Fragile X condition detected 20 years before symptoms appear

"Identifying these brain changes when the individuals who carry the gene mutation are young is important, because there are medical interventions that can help them avoid or reduce their symptoms," says Randi Hagerman. (Credit: Kevin Christopher Burke/Flickr)

The very earliest signs of a debilitating neurodegenerative disorder, in which physical symptoms are not apparent until the fifth decade of life, are detectable in people as young as 30 years old using a new type of neuroimaging.

People with the condition—fragile X-associated tremor/ataxia syndrome (FXTAS)—experience tremors, poor balance, cognitive impairments, and Parkinson’s-like symptoms.

The genetic condition results from a mutation in the fragile X mental retardation gene (FMR1). FXTAS develops in about 40 percent of male and 15 percent of female carriers of the mutated FMR1 gene.


“Our findings suggest that the brain abnormalities of FXTAS may begin to develop about two decades before symptoms might occur,” says Tony J. Simon, study senior author and professor in the department of psychiatry and behavioral sciences at University of California, Davis.

Published in the journal Human Brain Mapping, the study included 88 participants, between age 20 and 40. Of these, 46 were symptomless carriers of the FMR1 gene mutation (fXPCs). They were matched by age and gender with 42 healthy individuals without the gene mutation. IQ test results did not differ between the fXPCs and controls.

The findings showed a correlation between the efficiency of a healthy male carrier’s brain network and the extent of his gene mutation. The correlation may prove to be an effective marker of early brain aging in neurologically symptomless fXPCs. The study also revealed that the volume of the brain stem is smaller in male fXPCS than in male controls.

In a new finding, among female participants, researchers detected volume differences in several brain areas of female fXPCs and female controls.

Brain connectomics

“These suggest the presence of compensatory mechanisms in neurologically symptomless females but not in similar male carriers of the gene mutation,” says Simon, a researcher affiliated with the MIND Institute.

Despite the absence of any clinical symptoms of FXTAS, the male and female gene mutation carriers performed significantly worse in several tests when compared to unaffected controls.

“Given the lower risk for FXTAS or related neurological symptoms in female fXPCs, we were surprised to find such differences when their minds and brains were compared with those of the unaffected female controls,” Simon says.

Both groups were evaluated by cognitive testing as well as novel neuroimaging techniques termed brain connectomics, based on diffusion tensor imaging (DTI) whole-brain tractography. A connectome is a comprehensive map, like a wiring diagram, of neural connections in the brain.

The methods used were partly developed by study first author Alex Leow of the University of Illinois, Chicago. The investigation is the first-ever connectome study using DTI-whole brain tractography to compare fXPCs and controls.

Grey-white matter connection

The technology allowed researchers to conduct a system-wide investigation of the connections between the brain’s grey matter, which is involved in movement control, sensory perception, memory, emotions, speech, decision-making, and self-control, and the white matter structures that transmit the signals that underlie these actions and behaviors.

The study suggests that combining analyses of cognitive function, clinical data, and connectome patterns in premutation carriers may be more effective ways to characterize an individual’s underlying brain pathophysiology, and possibly assessing risks for later degeneration, than is possible using current methods.

In addition to FXTAS, the fragile X-associated disorders include fragile X syndrome, the most common form of intellectual disability in children, and fragile X-associated primary ovarian insufficiency (FXPOI).

“Identifying these brain changes when the individuals who carry the gene mutation are young is important, because there are medical interventions that can help them avoid or reduce their symptoms,” says MIND Institute Medical Director Randi Hagerman.

Other researchers from UC Davis, University of Illinois at Chicago, and UCLA contributed to the study that was supported by the National Institutes of Health and the National Institute of Dental and Craniofacial Research.

Source: UC Davis