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Mutation Puts Older Men at High Risk for Tremor Disorder

By Nancy Touchette

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Patients with a new syndrome caused by mutations in the fragile X gene accumulate protein deposits in brain cell nuclei.
A form of a mutation that causes mental retardation in children can also cause neurological problems for men in their twilight years. Researchers, who first recognized the new syndrome in 2001, now report that the risk of the disease, which increases markedly with age, may be more common than originally thought.

A few years ago, Randi J. Hagerman, a California pediatrician who specializes in a type of retardation known as fragile X syndrome, noticed a pattern among some of her patients’ families . Mothers of children who have fragile X syndrome often reported that their fathers, the children’s grandfathers, were experiencing tremors and balance problems.

Hagerman mentioned the problem to her husband Paul J. Hagerman, who studies the genetics of fragile X and related disorders. The pair teamed up to examine the fragile X mental retardation 1 gene more closely in families affected by the syndrome.

They already knew that an unusual mutation in the fragile X gene—a tiny segment of the DNA sequence repeated more than 200 times—could lead to developmental problems or severe retardation in children. Carriers of the mutation have far fewer DNA repeats, but the number of repeats can increase when passed from mother to child.

The researchers noticed that men who had 50-200 repeats in the fragile X gene often developed problems with movement and balance, tremors, memory loss, and dementia. They called the new syndrome fragile X-associated tremor/ataxia syndrome, but did not know how often carriers with the repeats developed symptoms of the disorder.

In the latest study, the Hagermans and their team at the University of California, Davis, found that for men with 50-200 repeats, the likelihood of developing the new syndrome increases dramatically with age. Between the ages of 50 and 59, 17 percent of male carriers develop symptoms. But over the age of 80, 75 percent of men with repeats in the gene develop disease.

According to Paul Hagerman, the syndrome is frequently misdiagnosed, because the symptoms are similar to those of other neurological disorders, such as Parkinson’s disease. However, the brain pathology and the genes associated with the diseases are quite different.

“It’s important that these patients receive the correct diagnosis,” says Hagerman. “Often they are sent to six or seven doctors and are frustrated because the doctors don’t know what’s wrong. They often receive treatments that don’t help.”

Currently there is no cure for the disorder. Hagerman says studies are needed to find out whether some drugs currently in use to treat other neurological disorders might help relieve the symptoms of these patients. Ultimately, he hopes to figure out why the unusual gene mutations cause the disease.

Jacquemont, S. et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 291, 460-469 (January 28, 2004).
Hagerman, R.J. et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 57, 127-130 (2001).

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