STANFORD, Calif. — Fragile X syndrome is the most common known cause of inherited intellectual disability and autism. Now, researchers using advanced, noninvasive imaging techniques have shown how the brains of very young boys with fragile X syndrome differ from those of young boys without it, providing critical information for the development of treatments for the condition.
In a longitudinal study to be published online May 3 in Proceedings of the National Academy of Sciences, researchers from the Stanford University School of Medicine and collaborators from the University of North Carolina-Chapel Hill monitored anatomical changes that, over time, progressively differentiate the brains of children with fragile X syndrome from those of children without it.
Triggered by a mutation in a gene located on the X chromosome, fragile X syndrome affects about one in every 4,000 people, with more significant symptoms occurring in males than females. This condition's genetics and neurobiology are relatively well understood, accelerating the pace with which potential drug therapies have been moving through the pharmaceutical pipeline, said the study's senior author, Allan Reiss, MD, the Howard C. Robbins Professor of Psychiatry and Behavioral Sciences and professor of radiology.
Reiss, who directs Stanford's Center for Interdisciplinary Brain Sciences Research, has been studying fragile X syndrome for more than two decades. "A number of years ago, we saw new treatments quickly coming down the line," he said. "So we wanted to provide information that could be used to guide those treatments." Application of these new findings might enable scientists and clinicians to tell if a therapy is working in the very youngest of children diagnosed with this condition.
Fragile X syndrome alone accounts for about 2-3 percent of all cases of autism, making it the most common known, specific genetic risk factor for that disorder, although not all people with fragile X syndrome develop autism. Autism is increasingly viewed as not a single disease but a spectrum of them. A large number of diverse genes have been identified as contributing to autism, but with each responsible for only a sliver of cases. Fragile X syndrome patients often manifest discomfort with eye contact, hypersensitivity to sound or touch, abnormalities of language and movement, and varying levels of developmental delay.
In the study, the Stanford and UNC investigators used high-resolution MRI to obtain detailed images of 1- to 3-year-old boys' brains, and followed up two years later with a second imaging session. The MRI results were analyzed at Stanford, primarily by Reiss and the study's lead authors: Fumiko Hoeft, MD, PhD, an imaging expert and instructor at the CIBSR, and medical student John Carter. Brain images from 41 fragile X syndrome boys were compared with those from age- and developmentally-matched control subjects: 21 boys who were developing typically, and seven others who were experiencing non-fragile-X-related developmental delay.
While many aspects of brain anatomy were similar from one group to the next, the fragile X brains evidenced at an early age (that is, during their first imaging session at 1-3 years of age) an overabundance of gray matter in such regions as the caudate and thalamus, and a diminished presence in a part of the cerebellum called the vermis. This suggests that the fragile X syndrome mutation had already begun to cause identifiable, consistent alterations in brain development, perhaps even before birth. However, the basal forebrain as well as a different part of the thalamus and many regions of the cerebral cortex of fragile X patients, while indistinguishable from those of control subjects during the first imaging session, diverged from their counterparts two years later. These results suggest that certain downstream effects of the mutation become evident only later in brain development.
Knowing the locations of fragile X syndrome brain-structure abnormalities and the developmental time course over which they occur — and being able to noninvasively detect those changes in young patients — will make it possible to monitor new therapies' effectiveness in (it is hoped) restoring patients' brain structure and function to normality.