Dr. John Day found the scenario perplexing. A Minnesota family visiting the University’s Muscular Dystrophy Clinic had all the symptoms of the disorder, but existing genetic tests yielded negative results.
None of the family carried the known mutated gene responsible for myotonic dystrophy — the most common form of adult muscular dystrophy.
And Day knew where to look. Only one region of the human genetic code was known to house the altered gene linked to the neurological disorder.
Day, a neurology department assistant professor, and 63 members of a Minnesota family have their answer nearly three years after setting out to solve the mystery.
Using DNA collected from the large family, Day and neurology colleague Dr. Laura Ranum identified a second rare cause of the disease. They found it located in a different region of the human genetic code after scanning all 23 chromosomes in human DNA.
The results, published in June’s Nature Genetics, are only the second time scientists have been able to identify a source of the disease.
Numerous organs, including the heart, can be affected by the neurological disorder. The disease can also cause muscle weakness and cataracts, and can lead to lung failure.
The discovery can lead to early identification of the disease. Myotonic dystrophy has been known to lie dormant in the body for as many as 50 years.
Ninety-eight percent of those with the disease carry an abnormal gene identified in 1992 by researchers funded by the Muscular Dystrophy Association. Day and Ranum’s research participants represent the 2 percent that could not be diagnosed using data from the 1992 breakthrough.
The 1992 discovery raised hopes, but a cure remains elusive. Though the altered gene is undeniably linked to producing the disease, the cause-and-effect relationship between the two remains a mystery.
“It didn’t pan out,” Day said. “It’s still very confusing. No one can understand why that mutation, in a very silent part of the gene, can cause all those problems.”
By comparing data from the two discoveries, Day and Ranum said they hope to unravel how all forms of myotonic dystrophy occur.
“It remains such an enigma,” Ranum said. Ranum’s genetics lab conducted two years worth of tests, which eventually identified the chromosome through a tedious process of elimination.
“There is a lot left to do,” Day said. Working with a second large Minnesota family, Day and Ranum said they want to further clarify their discovery.
The lab must now sift through the 10 million possible genetic codes that form a human’s genetic blueprint. The mutation might be as simple as one missing combination, or the problem might be additional sequences cluttering the genetic instructions.
Sorting through the myriad of possible combinations will not be easy.
“You’re looking for the proverbial needle in the haystack,” said Dr. Ralph Krahe, assistant professor in the division of human cancer genetics at Ohio State University.
Monday’s publication sparked the interest of a small core of scientists across the globe who study the rare neurological disorder, including Krahe.
Krahe’s research on myotonic dystrophy spans eight years. The University’s research creates an exciting foundation for scientists in the field, he said.
“I’m building as we speak,” Krahe said. The Ohio State researcher said he will test the four families involved in his research for the genetic anomaly Ranum’s lab located.
The study contributes to a rapidly expanding body of information about the disease that affects 100,000 Americans, said Jim Brown, director of public affairs for the National Muscular Dystrophy Association.
A second cause for the disease could help explain its far-reaching consequences, he said.
Ranum and Day traveled across the state to visit affected family members, and even attended large family gatherings. Day continues to tour the United States to visit family members, though most are located in Minnesota and the Midwest. Their ranks continue to grow as additional family branches are uncovered. Day has received an enthusiastic welcome from those he has met.
Until the lab pinpoints the specific sequence of genetic code responsible, family members will not know the results of their individual make-up. At that point, a genetic counselor will discuss with family members the repercussions of having genetic information.