That electric feeling  pg. 5

Soon after coming to Vanderbilt in 1995, Blakely began collaborating with Dr. David Robertson, professor of Medicine, Pharmacology and Neurology, and an internationally known expert on heart rate and blood pressure regulation. They suspected that a mutation in the norepinephrine transporter might be responsible for orthostatic intolerance experienced by one of Robertson’s patients and her identical twin sister. The syndrome is characterized by a racing heart, nausea and dizziness when a person stands up.

Upon testing the women and their family, the researchers found a genetic mutation that effectively disabled the transporter in five family members, including the twins and their mother. All five had high blood levels of norepinephrine, and their heart rates jumped when they stood up, although only the twins had the full-blown syndrome.

The finding, reported three years ago in The New England Journal of Medicine, does not explain all cases of orthostatic intolerance, but this was the first neurotransmitter transporter mutation associated with specific symptoms of a disease, Blakely says.

The norepinephrine transporter in the heart comes from the same gene that makes the norepinephrine transporter in the brain. Since the mutation also would be expected to affect brain norepinephrine, the researchers recently evaluated members of the same family for attentional problems.

“The folks we were able to interview who have this particular (genetic) alteration had a consistent complaint that they had a hard time maintaining focused attention and concentration,” says Shelton, who has not yet published his findings in a scientific journal. “That certainly sounds very much like attention deficit disorder, and in fact if you go down through the symptoms, what they had was an alteration in attention without apparent hyperactivity.”

More than genetics

In another study, Blakely and Dr. Steve Couch, assistant professor of Pediatrics, are looking for genetic mutations that may affect the function of dopamine and norepinephrine transporters in children with ADHD and their family members.

“We’re dealing with a syndrome with many, many complexities and variable presentations,” Blakely explains. “We need to be able to categorize subjects better. And one way to do that would be if we could link their genetics with the risk for this disorder, and link more than their genetics, link specific biochemical pathways.”

Just as dopamine alone cannot explain ADHD, neither can genetics. Environment must play a role. Exposure to nicotine, cocaine and environmental pollutants in the womb has been implicated in the later development of ADHD, as have thyroid problems. Stress has been linked to various behavioral and attentional problems, and chronic sleep deprivation paradoxically produces hyperactivity in children.

In the late 1990s, Michael McDonald, Ph.D., and his colleagues at the National Institutes of Health became interested in a rare genetic condition called resistance to thyroid hormone (RTH) syndrome, which can cause mental retardation, short stature, deafness – and ADHD.

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