Scientists Edge Closer to Cause of Huntington's Disease

It has been almost 15 years since the gene variant that causes Huntington's disease was discovered. Yet how the variant—a mutated version of a gene on chromosome 4 called huntingtin—actually causes this devastating illness is still a mystery.

Nonetheless, a new study suggests that the variant may somehow lead to abnormal brain development.

The study, headed by Peggy Nopoulos, M.D., a professor of psychiatry at the University of Iowa, was published in the September American Journal of Psychiatry.

The study included 48 subjects. Twenty-four had preclinical Huntington's disease—that is, they were known to possess the huntingtin gene variant that causes Huntington's disease, but had not yet started exhibiting the motor symptoms of the disease, which is a criterion for clinical diagnosis of Huntington's. The other 24 were matched, healthy control subjects.

Nopoulos and her colleagues used magnetic resonance imaging to scan the cerebral cortex surface of all 48 subjects. They found that the volume of the cerebral cortex was significantly larger in the pre-Huntington's group than in the control group. Also, the surface anatomy of the cerebral cortex—that is, its gyri and sulci—was strikingly different in the two groups.

For example, although the total cerebral surface area was not significantly different between the pre-Huntington's group and the control group, when the total surface area was divided into gyral and sulcal surface areas, the pre-Huntington's group showed a significantly larger gyral surface area than the control group did. “That sulci and gyri differed in structure is most likely not random and therefore biologically important,” Nopoulos and her group pointed out in their study report.

Thus they concluded that their findings suggest that abnormal brain development may be “an important process in the pathoetiology of Huntington's disease.”

But if abnormal brain development underlies Huntington's, why do the psychiatric and motor symptoms of the illness appear only in adulthood?“ Abnormal brain development may lead to changes in brain structure and function that are present lifelong, but subtle,” Nopoulos told Psychiatric News. Such longstanding changes, she conjectured, might then lead to neurodegeneration, and only with the onset of neurodegeneration might the classic symptoms of Huntington's become apparent.

Another illness that may be due to abnormal brain development followed by neurodegeneration is schizophrenia, she pointed out. “Subtle signs of the disease may be present lifelong, but manifestation of the symptoms of the disease do not appear until adulthood.”

Yet if abnormal brain development followed by neurodegeneration underlies Huntington's, where does the huntingtin gene variant that causes the disease fit into the picture? The normal huntingtin gene is known to be vital to life—it has been shown that if it is “knocked out” in a mouse model, the growing fetus does not survive, Nopoulos said. So the huntingtin gene variant that Huntington's patients possess may interfere with normal brain development, and this interference may lead to abnormalities in brain architecture, neurodegeneration, or other brain anomalies, she said.

Yet how the huntingtin gene variant might actually sabotage brain development remains to be determined. For example, does the protein made by the variant possess a toxic function? Or has it lost some of the functions possessed by its normal counterpart? “Fifteen years out, these remain fundamental questions, and the therapeutic implications will be quite different, depending on the answers,” J. Timothy Greenamyre, M.D., Ph.D., a professor of neurology at the University of Pittsburgh, stressed in an accompanying editorial.

The study was funded by the National Institutes of Health, the Roy J. Carver Charitable Trust, and the Howard Hughes Medical Institute.

“Morphology of the Cerebral Cortex in Preclinical Huntington's Disease” is posted at<http://ajp.psychiatryonline.org/cgi/content/full/164/9/1428>.▪