When "Lorenzo's Oil" hit movie houses in 1992, Americans were floored by the gritty, in-your-face view of adrenoleukodystrophy (ALD), an X-linked, degenerative disease few knew about. Susan Sarandon and Nick Nolte portrayed the parents of Lorenzo Odone, a bright, exuberant 5-year-old who went into a sudden, shocking decline as broad brain demyelination brought cognitive loss and left him unable to walk, see and hear.
"The disease hits families like a ton of bricks," says Hugo Moser, M.D., who heads neurogenetics research at Kennedy Krieger. Moser, also a professor of neurology at Hopkins, had researched the illness long before the film spotlighted it. At 80, he's spent 30-odd years explaining ALD's pathology and seeking ways to detect and treat it. Moser's background in neurology and in lipid biochemistry have served him well. The NIH keeps extending his research grants. If he weren't so modest, his walls would be lined with the awards he holds.
ALD lets unusually high titers of very long chain fatty acids (VLCFAs) build in patients' blood and brain tissues, among others. But the disorder is at heart a peroxisomal disease, caused by one of a slew of mutations-640 have surfaced so far-that warp a key membrane protein in that organelle. Enzymes can't get into peroxisomes to cleave the saturated fatty acid chains so the fatty acids build up. Moser's team definitively linked the long molecules to the disease-which also causes adrenal insufficiency and testicular flaws. Those with the childhood cerebral form of ALD-other milder types exist-typically die in a few years. "At best," says Moser, "it's an awful disease."
In an odd twist for science, the "Lorenzo's oil" of the film, a blend of certain fatty acids Lorenzo's parents commissioned for their son to drink, may help patients. Neither of the Odones was a scientist. But they launched a blitzkrieg short course for themselves that included reading Moser's and others' work. The result was the oily liquid. But both film and oil, Moser says, are a mixed blessing. Q. Talk about "Lorenzo's Oil." Did it help the cause? A. The film had a huge impact in making people aware of the disease. Adrenoleukodystrophy -- the word itself is a terrible barrier. But say "the Lorenzo's oil disease" and it rings a bell for most people. That's been a tremendous help.
Q. What about a hindrance? When Peter Ustinov played you, well, that wasn't quite the Hugo Moser we know. A. One reason "Lorenzo's Oil" attracted attention -- a drawback -- was that it pitted the parents' interests against established medicine. Mr. Odone calls this "Hollywood's version of man bites dog." Also, the film hyped the oil's benefits. Soon, physicians were plagued by unverified claims. The medical community became dubious about the whole idea. As a result, our first grant applications to test the oil were turned down.
The film's optimism also caused suffering. Women who are carriers can be identified and offered genetic counseling. ALD is identifiable prenatally. But some women in families at risk -- even those who know they're carriers -- rent the video and say, "It's OK; if I have a child with ALD, I'll just give him Lorenzo's oil." They don't know what they're getting into. If a child is born today with ALD, there's no doubt that life is never the same for that family.
Q. How does LO work? A. The oil patients drink enters into a molecular competition that greatly diminishes the synthesis of saturated very long chain fatty acids.
Q. How well does it work? You're studying effects of the oil in young boys who have the ALD gene but who don't yet show neurological symptoms, right? A. Yes. We've gathered data on patients for a dozen years. It takes so long because of the rarity of the disease and the difficulty of finding subjects and monitoring them long enough to make the results trustworthy. The children drink a daily dose of the oil -- a few spoonfuls -- plus supplements of essential fatty acids. They also cut back sharply on other fats in the diet. VLCFA levels drop to normal in those who follow the diet and take oil religiously. If you give the treatment to asymptomatic young boys, you see an apparent drop in their risk of developing brain abnormalities, but, of course, the study's not finished.
Q. And if you start to detect neurological problems? A. We start boys who are perfectly normal but who have high VLCFA on the diet. We work hard to get plasma fatty acids down. They'll have an MRI every six months. If it's normal, wonderful! If not, we'll have caught damage at a very early stage and recommend a bone marrow transplant (BMT).
Catch a child early on and the BMTs can work very well. Why? We don't know exactly. We suspect changes in immune function are behind it. So we have grown transplant patients with jobs and families! But, we argue strongly that marrow transplants are not for children who lack signs of brain disease. (Up to half of boys with an ALD mutation never get the brain-damaging form.) You wouldn't subject them to a major procedure that carries risk unless there's good reason. BMTs carry significant risk.
Q. So Lorenzo's oil isn't a cure? A. We badly need other therapies. We're investigating some now. Today, given what's available, the most important thing we can do is preventive; identify carriers and have people get genetic counseling about the risks.
Q. You have a good ALD screening technique? It could be better? A. My wife, Ann, found you could analyze a few drops of blood plasma for VLCFAs with chromatography. It works for patients with or without symptoms and is tremendously robust. A sample mailed to her from South America sat is a file drawer and tested accurately three years later! For men, the test is 100 percent accurate. But women who are carriers face a 20 percent false negative rate, so we're just using it postnatally for boys. You can add other tests to verify carriers.
My goal is to help develop convenient neonatal screening for ALD. You'd do italong with PKU screening in newborns, catch them three years before symptoms start. At the very least, we'd be able to begin treating patients who test positive for the adrenal malfunction -- the Addison's disease -- that accompanies ALD and by itself causes sickness or death. With neonatal screening, you'd get a whole new ball game.
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