The disease, named Timothy syndrome after one of the paper's authors, is characterized by a variety of problems including heart arrhythmias, congenital heart abnormalities, webbed hands and feet, a weakened immune system, cognitive abnormalities, and, surprisingly, autism. The researchers have identified 17 children with the syndrome, seven of whom were living.
Despite the complexity and severity of Timothy syndrome, the researchers show that it arises from a single, spontaneous, very subtle gene mutation in the mother's egg or father's sperm – substitution of a single base pair. The reason so many body systems are affected is that mutation impairs a very fundamental molecule – a type of calcium channel – that is found in many tissues and organs.
Calcium channels control how much calcium can get inside a cell. Calcium is one of the body's most important signaling molecules, and normally, cellular calcium levels are tightly regulated. Dr. Mark Keating, senior author of the study and a Howard Hughes Medical Institute investigator at Children's Hospital Boston, likens the calcium channel to a screen door.
"After you go through the screen door, it automatically closes," he says. This mutation dismantles the automatic closing mechanism, so the door just stays open."
As a result, cells are overwhelmed by an influx of calcium. Because calcium-channel blocking drugs can ameliorate calcium overload, these medications may be useful for treating arrhythmia and cognitive deficits in individuals with Timothy syndrome, Keating says.
Experiments also showed that the gene encoding the calcium channel was active not only in heart muscle cells, but in tissues of the gastrointestinal system, lungs, immune system, smooth muscle, testes, and brain – including brain regions that are known to show abnormalities in autism. Keating notes, however, that autism is a complex disorder with many different causative factors.
The study was led by Igor Splawski, PhD, in the Cardiovascular Research Division at Children's Hospital Boston in collaboration with the University of Utah and the Boston University School of Medicine. The researchers will continue to treat patients with Timothy syndrome and evaluate their response to calcium-blockers. They will also continue to look for arrhythmia genes and other calcium channels that might be involved in arrhythmia, and try to determine whether this calcium channel is involved in other forms of autism.
Children's Hospital Boston is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts' children, and the primary pediatric teaching hospital of Harvard Medical School. Children's provides pediatric and adolescent health services for patients from birth through age 21. In addition to 325 inpatient beds and comprehensive outpatient programs, it houses the world's largest research enterprise based at a pediatric medical center. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit: www.childrenshospital.org.