Fragile X Syndrome

To find patient care programs (Fragile X Clinicand faculty treating Fragile X Syndrome at Kennedy Krieger Institute, as well as research investigating this disorder, please see the right-hand column below. Additional helpful information, including definitions, symptoms, Institute press releases, Potential magazine articles, and other resources outside the Institute, have also been provided for readers on this page.

Fragile X Syndrome Overview:

Fragile X syndrome (FXS) is the leading known inherited cause of intellectual disability and autism spectrum disorders (ASDs). Over 100,000 Americans have FXS; moreover, it is estimated that over one million are Fragile X carriers. Nationally, over one million individuals have ASDs, which is a phenomenological, DSM-based diagnosis and originates from a different group of disorders. The gene that causes FXS is called “FMR1,” which stands for “fragile X mental retardation.” The FMR1 gene is located on the X chromosome. Chromosomes are the structures that contain our DNA and our genes. Genes are the instructions for our body to grow, develop, and function.

The FMR1 gene makes a very important regulatory (‘supervisor’) protein called “fragile X mental retardation protein” (FMRP), which is found in all our cells, but it is most abundant in the nerve cells. The FMR1 gene encodes the FMRP, an RNA-binding protein that inhibits protein synthesis. A mutation is any change in a gene. FXS is caused by mutation and silencing (“shut-down”) of the FMR1 gene. The gene is “shut-down” because of an expansion mutation of the CGG triplet repeat in the regulatory region of the FMR1 gene that increases over generations from normal number (4-45 CGG repeats) to permutation or “carrier status” (55-200 CGG repeats), and eventually to >200 repeats, termed full-mutation. The FMR1 gene then gets turned off (no FMRP) by process called ‘methylation.’

Currently, there are two tests (PCR and Southern Blot) that need to be performed to determine whether someone has FXS, and to determine whether family members have a potential to transmit the expanded FMR1 gene to their children. The pattern of transmission of the FMR1 gene is complex. While FXS affects both genders, as expected in an X-linked condition, the characteristic features of FXS are more frequent and severe in affected males. Females with full-mutation are typically less severely affected and show substantial phenotypic variability because of variable X inactivation (i.e., some cells being able to produce FMRP). Overall, following classical X-linked inheritance, FXS tend to be more severe in males, and autism is almost exclusively a clinical issue in the same population.

Regardless, social impairment is a core feature of both FXS and ASDs. FMRP’s ‘fingerprint’ is found in roughly half of the estimated 400 to600 genes linked to autism. Thus, it is not surprising that many of the problems with cellular dysregulation in FMRP-deficient neurons also parallel the cellular abnormalities that have been documented in severe form of ASDs of unknown origin. As such, it has attracted much attention as a model for the study of autism and other developmental disorders. FMRP (“brake”) deficit results in an excess of glutamate (“accelerator”) on the synapse, which impairs communication among the broader spectrum of neurons by making them over-stimulated (i.e., increase protein synthesis). Fragile X molecularly targeted therapeutics show potential to regulate/decrease the protein synthesis and modify social behaviors in FXS and ASDs. Namely, different targeted molecular treatments that address the specific molecular pathophysiology of the disease (i.e., mGluR5 antagonists, GABA-B agonists) are underway in multi-site clinical trials, including at the Kennedy Krieger Institutes’ Clinical Trials Center.