Gene hunters have moved a step closer to finding the mutation responsible for a rare inherited illness that has crippled scores of people in a single Maryland family, the descendants of Thomas Mattingly, an English colonist who died in St. Mary's County in 1664.
In the current issue of the American Journal of Human Genetics, a team of scientists say they have narrowed their search to one tip of chromosome No. 9, one of the 23 that contain the human genetic blueprint.
In doing so, they've winnowed the number of suspect genes from the 100,000 that comprise the human genome to perhaps 100. Pinpointing the gene could one day yield therapies for the Mattingly family illness, researchers said yesterday. And it could shed light on the causes of other neurological ailments.
"Our plan at this point will be to continue mapping studies with the family to try to narrow the region to be studied even further," said Dr. Phillip Chance of the University of Washington, who leads the hunt for the gene. "It's still very much a fishing expedition, but at least we know where to fish now."
Dr. David Cornblath, a Johns Hopkins University neurologist who has examined more than 100 members of the Mattingly clan, said tracking down genes is like looking for a missing person somewhere in the United States. Researchers, in effect, have zeroed in on a specific block in Baltimore, Cornblath said. "Now we just have to figure out which is the right house."
Mattingly disease first strikes its victims in their teens, and typically surfaces as a sudden weakness in the ankles and wrists. Over the course of decades, it paralyzes hands, feet, arms and legs.
Its effects resemble those of amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease. Unlike ALS, Mattingly disease has never been found outside of one branch of the Mattingly clan. It starts much earlier in life and advances much more slowly. And it is not known to be fatal.
Andrew Mattingly Jackson Jr., a 70-year-old Parkville resident, can't bathe, dress or feed himself, and can barely lift his arms. The retired Black & Decker manager, who worked for years to get scientists interested in studying his family's rare ailment, is gratified that they are finally close to finding the mutation.
But he's also anxious for answers.
"I'd like to see something happen real fast," said Jackson, whose 48-year-old son, Dwight, can still walk short distances, but now spends most of his time in a wheelchair. "I would like to see a drug that I could take that would stem the tide of this disease."
Fifty-two members of the Mattingly clan have the illness, while another 37 are likely to develop it one day.
For years, the disease went unrecognized. Jackson discovered he was ill in 1947 but didn't know with what. Scientists at the National Institutes of Health first studied Mattingly disease 35 years ago. But they didn't have the modern tools needed to track down its source.
Chance, recruited by Hopkins researchers, began searching for the mutation five years ago. He and his team spent hundreds of hours in the laboratory until they found a segment of chromosome No. 9 shared by all of the affected Mattinglys.
About 100,000 genes are scattered through the chromosomes packed into every human cell. Each chromosome is a tiny coil made of molecules of DNA, or deoxyribonucleic acid. Each gene consists of a separate sequence of DNA along one of those coils.
Taken together, the chromosomes contain all the instructions needed to build and operate a human body.
There is no guarantee that identifying the gene will lead to a treatment. But, Chance said, it's the Mattinglys' best bet.
"If you don't know anything about the basic molecular mechanisms in a disorder, it is very unlikely that you will come up with a suitable therapy," Chance said.
Once the gene is identified, Cornblath said, researchers will try to create a strain of mice with the same mutation so the disease can be studied in the lab. Eventually, doctors may try inserting a working copy of the affected gene into diseased nerve cells.
"At this point it's in the hands of the gene guys to tell us what it is, then we can move forward," Cornblath said.
Pub Date: 3/03/98