Chronic fatigue syndrome (CFS) is a state of fatigue lasting six months or longer and is a term given to a variety of debilitating disorders whose cause in uncertain. When a patient has symptoms of fatigue and the doctor suspects CFS, the tests begin – physical exam, blood tests, urine tests, a mental status exam and a fatigue or symptom inventory. Yet the results of all those tests don’t definitively diagnose CFS; instead, they help exclude other conditions.

If it’s not mononucleosis, multiple sclerosis, kidney disease or an autoimmune disease, and you’ve had fatigue for 6 months or longer, you might have CFS. “Might” is the important word, though. Even when handed a diagnosis of CFS, the nagging feeling that it could be something else lingers.

“The symptoms of chronic fatigue syndrome (CFS) have been compared to having a flulike illness,” says Lucinda Bateman, MD, director of the Fatigue Consultation Clinic in Salt Lake City. “Weakness, exhaustion, achy muscles and joints, tender lymph nodes, feverishness, headache, dizziness and feeling too sick to be active or even sleep restfully are common,” she says.

The problem is that many of those symptoms are shared by other conditions, including arthritis. Like many people with an arthritis diagnosis, people with CFS may look perfectly fine. But unlike arthritis, there are no damaged tissues to see on X-ray or MRI and no elevated levels of cytokines or biomarkers to detect in the blood. And that makes diagnosing the condition very difficult. 

In 2006 the Centers for Disease Control and Prevention (CDC) in Atlanta showed CFS is associated with three genes that affect the body’s ability to handle stress.

“This research is validation to people who have CFS  that it’s not all ‘in their heads,’ and to the medical and scientific communities that a detectable biologic basis for CFS exists,” says Suzanne Vernon, PhD, a researcher with the Molecular Epidemiology Program at the U.S. Centers for Disease Control and Prevention. “Common DNA variations in genes, called polymorphisms, that are important in the function of the hypothalamic-pituitary-adrenal (HPA) axis were the ones associated with CFS in the study,” she says.

The HPA axis is part of the neuroendocrine system – the brain, nerves and hormones that control stress and mood, the immune system, digestion, use of energy and sexuality. The genetic variations, along with environmental influences, may make the HPA axis less efficient in responding to stress and trigger CFS in some people.

Still developing a test or tests to diagnose the condition has yet to occur.

“Because there are multiple genes and polymorphisms that contribute to CFS, there likely are many more genes and polymorphisms that need to be identified before a test that relies on genetic information can be useful,” says Vernon. “However, it is now possible to scan the entire human genome for these polymorphisms, and we currently are in the process of doing this,” she says.

As scientists understand more about how the genes and the symptoms, such as cognitive impairment or sleep disturbance, are connected, they can help doctors improve therapies, says Vernon.