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Mutant Genes Blamed for Deadly Childhood Disease

Rare condition leads to progressive brain damage, coma

MONDAY, Nov. 12, 2001 (HealthDayNews) -- A rare childhood disease that leads to progressive loss of movement and speech, and sometimes seizures or coma, appears to have mutant genes at its roots, say Dutch scientists.

Delayed onset of the disease can allow people to live into their 20s or 30s, but some children fall into a coma and die between ages 1 and 5.

Known as leukoencephalopathy with vanishing white matter (VWM), the disease is one of a family of diseases known as leukodystrophies, characterized by degeneration of the white matter of the brain.

It's believed to affect between 200 and 300 people in the United States, says Timothy Brazeal, executive director of the United Leukodystrophy Foundation. But because VWM shares many characteristics with other leukodystrophies, he says it's often misdiagnosed, and the number of people affected may be higher.

"The cause of the disease VWM is mutations in genes which determine a protein complex," says senior researcher Jan Pronk, a geneticist at the Free University Medical Center in Amsterdam, the Netherlands. Either of two mutated genes causes a mutation in the protein complex known as a translation initiation factor, he says.

The shape of the protein complex is abnormal in people with VWM, the study says.

Because patients with VWM deteriorate very quickly if they develop a high fever, the researchers suspect temperature affects the protein complex.

"When the temperature rises in the patient when they have fever, protein synthesis has to be shut off. This complex plays a key role in that process," Pronk says.

When protein synthesis doesn't stop because the complex is mutated, he says normal cell function is interrupted. Details appear in today's issue of Nature Genetics.

Although the genes in questions have been studied extensively, Pronk says more research is needed to better understand the mechanisms. New therapies are still three to four years from development, he says.

Although the protein complex can be found in all body cells, the researchers say the effect is limited to nerve cells in the brain. Pronk suspects the damage occurs to brain cell axons -- thin filaments that transport electrical impulses away from the cells. Neurons are the only cells with axons.

Cécile Julier, head of the Laboratory of Genetic Predisposition to Infectious Diseases at the Institut Pasteur in Paris, says the study is the first to link a translation initiation factor to a genetic disease in humans.

Any knowledge gathered about the disease could aid efforts to develop treatments, she says.

"Most interesting will be whether this has also something to do with more [common] diseases, such as multiple sclerosis," Julier says.

Pronk says the findings could be relevant to other neurological conditions that, like multiple sclerosis, are affected by temperature.

"In multiple sclerosis, patients deteriorate if they get a fever," says Pronk. A similar reaction might be involved in both that disease and VWM, he says.

But he says that's just a theory that must be confirmed by future studies. The findings have no immediate implications for people with multiple sclerosis, he says.

What To Do

To learn more about VWM, sometimes referred to as childhood ataxia with central nervous system hypomyelinization, or CACH, check information from the United Leukodystrophy Foundation.

For more on multiple sclerosis, visit the National Multiple Sclerosis Society or the National Institute of Neurological Disorders and Stroke online.

SOURCES: Interviews with Jan C. Pronk, Ph.D., associate professor, department of human genetics, Free University Medical Center, Amsterdam, Netherlands; Cécile Julier, Ph.D., head, Laboratory of Genetic Predisposition to Infectious Diseases, Institut Pasteur, Paris; Timothy R. Brazeal, executive director, United Leukodystrophy Foundation, Sycamore, Ill.; Nov. 12, 2001, Nature Genetics
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