In a finding that adds a strange new twist to traditional genetics, scientists have discovered that the most common form of muscular dystrophy is caused by a gene that gradually grows bigger each time it is inherited. And the bigger it gets, the worse the disease.
The discovery about myotonic dystrophy, made at the same time by three separate groups of scientists, brings to light a novel mechanism of inheritance, involving a sliding scale of genetic damage that gets more severe with subsequent generations.
This is in distinct contrast to the prevailing concept that genes are handed down through generations essentially unchanged and that either a gene is normal or it is not.
It means, for example, that a genetic counselor may have to advise patients that they are carrying a gene that will not affect them or their children but may affect their great-great-grandchildren.
"This opens up moral, social and ethical problems that were totally unanticipated," said Dr. David Housman, a molecular geneticist at the Massachusetts Institute of Technology, who is a member of one of the groups that made the discovery.
Three papers describing the findings are being published today in Nature, a British science journal.
Geneticists said the finding was a complete surprise. It comes hard on the heels of similar findings for two other genes, one that causes fragile X syndrome, an inherited form of mental retardation, and one that causes X-linked spinal and bulbar atrophy, a rare wasting disease whose gene is on the X-chromosome.
Dr. Housman said that in the two other diseases, the expanding region of the gene consists of three nucleotides, the chemical building blocks of the gene, that even in normal individuals are repeated. In people with the disease, this region starts growing out of bounds, a "replication catastrophe," Dr. Housman said.
He said he would not be surprised if the same sort of replication catastrophe underlies the expansion of the myotonic dystrophy gene. And, he added, once the process begins it continues with each generation, with the region growing ever bigger.
"This whole business is fascinating and to a large extent completely unexpected," said Dr. Bert Vogelstein, a molecular geneticist at Johns Hopkins University School of Medicine.
He said that now that it has been established that a gene can grow and become more mutant with each generation, geneticists have to consider the startling possibility that other mutant genes might gradually cure themselves over generations.
"It really opens up a whole new way of thinking about inheritance," he said.
Dr. David Ledbetter, a geneticist at Baylor College of Medicine in Houston, said, "Now we have three examples, so we know it's not just one bizarre situation." He added that researchers throughout the world were hunting for other genetic disorders inherited in the same way.
As a result of the new findings, investigators now have a precise way of diagnosing myotonic dystrophy by looking for the expanded genetic region.
Myotonic dystrophy affects at least 1 in 8,000 people. But it has been difficult to determine the true incidence of the disease because only its severe form is clearly recognized.
People with myotonic dystrophy have trouble relaxing their grip. Ifthey shake someone's hand, for example, they find it hard to let go. Their muscles also weaken and atrophy. But, unlike many other genetic disorders, myotonic dystrophy also affects virtually every organ and tissue of the body.
It causes cataracts, alters the conduction of electrical impulses in the heart, makes men go bald, makes men's testicles and women's ovaries wither and can cause diabetes.
The first signs of myotonic dystrophy can appear at any time from birth to old age. And the symptoms can range from so mild as to be all but unnoticeable to deadly.
Myotonic dystrophy is a dominant disease. Any child who inherits the gene from a parent will get it.
For years, neurologists, who saw the worst cases, reported that the disease seemed to get worse with every generation.
Dr. Robert Korneluk said that often the first time a family learns it carries the gene is when a baby is born with the severe form.
But then, he said, he will test the mother and learn that she has a slight difficulty in relaxing her grip, which she had never noticed before. Probing further, he will find that her father had cataracts.
Dr. Korneluk is a member of one of the groups that made the discovery about the nature of the myotonic dystrophy gene.
Dr. Housman said that when neurologists described the way the disease grew more devastating with each generation, geneticists dismissed the information. They argued that that observation made no genetic sense.
Now, Dr. Housman said, it turned out that the neurologists were right. The more the gene is expanded, the more severe the disease and the earlier its age of onset. And the gene gets bigger with every generation.