by Jesse Evans

One of the first genetically diagnosed causes of autism and most common inherited single gene cause of intellectual deficiency is Fragile X Syndrome, or FXS. Individuals with FXS present with psychiatric symptoms including anxiety, attention disorders, aggression and self-injurious behavior. In addition, these individuals may have medical conditions such as cardiac disorders. Affecting males more severely than females, the physical characteristics are usually more pronounced after puberty and include a narrow face, large head and ears, flexible joints, flat feet, and a prominent forehead.

Residing on the end of the X chromosome, the gene FMR-1, or Fragile X Mental Retardation 1 gene, has trinucleotide repeats of Cytosine-Guanine-Guanine (CGG). In non-symptomatic individuals, this sequence is repeated less than 45 times and is used to form the Fragile X Mental Retardation Protein (FMRP), which contributes in both positive and negative regulatory mechanisms of neurochemical pathways. However, when the CGG repeat ranges from 200 to 1000, the cytosines are methylated, preventing transcription of the FMR-1 gene and causing dysregulation of FMRP’s regulatory processes within developing nerve cells.

Pharmacologically, SSRIs, antidepressants, anticonvulsants, or antipsychotics are used to manage psychiatric symptoms.  However, with increased understanding of neurological development, scientists hope other aspects of FMRP’s regulatory pathways may hold promise as potential therapeutic targets. Two promising pathways are the GABA and MMP pathways.

GABA Pathway

One promising pathway is the GABA pathway. GABA, or gamma-aminobutryic acid, is a non-alpha amino acid synthesized by cells within the central nervous system. GABA receptors are responsible for controlling the concentrations of chloride within cells and are activated by GABA molecules. With FXS, either the amount of GABA is diminished or the subunits of the GABA receptors are malformed. Since injected GABA cannot cross the blood-brain barrier, GABA agonists have been successful in improving FXS symptoms in animal models. Unfortunately, clinical trials with children showed minimal results.

MMP Pathway

A second pathway is the negative regulation of Matrix Metalloproteinases (MMP). Matrix metalloproteinases are a family of over 20 endopeptidases responsible for tissue remodeling. One subset of these proteins, MMP-9, functions in the brain and assists in learning and memory during human development. When FMRP is absent, the gene for MMP-9 is not regulated and the levels of MMP-9 are increased. Studies have demonstrated the tetracycline antibiotic Minocycline, decreased MMP-9 levels in clinical trials. However, due to the side effects of the antibiotic and the potential for it to increase the antibiotic resistance epidemic, this medication did not pass through to the next phase of clinical trials.

As with other diseases, finding pharmaceuticals with minimal side effects has been a challenge for FXS and autism.  Even though individuals diagnosed with FXS compose less than 6% of ASD, FMRP’s malfunction and the dysregulation of its pathways are critical in helping the scientific community understand its role on a molecular level.

About me

I have a B.Sc in Biology and a M.Sc. in Chemistry. I completed one year in a Biochemistry graduate program before leaving to pursue a new-found interest in improving behavioral healthcare. I currently work at a non-profit assisting individuals with developmental disabilities.  However, I hope to use my background in science and passion for improving behavior healthcare to contribute to a better tomorrow for those afflicted by mental illness.