Investigators funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) have identified the gene responsible for a rare form of dystonia known as rapid-onset dystonia parkinsonism (RDP). The study appears in Neuron.
RDP usually occurs in adolescents or young adults. It strikes suddenly over the span of hours to days, causing tremors, speech and swallowing problems, muscle spasms, and disturbed balance. Some people experience seizures. RDP often follows a fever, prolonged exposure to heat or exercise, childbirth, or emotional stress. Symptoms often stabilize within a month and may even improve slightly over the years, but once they occur, they are permanent.
RDP is inherited in an autosomal dominant manner. By studying the chromosomal region known to be implicated in the inheritance of the disease in seven unrelated families with RDP, the researchers were able to identify one mutated gene, called ATP1A3, common to all the families. ATP1A3 makes a protein involved in pumping sodium and potassium ions across the membranes of neurons, a process crucial to the nerve cells' ability to activate muscle cells. Prior to this discovery, five other dystonia genes had been identified, but the ATP1A3 gene is the first one found to affect the communication between the brain and muscles by this method.
The scientists found six different mutations in the ATP1A3 gene. Each of the mutations caused a different incorrect amino acid to be incorporated into the protein. When mixed in a culture with normal cells, each mutation was likely to kill those cells. The investigators also determined that the production of the ATP1A3 protein was lowered in the cells, leading them to theorize that the sodium/potassium transport system in people with these mutations may be unable to keep up with the body's needs in times of high demand, thereby triggering RDP.
Future studies will be necessary to determine whether mutations in the ATP1A3 gene are involved in other forms of dystonia, parkinsonism, or even epilepsy.
The NINDS, a component of the National Institutes of Health within the U.S. Department of Health and Human Services, is the nation's primary supporter of biomedical research on the brain and nervous system.