mutations in the dystrophin gene are nonsense mutations--point mutations in a sequence of DNA that can result in mistakes in gene expression and nonfunctional proteins. New data published online in the current edition of the journal Nature show that PTC124, an investigational new drug designed to bypass dystrophin nonsense mutations and restore a functional protein, was effective in a preclinical (animal) model of Duchenne muscular dystrophy (DMD). (www.clinicaltrials.gov).