Researchers Lupski and Chance study a baffling genetic disease – their own from At Large With Dennis L. Breo with permission of the Journal of the American Medical Association, reprinted from JAMA, November 17 issue, 1993-Vol.270, No.19:2374-2375

Charcot-Marie-Tooth (CMT), a progressive neuromuscular disorder of variable severity, is named after the French and British neurologists who first described its symptoms of muscle weakness and wasting in the feet and hands in 1886. Today, CMT affects one of every 2500 Americans, or 150,000 people, and is the most common inherited peripheral neuropathy.

The search for its causes has led to cutting-edge genetic findings, notably by two rising young researcher stars–James R. Lupski, MD, 40, a pediatrician and medical geneticist at the Institute for Molecular Genetics at the Baylor College of Medicine in Houston,Texas, and Philip F. Chance, MD, 36, a pediatric neurologist at The Children's Hospital of Philadelphia and the University of Pennsylvania.

Their latest findings are described in an article published in this issue of JAMA, but what is not revealed is that their interest in the disease is intensely personal–both men have suffered, both physically and psychologically, since their early teens from this often-misunderstood disorder.

Chance gave up a potential career as a clarinetist because of weakness of his hands and now walks with the aid of plastic braces; beginning at age 14, Lupski endured 11 surgical procedures on his feet to enable him to walk with difficulty, and he now suffers from arthritis. Colleagues, competitors–and friends–Lupski and Chance both agree that Charcot-Marie-Tooth is a terrible name for their affliction. The two researchers took time out from their activities at last month's meeting of the American Society of Human Genetics (ASHG) to discuss their unique perspective on CMT with this reporter.

Chance, a quiet, reserved, slender man who is publicly discussing his ailment for the first time and who is given to wry understatement, notes, "I do tell my patients that Charcot-Marie-Tooth disease has nothing to do with the teeth!" Lupski, a big bearded man who is given to effusive outbursts of enthusiasm, adds, "The details of this are not for publication, but I once had a grant application returned with the notation, ‘Your request for research on tooth decay has been approved!'"

‘Totally novel' discovery
Both researchers have certainly done their part to explain the disease. In 1991, working with blood samples drawn from a cluster of large Cajun families in southern Louisiana who were being treated for CMT, Lupski and his Baylor team identified an area on chromosome 17 in which a portion of DNA was duplicated, leading to a triple dose of genetic material, rather than the normal two. This erroneous triple helping of DNA–"too much of a good thing," in Lupski's words–causes 85% of all cases of CMT.

Lupski calls the discovery "a completely new mechanism for human disease." The finding opened up the possibility that DNA duplication, rather than gene mutations, might hold the answer to such devastating genetic disorders as Alzheimer disease, schizophrenia, and even breast cancer. Instead of looking for a needle in a haystack–the chance mutation of one of the 50,000 to 100,000 human genes–researchers were alerted to the possibility of simply finding too much hay. Chance calls this 1991 discovery by Lupski "totally novel" and the "premier observation in genetics during 1991."

Nevertheless, Lupski had to scramble to even get his results published (in Cell, 1991;66:219-232), and they were not found worthy of making the ASHG meeting agenda that fall. "To receive proper credit," Chance says, "observations about a little-known disease like CMT have to be 10 times as important as most other genetic findings." Lupski says, "CMT does not get the respect it deserves."

There are 30 to 50 genes in the duplicated portion of DNA on chromosome 17 that causes CMT, so Lupski and his team stepped up their efforts to isolate the culprit gene. This summer, he reported (in the New England Journal of Medicine, 1993;329:96-101) that a specific gene in the duplicated material–PMP22, or the peripheral myelin protein of molecular weight 22–causes CMT in mice when the gene is mutated. He now says, "The PMP22 gene appears to be the major player in causing CMT."

In the meantime, Chance and his research colleagues have identified a gene on chromosome 1, changes in which also lead to a form of CMT. And Chance discovered that deletion of DNA material on chromosome 17, a reciprocal phenomenon to the duplication that causes CMT, is responsible for a milder genetic disease known as hereditary neuropathy with liability to pressure palsies (HNPP). The genetic causes of these inverse diseases are reported in this issue of JAMA an event that moves Lupski to observe "I'll be honest with you–this is a great paper!"

Lupski sums up, "We've learned more about CMT in the last two years than in the previous 100. Still, I would say that we're only at 5 on a scale of 10 in terms of understanding this disorder. We won't be satisfied until we're able to offer therapy to patients." Chance adds, "We've learned a lot but I can't sit down with my patients and write a prescription to help them."

Interestingly, the two researchers have yet to solve their own cases of CMT. The DNA duplication and point mutations in PMP22 account for 90% of all CMT cases, with the remaining 10% caused by changes on four other chromosomes: 1, 8, the X chromosome, and an unknown fourth chromosome.

"The very day we found the DNA duplication on chromosome 17," Lupski says, "I had my blood drawn, but there was no duplication. When we discovered the point mutations in the PMP22 gene I had my blood checked, but there was no mutation. And when Phil's lab discovered the CMT-causing gene on chromosome 1, I also had my blood checked, with no luck. Neither of my parents had CMT, but four of their eight children do, so my inheritance is obviously due to a recessive gene. I may never find out what caused my disease."

Chance says, "Jim and I have a bet for dinner on who will find his cause of disease first and I think Jim will have to pay. I'm getting very close to proving that my case is linked to genetic errors on the X chromosome."

Whatever the cause, CMT made the young Chance and the young Lupski suffer, and there were few places to turn for help. As he draws a diagram on a blackboard to explain to this reporter the reciprocal DNA duplication/deletion that is the common cause of CMT and HNPP, Chance drops the chalk. Several times. He sighs, as he recalls:

"My case was very poorly handled. My parents and friends (in Memphis, Tenn.) were not terribly sophisticated medically and there was a tendency to ignore my condition. With CMT, you have trouble picking up your feet and walking normally. It's often called a ‘slap-step.' You get tired very quickly and you can't play sports at all. Later, your hands become weak and you have trouble with zippers and doorknobs. It's very embarrassing and distressing, especially when you're a teenager.

Coping with ‘a lot of pain'
"To keep from tripping over your toes, you tend to raise your feet high into the air, almost as if you're marching. Mother used to yell at me, ‘Pick up your feet and walk normally!' as if I were walking funny just to annoy her. Even today, mother and I don't talk about my condition because of those early days. I ignored my problem until my high school physics teacher intervened. She was the daughter of an orthopedic surgeon and insisted that I pay him a visit. There ensued a variety of unnecessary, expensive, and painful tests–myelograms and spinal taps–to rule out damage to my spinal cord. Finally, I was seen by a neurologist who performed nerve conduction velocity tests to make the diagnosis. Then, all the doctors I had seen just dropped my case. Apparently, there was nothing more to be done."

Chance literally tiptoed through medical school (at the University of Tennessee, Memphis), "shambling about with great effort and great fatigue. My classmates and teachers thought I probably had had polio when I was younger, but nobody ever said anything. After all, this was the South and people simply don't ask. Plus, I was into denial, not wanting to admit that I was impaired.

"This pattern of denial persisted until I began a fellowship in medical genetics at the University of Utah School of Medicine. My mentor, Fred Ziter, MD, insisted that I do something and I was soon fitted for braces. My, was that a rebirth. Suddenly, I could walk almost normally. It was one of the greatest things ever."

By then, however, Chance had turned his back on his first love–music. As the first clarinetist in the Memphis Symphony, he had once planned a career as a professional musician, but it was not to be. "I was a very good clarinetist," he says, "and I have the tapes to prove it, but I knew that the advancing weakness in my hands wouldn't allow it and that medicine would be a better choice for me in the long run."

Looking back, he says, "Of course, I should have been referred to a muscular dystrophy clinic as soon as I was diagnosed and been given the options of braces or surgery. It would have saved a lot of pain."

Lupski's feet were so bad "that I was walking on the sides of my feet and always spraining my ankles. I loved sports, especially football, but there was no way I could ever be any good. I was referred to a Long Island (NY) orthopedic surgeon who recommended surgery to stabilize the ankles. I spent almost one year in a wheelchair after both my feet were operated on, and that gave me a lot of time to think about what I wanted to do with my life. I chose medicine, and in my wildest dreams I never thought that the genetic research I am doing would be as fascinating as it is."

Lupski is quick to credit Carlos A. Garcia, MD, a New Orleans neurologist and the third author of the article on CMT in this issue of JAMA, with making possible much of his landmark research. "To do research in this area," he says, "you need the assistance of a clinician who enjoys the trust of his patients. For 20 years, Carlos has run three Muscular Dystrophy Association clinics in southeast Louisiana, and over that time he has come to know a lot of large Cajun families with CMT. He arranged a Cajun barbecue in Houma, LA, and put the word out for all these family members to come and give blood for the ‘important research' that my team was doing. That's how we were able to make our 1991 discovery of the DNA duplication.

Both Lupski and Chance also see CMT patients in their pediatric clinics. "I tell my patients," Chance says, "that this condition will not shorten their life and it will not affect them mentally. And I try to help them make wise career and family-planning choices." Lupski adds, "Right now, we can offer braces and surgery and career counselling and, someday, we may be able to offer genetic therapy to actually regulate the expression of the PMP22 gene and stop it from doing its damage."

Neither Lupski nor Chance is worried about the risks to their families. Lupski has two very young daughters and says, "I am in favour of presymptomatic testing and, if my wife agrees, will probably have my daughters tested for CMT when the time is right. I don't want them planning a career in ballet if the disease is present." Chance says, "My wife and I want to have children, and the fear of the unknown won't stop us."

Reflecting on all the needless suffering he endured, Chance concludes, "I try to give all my CMT patients an overriding message–hope."