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"Marco Polos" at DHMC discover a new genetic disorder

"A Marco Polo effect," explains James Filiano, M.D., an associate professor of pediatrics and of neurology, "is where two cultures —in this case the clinical culture and the basic science culture —come together to create our own, third culture." Such a joint culture at Dartmouth was recently responsible for the rapid identification of a novel genetic metabolic disorder, called CDG type Ie (CDG stands for congenital disorder of glycosylation).

Tale: The full story of CDG type Ie, like any modern tale of discovery, is much more than the saga of a lone investigator. It involved several teams of physicians and researchers at DHMC, as well as collaborators at the Mayo Clinic in Rochester, Minn., and the Burnham Institute in La Jolla, Calif. There are two beginnings to this story of discovery—one quite recent and the other many decades ago.

A little over two years ago, a baby boy, a few months of age, was brought for evaluation to the Children's Hospital at Dartmouth (CHaD). His abdomen had been full of fluid since his birth, and he'd had low muscle tone and difficulty breathing all of his short life. He was growing poorly and had recently developed seizures. Filiano, who is the head of CHaD's neurometabolism program, saw the infant and suspected a metabolic disorder— a defect at some step of the basic, daily operation of the boy's cells. It took barely a year for the defect to be identified and the disease to be classified as CDG type Ie—unusually quick progress from presentation to definition of a new genetic disorder.

But the story goes back even further: Filiano makes a point of noting that the foundation for this achievement was laid at DHMC in the 1960s, when Richard Hoefnagel, M.D., now a professor emeritus of pediatrics, established a chromosome analysis lab to look for genetic causes of birth defects. During the 1970s, DHMC's genetic arsenal expanded to include amniocentesis, which allowed doctors to screen for genetic abnormalities before birth, and genetic counseling, to help parents and patients understand and live with such disorders. [See ERRATUM note below.]

And over the past 20 years, DHMC has kept up with other genetics advances. The speed with which the single genetic defect responsible for CDG type Ie was pinpointed reveals the extent of those advances.

Process: Glycosylation is a multistep process by which proteins (which are gene products) are modified by sugars, such as mannose. Inborn errors in the glycosylation process cause many things to go awry. Nerves in the periphery of the body are not properly insulated, leading to poor muscle tone and difficulty breathing. Patients with other types of CDG also have bleeding disorders, because glycosylation is important in making functioning blood-clotting factors.

Among those who first saw the baby boy with Filiano were two of his colleagues in pediatrics —John Moeschler, M.D., and genetic counselor Susan Berg. They worked to narrow down the diagnostic possibilities, since the patient's symptoms could have been caused by several disorders. A hematologist joined in when a glycosylation problem was suspected, to help look for blood-clotting problems.

Novel: Once it became clear that this was a novel glycosylation defect, help arrived from pathology, in the form of T.K. Mohandas, Ph.D., and Jonathan Park, Ph.D., who cultured cells from the patient's skin to help look for the defect. Then came collaborations with scientists at other institutions—experts in glycosylation who could do further experiments to pinpoint and characterize the defect.

The bright side of this story is the speed with which the defect was identified, but there is a darker side, too, in that treatments for most genetic disorders are still in their infancy. For the baby boy with CDG type Ie, supplementing his diet with extra mannose helped him gain weight and improve in size and strength. But there has been no way to correct the mental retardation that he also suffers from.

As of now for such patients, says Filiano, "the best that we can do is treat their seizures and know what they have, so that we're not doing a lot of expensive studies to find out. And the parents can make a decision regarding whether they want to have other children" as a result of knowing the defect is genetic.

But the paucity of treatments does not discourage Filiano. He sees clinical genetics as being in an early and exciting phase of identification and diagnosis. "If we made the analogy with infectious disease," he explains, "by the turn of the [20th] century we were identifying diseases all the time—[using a] combination of microscope, culture media, histological stains.

"We could tell the difference between bacterial infections, viral infections, fungal infections, parasite infections, but we didn't have any treatment," Filiano continues. "Then came Fleming and penicillin and after that came treatments." So for now, Filiano is satisfied with being able to give solid diagnoses.

He says that uncovering what was wrong with the baby boy is a testament to the fact that "the infrastructure was available. . . . There were a lot of minds on this case, and everything happened as a matter of course. That takes years to put together, and I and my patients have benefited from it." The identification of CDG type Ie would not have been possible, he says, without the right people and equipment to take care of the patient, rule out other diagnoses, and perform the lab experiments that showed he had a cellular defect.

Prepared: "Everyone was prepared and ready and used to thinking this way and operating this way," Filiano says of his colleagues. Then, in a twist on Louis Pasteur's observation that "chance favors the prepared mind," he adds: "Chance favors the prepared institution."

Marta Hristova

ERRATUM: The above article contains this statement: "The foundation for this achievement was laid at DHMC in the 1960s, when Richard Hoefnagel, M.D., now a professor emeritus of pediatrics, established a chromosome analysis lab to look for genetic causes of birth defects." But Hoefnagel says that although he was instrumental in establishing the clinical genetics initiative at Dartmouth, the chromosome analysis lab was actually started by Kurt Benirschke, M.D., a former professor of pathology; also, Hoefnagel's full first name is Dick, not Richard.

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