Fragile X men: mutations affect the next generation

Many Parkinson's patients may be misdiagnosed. A newly discovered genetic disorder could be the culprit

By Graham Furness

A new disease has been identified that may be the real cause of symptoms in thousands of patients who are currently diagnosed with Parkinson's. Fragile X-associated tremor/ ataxia syndrome, or FXTAS (pronounced fax-tass), was described in the January 28 issue of the Journal of the American Medical Association.

The neurological condition is caused by the fragile X mental retardation 1 gene (FMR1), responsible for fragile X syndrome, the leading cause of inherited mental retardation. Fragile X sufferers carry a dysfunctional gene that's unable to produce the protein FMR1, essential to brain development. Men with fragile X syndrome suffer from mental and motor impairment, autism, elongated faces, enlarged ears and testes and connective tissue problems. In women, retardation may be accompanied by premature menopause in about 25% of those with the disorder.

The families of fragile X patients often carry a premutation expansion in the same gene, in which a meaningless sequence of DNA is reproduced. Previous American research suggests that about one in 800 men and one in 250 women are born with this premutation expansion. Men with these expansions pass them on to their daughters, who pass them on to their own offspring of both sexes. In that third generation, the expansion of useless DNA often multiplies, leading to fragile X syndrome. But it's always been assumed that the premutation expansion found in their grandfathers has no neurological effect.

Three years ago neurologist Randi Hagerman, director of the University of California's Medical Investigation of Neurodevelopmental Disorders (MIND) Institute, was at a meeting of the National Fragile X Foundation when she decided to put a pet theory to the test. She'd noticed over the years that mothers of young fragile X patients often mentioned that their own fathers had balance and tremor problems. So she put the question to the assembled audience - did their fathers have similar symptoms? A third of the hands went up.

Now research by Dr Hagerman and her colleagues has reproduced the results of that straw poll exactly. One third of men with FMR1 premutation expansions really do have neurological symptoms and most of them have already been wrongly diagnosed.

Of 192 patients studied, all of whom had relatives with fragile X syndrome, 40 were men with premutation expansions. The researchers found that these men were 13 times more likely to suffer from gait, tremor and balance symptoms. They also scored less on neurological tests. The likelihood of symptoms increased steadily with age.

FXTAS follows a very different course to fragile X syndrome. The premutation expansion can actually lead to an excess production of FMR1, rather than a lack of the protein. Dr Hagerman said these men often grow up to be highly intelligent and productive. But from around age 50, protein deposits can begin to grow on the neurons.

The study suggested that about one in 3,000 men will develop FXTAS later in life. Men with signs of parkinsonism whose relatives suffer from fragile X syndrome are good candidates for re-evaluation, said the authors. Just as importantly, the grandchildren of men with FXTAS should be screened as well. Grandchildren born to an FXTAS patient's daughter have a 50% chance of carrying the gene for full-blown fragile X syndrome.

There is no cure for FXTAS, but some patients respond to drugs for Parkinson's symptoms, cognitive problems, anxiety and depression.