National Institutes of Health develops research plan on Fragile X syndrome and associated disorders

The National Institutes of Health has developed a research plan to advance the understanding of fragile X syndrome and its associated conditions, fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Fragile X syndrome causes intellectual and developmental disabilities and results from a mutation in a gene on the X chromosome.

The plan puts forward goals to guide future research, setting research priorities for each of the conditions. A major priority of the plan is to investigate the biological processes underlying all three disorders and how to better diagnose and treat them. Other priorities are studying how widespread the gene variations are in the population and how the three conditions affect families.

"NIH's research efforts have made great strides in understanding these conditions," said Raynard S. Kington, M.D., Ph.D., acting director of NIH. "We now intend to build on these advances."

Although the three disorders have very different symptoms, all result from variations in the same gene, known as the Fragile X Mental Retardation 1 (FMR1) gene. Full mutation of the gene means that cells do not produce a protein involved with communications between neurons in the central nervous system. The resulting disorder, Fragile X syndrome (FXS), occurs in approximately one in 2,500 births. People with FXS often have intellectual disabilities ranging from mild to severe. They may also have emotional and behavioral problems, including attention problems, hyperactivity, anxiety, aggression, and autism or autism spectrum disorder.

People with a less dramatic change in the gene have what is called a pre-mutation, which increases their chance of having a child with FXS. These people may not have any apparent health problems or may have symptoms of Fragile X-associated Tremor/Ataxia syndrome or Fragile X-Associated Primary Ovarian Insufficiency.

Fragile X-associated Tremor/Ataxia syndrome (FXTAS) occurs primarily in older men. The principal symptoms are tremor and gait problems, but the condition also includes cognitive decline, anxiety, and depression. Fragile X-associated Primary Ovarian Insufficiency (FXPOI) occurs in women of childbearing age. Women with FXPOI may experience early infertility and increased risk of osteoporosis and heart disease.

"Collectively, these disorders represent a major health burden and have far-reaching implications for individuals as well as their family members," said Tiina Urv, Ph.D., of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, chair of the trans-NIH Fragile X Research Coordinating Group. It is possible, Dr. Urv explained, for the gene to be abnormal in multiple family members. For example, the mother of a child with FXS may eventually show symptoms of FXPOI, and her father, and the child's grandfather, may develop FXTAS.

"These disorders may affect multiple family members, and multiple generations," Dr. Urv said.

To develop the plan, the NIH convened three working groups of experts, one for each of the conditions. Members of each group included experts from the scientific community, members of advocacy groups for individuals and their families affected by the disorders, and other federal agencies. The research plan identifies research goals for each of the three conditions, and outlines strategies for better diagnosis, treatment and prevention of the three disorders.

"The goals were designed to be used by the NIH and FXS, FXTAS, and FXPOI research communities and to be shared with other federal agencies to facilitate coordinated research activities that will lead to timely detection, diagnosis, treatment, and prevention of the targeted disorders," the report stated.

Studies funded by the NIH have been instrumental in contributing to the understanding of Fragile X syndrome, including the discovery of the fragile X expansion mutation in 1991 by 3 groups of scientists, two of which benefited from funding by the NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NIH-funded researchers also played a pivotal role in identifying FXTAS and FXPOI.

The report also highlights ongoing research, including collaborative efforts from several NIH institutes: the NICHD, the National Institute of Neurological Disorders and Stroke, the National Institute of General Medical Sciences, the National Institute of Mental Health, and the National Institute on Aging. The NIH funds a network of centers devoted to Fragile X syndrome and its associated conditions, as well as studies by independent scientists.