Fragile X syndrome, the most common form of genetically caused mental retardation after Down syndrome, produces severe intellectual deficits in children, as well as behavioral, emotional, and some physical problems. Recent findings indicate a surprising second effect from the same gene: vulnerability to a neurodegenerative disorder known as fragile-X-associated tremor/ataxia syndrome, or FXTAS, which usually strikes men older than 50. Older women can develop problems as well.
Fragile X syndrome results from a defective fragile X mental retardation gene, known as FMR1. Like all genes, FMR1 resides on a ribbon of DNA made up primarily of four molecules: cytosine, guanine, adenine, and thymine.
One spot on the FMR1 gene, consisting of a cytosine molecule followed by two guanines (CGG), has a tendency to repeat itself dozens or even hundreds of times. If the number of repeats exceeds about 200, the gene can no longer produce fragile X mental retardation protein (FMRP), a master protein that regulates dozens of other proteins. With so many repeats, the leg of the X chromosome where the gene is located often looks stretched and fragile, which gives the syndrome its name.
FMRP is crucial for strengthening synaptic connections in the developing brain and, at least as important, for pruning unneeded connections. Without this vital protein, the dendrites that branch from the cell body and connect to other neurons remain stunted and neural connections fail to organize themselves into efficient networks.
People with 55 to 200 CGG repeats on their FMR1 gene have what is called a premutation—an abnormality that falls short of the characteristics of a full mutation—and do not develop fragile X syndrome. Until recently they were thought to be free of the problems caused by the full mutation of FMR1. Now it appears that men who carry a premutation of FMR1 are vulnerable to FXTAS, which produces symptoms that resemble Parkinson’s disease.
Some women who carry the premutation develop ovarian failure before the age of 40 and go into menopause, while some men and women, especially those with 150 or more repeats of CGG, have mild cognitive problems not unlike those children with fragile X syndrome may experience: attention deficit, learning disabilities, and high levels of anxiety.
Remarkably, the premutation of the FMR1 gene causes disorders in adults in a way entirely different from the full mutation that causes fragile X syndrome.
“If you look microscopically at the brain cells of a patient with fragile X, a lot of dendrites will have an immature appearance,” says Dr. Elizabeth Berry-Kravis, a pediatric neurologist at Rush University Medical Center in Chicago who has studied both fragile X and FXTAS extensively, and who founded the Fragile X Syndrome Clinic at Rush in 1992.
People with FXTAS, in contrast, have normal amounts of FMRP, but the machinery in their cells must work extra hard to make it. The nucleus copes with the multiple repeats of CGG by producing larger amounts of messenger RNA (mRNA) needed for creating FMRP. The extra mRNA, which can be 2 to 10 times greater than normal, becomes toxic to neurons, especially in the cerebellum, which is crucial for maintaining balance.
The relationship between fragile X syndrome and FXTAS was first noticed by Dr. Randi Hagerman, professor of pediatrics at the University of California-Davis and medical director of the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute. Mothers of children with fragile X syndrome kept asking her about their own fathers, who appeared to have Parkinson’s disease or a similar disorder.
“I started seeing the grandfathers of these children,” Hagerman said. “They all had similar problems. They would develop handwriting problems, then more significant tremor, ataxia, falling, weakness, and cognitive deficits. Many developed dementia. Because I was seeing such consistency, I thought it must be related to the premutation.”
In addition, some males who have the FMR1 premutation display symptoms of autism, such as an inability to read emotion in human faces, a fondness for fixed routines, and obsession with details.
Scientists hope to gain insight into autism by studying how mutations of the FMR1 gene interfere with the way neurons form connections.
“We believe that fragile X can provide a clue to understanding autism at the genetic level,” says William T. Greenough, professor of psychology, psychiatry, and cell and structural biology at the University of Illinois, whose lab does basic research on the development of the nervous system and the neurobiology of fragile X syndrome.