NICE, France—Genetic testing on samples from two elderly community population studies shows that gray zone expansion of the fragile X mental retardation 1 (FMR1) gene is associated with parkinsonism in men, researchers said here at the International Congress of Parkinson's Disease and Movement Disorders.
The findings are the first time the link has been found in a community population. The data came from two longitudinal studies of elderly subjects at the Rush Alzheimer's Disease Center and adds strong data to the growing evidence of a link between the fragile X gray zone and a heightened risk of parkinsonism in men.
"This is the third study to show similar results, albeit in a different population, making a real association of parkinsonism with the gene more likely," said Deborah A. Hall, MD, PhD, FAAN, professor of neurological sciences at Rush Medical College.
Those with an expansion of more than 200 in the CGG repeat region of the FMR1 gene are considered to have the full mutation of the gene and are at risk of fragile X syndrome. Expansion of 55–199 CGG repeats causes fragile X-associated tremor/ataxia syndrome (FXTAS). Researchers are trying to bring into better focus the significance of the expansion of 41 to 54 repeats—the "gray zone."
At Rush University, researchers conducted genetic testing on 2,380 participants, finding that 4.5 percent were fragile X gray zone carriers, which is higher than the two percent seen in the general population. Most screening studies are done in newborn populations, which may account for the discrepancy in frequencies, Dr. Hall said.
In addition to the link with parkinsonism (p< 0.01)—determined by a modified Unified Parkinson Disease Rating Scale score—researchers found that men who carried the fragile X gray zone had a shorter lifespan, by about three years. Dr. Hall said these associations could be relevant in conversations with patients, although this information needs to be delivered carefully.
"Currently genetic counseling guidelines suggest that a gray zone carrier should be told they will be neurologically normal. The conversation may need to be modified to inform a man who is a gray zone carrier that if he lives long enough, he will have a higher risk of developing parkinsonism."
Researchers found no differences between gray zone carriers and normal subjects in cognitive diagnosis, global motor function, or pathological findings, such as neuronal and glial intranuclear inclusions seen in FXTAS and other pathologies, even after controlling for age, sex, education, race, and ethnicity.
Melissa Nirenberg, MD, PhD, FAAN, clinical professor of neurology at the Icahn School of Medicine at Mount Sinai, said an important aspect of the findings was that the subjects had consented to brain donation, allowing researchers to determine whether gray-zone carriers had pathology similar to what is seen in premutation carriers, and finding they did not.
"These findings provide further evidence to suggest that fragile X gray zone alleles—which are relatively common in the general population—may be a genetic risk factor for parkinsonism in men," she said.
Many questions remain to be explored, she said. For instance, do gray-zone carriers have pathological changes similar to those in fragile X tremor ataxia syndrome or idiopathic PD, or are their changes unique?
It is also unknown what it is about fragile X gray zone carrier status that predisposes someone to PD, and the factors—whether environmental or epigenetic—that makes someone with a gray-zone mutation more likely to develop parkinsonism.
"Are the clinical features of parkinsonism associated with gray zone mutation carriers different from those with idiopathic PD?" she asked.
Drs. Hall and Nirenberg had no disclosures.
Link Up for Related Information:
International Congress Abstract 514: Hall D, Nag S, Berry-Kravis E, et al. Fragile X gray zone alleles in men are associated with parkinsonism.