Researchers at Johns Hopkins have discovered a gene mutation that causes a condition apparently identical to Huntington's disease, helping to explain why some people with the disorder do not have the mutation found in most cases. The finding may help reveal why some diseases, like Huntington's, Alzheimer's and Parkinson's, destroy some brain cells while sparing others.

"For all practical purposes this is Huntington's disease, yet it's caused by a different mutation on a completely different chromosome," says Russell L. Margolis, associate professor of psychiatry in the School of Medicine and director of the Laboratory of Genetic Neurobiology.

The new mutation is in a gene called junctophilin-3 on chromosome 16, and the disorder it causes is called Huntington's disease-like 2, or HDL2. The mutation that causes most Huntington's disease cases is called huntingtin, and is found on chromosome 4.

The scientists don't know how the new mutation affects the gene's function, but they do know that it leads to a pattern of brain cell death identical to Huntington's disease. The same types of nerve cells are destroyed, the same regions of the brain, called the basal ganglia and the caudate nucleus, are targeted, and one side of the brain is affected more than the other. People with HDL2 also have the same types of changes in emotions, thinking and motor skills as those with Huntington's disease. Like Huntington's, HDL2 occurs in midadult life and leads to death in about 10 to 20 years.

The type of mutation in the two genes is also similar. Both are repeat expansions, where a small segment of DNA, in this case three consecutive base-pairs, is repeated numerous times within the normal DNA chain. In HDL2, the more expanded repeats, or triplets, that the mutation has, the earlier the age of onset of the disease.

So far, HDL2 has been diagnosed in 14 families, most of African descent with a particularly high number of cases deriving from South Africa. Almost all of those with the disease have psychiatric symptoms, such as depression and personality changes, as a result of brain cell death.

"Knowing why some brain cells die and not others is crucial to figuring out how to intervene and stop or reverse the course of these diseases," Margolis says. "This is a rare version of an already rare disorder, but the mutation that causes it may not only help us better understand Huntington's disease but could boost our understanding of many other neurodegenerative disorders because we can now compare two different pathways leading to similar patterns of brain disease."

Margolis and his team described their findings in two presentations at the American Society for Human Genetics 2002 annual meeting, held this month in Baltimore.

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Johns Hopkins Department of Psychiatry and Behavioral Sciences