Down Syndrome


Spring 2004 Volume 16, Number 3	Tackling the Mountain With Down syndrome, you make inroads where you can.
	How could you not expect adults with Down syndrome to have sleep apnea?" asks George Capone, M.D., long a Kennedy Krieger specialist in the genetic disorder.

Capone has concerns that a number of adult patients with Down syndrome (DS) are prematurely saddled with a diagnosis of Alzheimer's disease or with depression when their symptoms stem from a sleep disorder. Their anatomy -- narrower airways, for example -- makes them especially prone to it.

The worry may seem small potatoes given such a broad-brush condition as DS. It's the most common genetic cause of mental retardation. It affects the heart, muscle tone, hearing, speech and, indirectly, most other functions. But Capone has seen too much sitting-on-hands merely because DS may seem overwhelming.

There's clearly value in chipping away at the disease, he says. "People 20 years ago would be amazed to know what we know now." Capone, who directs KKI's Down syndrome clinic, has helped with basic studies-mapping differences in hippocampal and cerebellar volume, for example. He's also sought drug therapy to optimize brain function. "A few percent improvement in some cognitive areas," he says, "could make a real difference."

Studies of the neurotransmitter-enhancer donepezil, for example, show the drug improves memory, learning and attention in lab animals and in patients with Alzheimer's disease. So Capone's directing KKI's arm of an international donepezil study of young adult DS patients. "We know brain acetylcholine drops in adults with the disease," he says. "Perhaps this drug may improve ability."

As for the sleep apnea study, it's an offshoot of work to halt the cognitive deterioration that strikes many patients by middle age. Pathology typical of Alzheimer's comes with DS, beginning well before age 50, though not all get dementia or decline. "But sleep apnea can mimic early Alzheimer's," Capone cautions. Reaction time slows. Patients may be slower, forgetful and confused, and have impaired executive function.

Almost all adults with DS whom Capone and colleagues tested had abnormal sleep patterns, reduced breathing and lower blood oxygen. Now he routinely sends adult apnea-suspects to sleep studies for diagnosis and follow-up therapy. The suggestion that long-term apnea may make the brain a more fertile ground for Alzheimer's gives him extra incentive.

Last, Capone's addressed the significant number of children in KKI's clinic who have both DS and psychiatric or behavioral problems. DS ups the risk of autistic-spectrum disorders 25-fold, for example. "These children face a genuine problem; often, physicians and educators don't recognize their autism as a distinct disorder." The result, he says, is that children don't get help and parents suffer tremendously.

As a key step in improving the situation, Capone has combined a standard behavioral checklist and classic diagnostic criteria to clearly winnow out autistic disorders in children with DS.

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GENE SCREEN

To call finding the cause of impaired thought or other hallmarks of Down syndrome a daunting task is understatement enough to make a researcher's eyes roll. DS begins in utero, involves hundreds of genes, developmental and otherwise, on the entire -- or perhaps just broad stretches of the -- 21st chromosome. It plays out over a lifetime. "Yes, it's somewhat complicated," neuroscientist Jonathan Pevsner, Ph.D., deadpans. And so far, research has yielded only a handful of insights, mostly about anatomy and differences in chemical levels from normal.

But Pevsner, who directs Kennedy Krieger's bioinformatics facility, says microarray technology may offer just the mountaintop view needed. Using the new technique that reveals which of thousands of known genes are active at any one time -- a molecular snapshot -- he got satisfying confirmation that in DS, there's far more of chromosome 21 gene activity than normal. Just what you'd expect with an extra chromosome.

More important, he says, he's picking up differences in gene activity from one patient to another. "That may explain why DS varies so greatly from person to person," says Pevsner. We believe finding which chemical pathways in the brain are perturbed in DS -- which tie to specific brain problems, for example -- is no pipe dream.