Groundbreaking research on type 1 congenital myotonic dystrophy

Each year, the parents of an estimated one in 20,000 newborns are shocked to learn their child has type 1 congenital myotonic dystrophy (CDM1), a progressive and crippling genetic disorder.

Although doctors know that babies inherit CDM1 from their mother and prenatal tests are available, many children are not diagnosed until they are born.

“In these instances, mothers don't know that they have type 1 myotonic dystrophy (DM1) – a common form of muscular dystrophy – because they have mild symptoms or none at all,” notes Mani S. Mahadevan, M.D. a pathologist at the University of Virginia Health System and winner of the 2007 Rachel Fund Award for myotonic dystrophy (DM) research.

DM1 is the nation's most prevalent inherited neuromuscular disorder, afflicting men and women equally. In general, parents with DM1 pass it along to half of their children. Affected sons and daughters usually begin exhibiting symptoms in their teens or twenties. Although symptoms tend to get more severe and appear earlier in life with each successive generation, some people inherit such a mild form of the disease that it goes unnoticed.

CDM1 is by far the severest form of DM. Because they lack muscle tone, afflicted newborns are floppy like rag dolls. Typically, they suffer from poor sucking and swallowing responses, respiratory ailments and impaired motor development. Twenty-five percent of them die within a month. The outlook for those who survive is bleak – they become increasingly weak and disabled and suffer from mental retardation.

Children with CDM1 face a lifetime of physical and occupational therapy and require special educational programs. Currently, there is no treatment that either slows down or cures this disorder.

Changing this prognosis is a goal of Dr. Mahadevan. Over the next two years, the Rachel Fund will be providing $239,756 (Canadian) for his research. In a groundbreaking study published last year, Dr. Mahadevan and his UVa colleagues discovered how to activate and deactivate DM1 in laboratory mice. Now, their goal is to translate what they have learned to benefit humans.

Dr. Mahadevan has been on the leading edge of DM research for more than a decade. In 1992, as a member of a Canadian research group, he helped discover the genetic mutation that causes DM1.

The mutation occurs when a gene called myotonic dystrophy protein kinase (DMPK) makes extra copies of nucleotide sequence consisting of cytosine, thymine and guanine (CTG). In normal individuals, the DMPK gene has between five and 30 copies of the CTG sequence. People with DM1 have 50 to several thousand copies. Babies with CDM1 have more than 1000 of them.

The Canadian team discovered that everyone with DM1 has the CTG mutation on chromosome 19, and this discovery led to the development of a simple gene-based diagnostic test for the disease. The test is now used around the world.

Today, scientists are trying to understand how extra CTG repeats cause DM. At UVa, Dr. Mahadevan has taken this research to the next level. To prove the theory that DM is caused by toxic RNA (ribonucleic acid), his team created a new kind of mouse model. It attached many added CTG repeats to the DNA of a gene that made the muscles in mice glow green under a microscope. This enabled easy observation of what occurred as the DNA converted into RNA and, subsequently, into the proteins that determine the function of the body's cells.

The UVa researchers also devised an “on switch” that activated DM when the mice drank water containing the antibiotic doxycycline. Within a few weeks, the doxycycline caused the mice to begin producing RNA made toxic by extra CTG repeats. The mice became unable to relax their muscles, developed heart rhythm abnormalities and other symptoms of DM1. When researchers removed the antibiotic, mice stopped producing toxic RNA and returned to normal. Only mice with severely damaged hearts did not recover.

“We showed in our mouse model that when you make this poisonous RNA, the mice get various aspects of myotonic dystrophy,” Dr. Mahadevan said. “Then, when you take away the toxic RNA, the mice get back to normal.”

The UVa study appeared in the September 2006 issue of Nature Genetics and can be found online at: http://www.nature.com/ng/index.html

Looking ahead, Dr. Mahadevan said, “The goal of our work is to understand the molecular mechanisms underlying DM and to establish model systems for therapeutic interventions. Based on what we've learned so far, a therapy that silences the expression of the toxic RNA molecule seems to be a viable treatment for DM.”

In the Rachel Fund announcement last month, Dr. Brenda Banwell with Muscular Dystrophy Canada (MDC) noted, “the work of Dr. Mahadevan's laboratory will provide novel insights into myotonic dystrophy – and bridges bench research to clinical observation. We are pleased to fund excellence in research and encourage scientists working on the mechanisms and treatment of myotonic dystrophy to work together to further new insights into this disorder.”

Established by Canadian philanthropist Al Libfeld in 2005, the Rachel Fund is dedicated to advancing research on DM. It is a partnership between MDC and the Canadian Institutes of Health Research – Institute of Muscoskeletal Health and Arthritis.

The grant received by Dr. Mahadevan, who grew up in Ottawa, Canada, is the first presented by the Rachel Fund.

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