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THE NATION

Chronic Fatigue Is in the Genes, Study Finds

Mutations are to blame for a syndrome often scoffed at as imaginary, researchers say.

April 21, 2006|Thomas H. Maugh II | Times Staff Writer

Chronic fatigue syndrome, often dismissed as the imaginings of depressed and whiny people, is caused by genetic mutations that impair the central nervous system's ability to adapt to stressful situations, according to a major new study by the Centers for Disease Control and Prevention.

Small changes in many of the genes in the brain prevent the nervous system from rebounding from everyday stress and from less frequent, stronger pressures, eventually triggering a cascade of molecular responses that leave the patient severely debilitated, researchers reported Thursday in 14 separate papers in the journal Pharmacogenomics.

"This is the first credible evidence for a biological basis" for the syndrome, said CDC Director Dr. Julie L. Gerberding.

The findings will provide immediate help in diagnosing the disorder, which often puzzles physicians because of the broad spectrum of symptoms and the absence of defining biochemical markers.

It should also lead to the development of effective treatments for patients, who receive only therapy to mitigate symptoms -- or in some cases are scoffed at as slackers.

"It is very hard to treat an illness until you understand what it is physiologically," said Dr. Lucinda Bateman of the Fatigue Consultation Clinic in Salt Lake City. "This is a very important foundation" for developing new treatments.

Chronic fatigue syndrome, commonly known as CFS, was first recognized in the 1980s but was long dismissed as the complaint of "a bunch of hysterical, upper-class white women," said Dr. William C. Reeves of the CDC, who led the new study.

Diagnosis is difficult because many of the psychological symptoms, in mild form, are common traits of a modern stressful life.

Over the last two decades, most physicians have come to recognize CFS as a valid illness, he added, but there has been virtually no information about its causes. It has even been difficult to provide a precise definition of the disorder.

Experts agree that it affects as many as 1 million Americans, causing severe exhaustion, widespread musculoskeletal pain, impairments in thinking and sleep disturbances.

It strikes four times as many women as men but is equally debilitating in both. It occurs most frequently between the ages of 40 to 60.

Physiological manifestations, which must be present for at least six months for a diagnosis, can include sore throat, tender lymph nodes, headaches of a new or different type from those experienced in the past, and malaise after exertion.

"They are as impaired as people with multiple sclerosis or AIDS or who are undergoing chemotherapy for cancer," Reeves said. "They don't die, but they are severely debilitated."

To learn more about the disorder, a CDC team focused on Wichita, Kan., which turns out to be a statistical microcosm of the United States in terms of wealth, urbanization, age, race and other factors.

Initially, the team surveyed a quarter of the population, or about 56,000 people, looking for symptoms of CFS.

Reeves said they found that about 16% of people with the disorder had been diagnosed and received some treatment.

The group then identified 227 CFS volunteers who each checked into a hospital for two days to undergo a complete set of mental, physical, blood, sleep and other tests. Included was an assessment of the activity of 20,000 genes.

Data in hand, the CDC assembled four independent teams -- each containing experts in medicine, mathematics, molecular biology and computer science -- and challenged them to interpret the results. Each team produced two or three of the new papers, and their results were surprisingly consistent.

The teams found that there were at least four distinct forms of the disease, each with its own genetic profile and symptoms but all including disabling fatigue. Some had relatively mild symptoms, whereas others were debilitating.

But all the forms shared genetic mutations -- technically called single nucleotide polymorphisms -- related to brain activity that mediated the response to stress.

In particular, five polymorphisms in three genes were "very important," said Dr. Suzanne Vernon of the CDC, co-leader of the study. Those polymorphisms alone were sufficient to diagnose about 75% of cases.

The genetic findings are particularly important because they can lead to new drugs, said Dr. K. Kimberly McLeary, president and chief executive of the Chronic Fatigue and Immune Dysfunction Syndrome Assn. of America.

"Pharmaceutical companies have been sitting on the sidelines because they have not been able to get their hands around CFS," she said. "This gives them something to latch onto" and identifies treatment possibilities that haven't been explored.

The teams also found a strong correlation between the severity of CFS and what they called allostatic load, the cumulative wear and tear on the body resulting from chronic or inadequate adaptation to stressors -- such as changes in everyday routine, disease, and physical and emotional trauma.

The CDC is gearing up to attempt to replicate the findings in a study of 30,000 people in Georgia, Reeves said.

The data have been given to 30 other groups of scientists who will meet at Duke University in June to present their own interpretations.

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