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.

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The scientists found that the DNA surrounding many late-firing origins contains repeats of a 10-basepair sequence that is rich in the nucleic acid component, guanine. Yompakdee and Huberman named these repeats "Late Consensus Sequences" (LCS). They found that one copy of an LCS produced no detectable effect on replication timing, two copies produced a partial effect, and three copies caused replication to occur in late S phase. The researchers confirmed this finding by removing the LCSs from a late-replicating origin to convert it to an early-replicating origin.

"Interestingly," noted Huberman, "in many cancer cells, the normal order of DNA replication is altered: regions that should replicate late sometimes replicate early and vice versa." As a result, tests for DNA replication timing may eventually become a method for the early detection of cancer.

"Replication timing assays are one of many promising techniques that are currently being studied that may, in the future, allow much earlier cancer detection than is possible today," concluded Huberman.

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