Two research teams have identified the genetic mutation that causes familial dysautonomia, a rare but devastating disease. Killing half of its victims by age 30, this inherited condition disrupts the nervous system’s reflexive control of functions such as digestion and breathing. The teams’ studies will appear in the March American Journal of Human Genetics.
The discovery paves the way for genetic screening of couples seeking to avoid passing the condition on to their unborn children, says Felicia B. Axelrod, a pediatrician at New York University Medical Center, who coauthored one of the reports. About 1 in 30 Jews of European descent carries the mutation.
Many Jewish people already undergo screening for another mutation, one that causes the neural disorder Tay-Sachs disease. Clinics will be able to use the same blood sample to test for familial dysautonomia, which is nearly as prevalent in this population as Tay-Sachs. “Once you have the DNA, it’s very easy,” says James F. Gusella, a molecular geneticist at Harvard Medical School and Massachusetts General Hospital in Boston. He coauthored the study with Axelrod.
The findings will also spur research into potential treatments for people already beset by familial dysautonomia, says Berish Y. Rubin, a molecular biologist at Fordham University in New York, who coauthored the other new study.
The affected gene is called IKBKAP. When mutated, it encodes a defective version of a protein called IKAP. While it’s clear that lack of IKAP can cause familial dysautonomia, the normal function of the protein is unknown, Gusella says. The body might need IKAP to switch on or off various genes that ultimately affect nerve cells, he says.
If both parents harbor the IKBKAP mutation, which is recessive, a child has a 1 in 4 chance of having the condition and a 50 percent chance of being a carrier of the defect. If only one parent harbors the mutation, a child won’t show the disease but has a 50 percent chance of carrying the mutation.
On occasion, physicians come across a second, milder form of familial dysautonomia. This apparently stems from inheriting an even rarer mutation in IKBKAP from one parent and the more common mutation from the other, Gusella says. Less than 1 percent of people with familial dysautonomia have the less common mutation, he says.
“This is the end of a long, difficult quest,” says David S. Goldstein, a neurocardiologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. The next step will be to ascertain “to what extent this gene [is active] normally in cells of the autonomic nervous system.”
The disease—also known as Riley-Day syndrome and hereditary sensory neuropathy type III—causes autonomic neurons to develop poorly and perhaps decay over time, Rubin says. In particular, it affects large nerves leading into and out of the spinal cord.
Symptoms can appear in the first year of life. The nerve damage causes uncontrolled vomiting, blood pressure fluctuations, trouble swallowing, and breathing disorders. People with the disease sometimes lack feeling in their skin, which makes them vulnerable to burns. They are often unable to produce tears, leading to severe eye problems.
Treatments of these symptoms extend the lives of people with familial dysautonomia but don’t cure the condition, says Axelrod.
Although other cells appear able to make IKAP protein, only autonomic nerve cells seem affected by the mutation. It could be that other cells compensate for the loss or just don’t need the protein to thrive, Gusella says. The tissue-specific nature of the protein’s effects might lead researchers to its mechanism of action, he says.