Researchers urge physicians to test for fragile X gene mutations in patients of all ages

Nov 25 2008

Writing in this week's Journal of the American Medical Association , UC Davis M.I.N.D. Institute researchers urge physicians to test for mutations of the fragile X gene in patients of all ages.

That's because, after decades of research, it is clear that mutations in this gene cause a range of diseases, including neurodevelopmental delays and autism in children, infertility in women and neurodegenerative disease in older adults.

"We want to notify specialists in a variety of areas, as well as allied health professionals, of the potential impact of the fragile X mutation at different times in patients' lives," said Randi Hagerman, director of the Fragile X Research and Treatment Center at the UC Davis M.I.N.D. Institute.

Hagerman, who is also the institute's medical director, co-authored the commentary with fellow M.I.N.D. Institute researcher and husband, Paul Hagerman, who is also director of the UC Davis NeuroTherapeutics Research Institute (NTRI).

Without testing for fragile X mutations, the Hagermans write, patients can be misdiagnosed.

"These patients don't have the advantage of targeted treatments and specific therapies," Randi Hagerman said.

The families of these patients are also at risk because the mutations are passed on from generation to generation.

"The patients don't realize that a genetic mutation is causing all of these seemingly unrelated diseases in their families," she said.

Research by the Hagermans and others has shown that mutations of the fragile X gene can cause, among other disorders, autism and ADHD in children, anxiety disorders at all ages, early menopause in women and dementia in the elderly.

Because the potential impact is so great, M.I.N.D. Institute researchers have created an inexpensive spot blood test for newborn screening that is currently in clinical trials.

Until testing for fragile X is widespread, the Hagermans urge genetic testing for all patients who show signs of diseases now known to be linked to FMR1 mutations.

Abnormalities in the fragile X gene fall into two categories: those caused by the full mutation and those associated with the premutation.

The full mutation involves greater than 200 copies of a three-nucleotide sequence (CGG) in the FMR1 gene found on the X chromosome.Normal individuals typically have fewer than 40 repeats.

The premutation involves 55-200 CGG repeats in this gene. Individuals with the premutation are known as carriers and the children of female carriers are more likely to be born with the full mutation.

The full mutation of the FMR1 gene causes fragile X syndrome, for which there is no cure, but targeted treatments that may reverse this disorder are currently being tested at the MIND Institute. Without a normal copy of the fragile X gene, a vital protein is not made and the result is the onset of characteristic mental disorders, which can range from learning disabilities to severe cognitive or intellectual disabilities, such as autism.

In fact, 30 percent of boys with the fragile X mutation are diagnosed with autism. Fragile X syndrome is the most commonly known single-gene cause of autism, responsible for between 2 and 6 percent of autism cases.

In girls, the full mutation often manifests as shyness, math learning disability and social anxiety.

Treatment of the syndrome depends on its manifestations in the individual, and ranges from behavioral therapy to medication.

Last year, the Hagermans and their colleagues reported that the fragile X premutation may be twice as common as previously suspected, potentially affecting over one million men, women and children in the United States.

The premutation can cause attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder in children; primary ovarian failure (early menopause) in women; and FXTAS, or fragile X- associated tremor-ataxia syndrome, in older adults.

The Hagermans and their colleagues at the M.I.N.D. Institute are conducting clinical trials of targeted drug treatments that have shown promise in animal studies.

They write: "These trials, if successful, make the case for newborn screening (for fragile X syndrome) more compelling and raise the prospect of future intervention during the developmental period to prevent long-term disability."