In the 1930s, for example, the evaluation of a family proved that there were two forms of neurofibromatosis (Elephant Man's disease), which in its most common form is characterized by tumors on or just beneath the skin. By studying a large family suffering from what he thought was case after case of classic neurofibromatosis, Dr. W. James Gardner, then a neurosurgery resident at University Hospital in Philadelphia, detected a consistent pattern of internal brain tumors--called acoustic neuromas--that had never before been seen in neurofibromatosis. Gardner's conclusion that there were two types of neurofibromatosis was later confirmed by modern genetic research. "That family paved the way--sounded the alarm--that there may be more than one form," says Dr. Roswell Eldridge, head of clinical neurogenetics for the National Institute of Neurological Disorders and Stroke.
More recently, researchers from the National Cancer Institute's epidemiology branch announced the discovery of a physical trait that can serve as a marker for melanoma, an often-fatal skin cancer that afflicts more than 27,000 people annually.
In 1974, two Cancer Institute researchers and Dr. Wallace Clark, a University of Pennsylvania researcher considered a leading expert in the disease, examined more than a dozen members of a family that had been plagued with melanoma over several generations. One researcher began to draw blood while the other two prepared to conduct physical examinations. Suddenly, the routine turned extraordinary.
"Hey, look at this!" Clark yelled from the examining room.
The others ran in, and Clark showed them a series of strange moles dotting the bodies of the study subjects. The team had never seen moles like these, which were numerous and irregular in shape, size and color.
The discovery that these lesions, called dysplastic nevus syndrome, afflicted all the family members suffering from melanoma was a key finding. The lesions are inherited, and the connection proved that they are a precursor to melanoma and frequently turn cancerous. They account for virtually all familial melanomas. No doctor had ever made the connection because no doctor had ever seen a whole family at the same time. The discovery was a major step in prevention: Those individuals who have the lesions are now advised to have them removed before they become life-threatening. Information gathered from family laboratories also can explain the way inherited diseases evolve. While studying a family, Dr. Susan Perlman, an assistant clinical professor of neurology at UCLA, and her colleagues discovered not only a new form of a disease but also a new population at risk for it and information on the way genetic disease works.
In 1988, Perlman began treating two siblings--a 30-year-old man and a 25-year-old woman--whose illness had been diagnosed elsewhere as Friedreich's Ataxia, an inherited degenerative neurological illness that affects coordination and, in its later stages, speech, vision and hearing. As she evaluated the Beauchamps in UCLA's neurological disorders clinic, Perlman was puzzled. "They had spasticity and weakness, which is not seen much in Friedreich's, and they did not have as much incoordination and sensory loss as you see in Friedreich's," she recalls.
The Beauchamps were French-Canadian, a highly inbred population and therefore prone to genetic diseases. Perlman decided to investigate other members of the Beauchamp family. There were nine siblings--another brother had weakness similar to his wheelchair-bound sister and brother, but it was milder. Three other sisters suffered from scoliosis, and two were healthy\o7 . \f7 "There was a brother nobody knew much about, but they thought he, too, had scoliosis," Perlman says.
"Freidreich's is a recessive disease; the chances of getting it are one in four," Perlman says. "So two should have had it, and six or seven should have been fine."
She ran routine tests, including one for another neurological hereditary disease, Tay-Sachs. It came back positive. Perlman had an anomaly on her hands.
Despite the fact that Tay-Sachs is an extremely rare disease, doctors know a great deal about it. Like Friedreich's Ataxia, Tay-Sachs is a recessive genetic disease. It most often occurs in Eastern European Ashkenazi Jews. The key to it is a gene found on chromosome 5, which controls the production of hexosaminidase A, an enzyme that breaks down fats that build up in the brain--without it, the terrible symptoms of Tay-Sachs occur: paralysis, blindness, mental deterioration.
"In some people, the gene has small chemical changes, so it can't make normal protein," Perlman says. "In others, parts of the gene are missing." The different gene abnormalities result in two forms of the disease: a relatively mild one that occurs in adults of all ethnic groups and the classic form that affects--and usually kills--Jewish children before the age of 5.