Dr. Edward McCabe was a pediatric fellow in Colorado, fresh out of medical school, in 1976 when he first met Joel and Kevin.
Only 2 and 3 years old, respectively, the brothers were short, physically weak and severely retarded, with IQs in the 30s. They had triangular, elfin faces, crossed eyes and remarkably sweet dispositions.
That chance encounter changed his life, says McCabe, who recently moved to UCLA, steering him in a career direction he had not anticipated. His realization that the brothers suffered from a previously unrecognized combination of genetic disorders led him to study molecular biology and genetics. He went on to become the world's leading expert on this rare genetic affliction and ultimately discovered a defective gene in the adrenal glands that causes the disorder.
It is rare, he acknowledges, that one researcher can discover a disease and then stalk it until he pinpoints its genetic cause.
"It's extremely gratifying to me to have had the opportunity to recognize a new disease and then to follow through with the investigation for a period of more than 18 years and be able to clone the genes that are involved in that disease," McCabe said recently. "It really feels like taking it full circle."
But that is not the end of the story. "There are a lot of diseases that are disorders of the adrenal gland, and now we've got a gene that is very specifically (active) in the adrenal gland," he said.
If he can figure out precisely how the new gene works, he added, "we can learn to target genes to the adrenal gland . . . and not have to worry that if somebody misses a dose of (therapeutic) steroids, he will die."
The discovery is "an extremely important contribution," said Dr. Melvin M. Grumbach of UC San Francisco, because the defect is also associated with a more common deficiency in the pituitary's production of hormones that stimulate the testes. "His work has shown that both the gonadal deficiency and the adrenal deficiency are caused by the same gene," Grumbach said.
McCabe has played a broad role in the genetics community. He has been instrumental in developing programs to screen newborns for sickle cell disease and other blood disorders. He also played a key role in the development of DNA "dog tags" to help identify members of the armed forces killed in combat and disfigured beyond recognition.
But it is his work with the disease he discovered that has been his passion.
Kevin and Joel (not their real names) had a rare combination of at least three distinct genetic disorders--Duchenne muscular dystrophy, a genetic defect in an enzyme called glycerol kinase and another defect called adrenal hypoplasia congenita. But McCabe and his colleagues had no clue about their nature when they were first confronted with the boys.
The first hint at an explanation came when the team analyzed the boys' urine and found a high concentration of a sugar-like molecule called glycerol. Although glycerol is an intermediate in the use of sugars by cells, "nobody had ever seen this before . . . coming out of a person," he said, which indicated that the boys had a new type of genetic defect.
Some elementary detective work soon showed that the boys were missing an enzyme called glycerol kinase, which allows glycerol to be broken down further. But it was clear that this absence alone could not explain all of their symptoms.
Before the team figured out what else was going on, however, Joel died. He had been hospitalized briefly for surgery to uncross his eyes. "He must have caught a virus at the hospital," McCabe said. "When he got home, he . . . died within two to three hours."
That should have alerted his team to the real problem, McCabe said, but Joel's symptoms were ambiguous and a pathologist "simply missed" some abnormalities of his adrenal glands. The ultimate cause of his death did not become apparent until nine months later, when Kevin got sick with similar symptoms. Kevin's symptoms--a marked salt imbalance, low blood pressure and circulatory collapse--were more pronounced, and clearly showed that he had Addison's disease--adrenal insufficiency.
Most cases of Addison's are caused by damage to the adrenal glands--which produce hormones that allow the body to respond to stress or disease. President John F. Kennedy, for example, developed Addison's when his adrenals were damaged in World War II. He had to receive injected steroids in times of illness for the rest of his life, but that need was kept secret from the public.
In their second major discovery, McCabe and his colleagues found that Joel and Kevin had a much rarer, and previously unrecognized, form of Addison's disease called adrenal hypoplasia congenita--they were born with poorly functioning adrenal glands.
Once physicians recognized the adrenal problem, maintaining Kevin's health became a relatively straightforward process. His parents administered daily doses of steroids to keep Kevin's body functioning properly, and at the first sign of illness, they doubled or tripled the dose to help fight off infection.
With two defects identified, the team was able to deduce that the remainder of Kevin's problems, such as muscle weakness, were the result of muscular dystrophy. They began looking for the genes that caused them.
The muscular dystrophy gene was found by an international team of researchers in 1987. McCabe and his colleagues found the glycerol kinase gene a year and a half ago and he reported the discovery of the adrenal hypoplasia congenita gene in December. It is now clear that all three genes lie next to each other on the X chromosome, one of the sex-determining chromosomes. Because the genes are adjacent, "we call this a contiguous gene syndrome," he said.
It now seems apparent that some still unidentified factor is interfering with the replication of this segment of DNA on the X chromosome, and it may be interfering with other genes as well. "We know that there are some other genes near these three that appear to be important in brain development, and defects in those are probably what leads to the mental retardation," McCabe said. "Unfortunately, we haven't (identified) those yet."
But the important gene, for the moment, is the one for adrenal hypoplasia congenita. Although McCabe knows of only about 50 patients worldwide with the same syndrome as Joel and Kevin, "we think that the problem with the adrenal (insufficiency) by itself . . . is much more common than people had realized before," he said. "Now we have a way to screen for it."
McCabe has long been interested in the development of new ways to screen for birth defects, and one of his major achievements involved the application of PCR techniques to screening. PCR (polymerase chain reaction) is a widely used technique for converting extremely small amounts of DNA into much larger quantities of identical material.
Before his studies began, it required about four months to diagnose sickle cell disease in newborn children. Unfortunately, sickle cell infants often develop overwhelming infectious diseases at about 3 months of age. Their survival can be improved if they are given prophylactic antibiotics before the infections develop, but physicians hesitate to use the powerful drugs in infants who are not sick and who are not definitely known to have sickle cell disease.
In a landmark advance, McCabe solved that problem by adapting PCR techniques to screening for sickle cell and improving the test so that it could be used routinely in state public health laboratories.
The new test shortens the diagnostic period to two months, allowing physicians to prescribe the antibiotics only to infants at risk. A similar technique that he developed is now being used to diagnose cystic fibrosis as well.