What does Fragile X teach us about autism?

There are currently no effective treatments for ASD. The primary ASD therapy is a combination of non-specific psychotropic medications that provide only partial benefits while imparting drug-related adverse consequences, which can be significant at times. There are efforts to develop better therapies for ASD, but these efforts are stymied by the lack of insight into the etiologies of ASD, which remain largely unknown. Given that ASD describes a wide spectrum of clinical manifestations, the heterogeneity in ASD also makes it difficult to dissect a clear biological cause.

It may seem quite unexpected, but one of the biggest hopes for understanding the causes of ASD actually comes from another neurodevelopmental disorder called Fragile X Syndrome (FXS).

FXS is caused by a genetic mutation in a gene called Fragile X Mental Retardation 1 (FMR1). This mutation causes the gene to not be able to produce a protein called Fragile X Mental Retardation protein (FMRP). The lack of FMRP disrupts connections between neurons, resulting in mental retardation accompanied with problems in social/behavioral functions.

What is very interesting here is that while the causes of ASD are mostly unknown, five percent of ASD arises from FXS. Up to 60 percent of children with FXS also meet the diagnostic criteria for ASD. The major clinical overlaps between FXS and ASD have major research implications. Trying to dissect a biological cause in the heterogeneous ASD patient populations is akin to searching for a needle in a haystack, yet here we have FXS with a homogeneous genetic cause that accounts for a significant portion of all ASD cases.

As a result, FXS serves as a homogeneous genetic model for ASD in which understanding the biology of FXS will also teach us a lot about ASD. It is therefore helpful to think of ASD as a cloud of different clinical presentations that converge on a similar neural pathway, and FXS represents one spot in this large cloud.

Why is there so much clinical overlap between FXS and ASD? The answer likely lies in FMRP, the protein that is absent in FXS. As an RNA-binding translational regulator, FMRP has been found to interact with four percent of the total RNAs in the mammalian. 842 of such target RNAs have been identified and many of them are implicated in ASD. In simpler terms, what this means is that FMRP is able to influence important aspects of neural function and some of these processes involved in neural function may overlap with ASD.

Because FMRP has so many downstream targets, it is very well possible that loss of FMRP disrupts many neural pathways and disruption of one such pathway leads to ASD. By focusing on FMRP, we may be able to discover common cellular and molecular pathways that are disrupted in FXS and ASD. Discovering the physical substrates of ASD may then allow us to develop better therapies that target the true underpinnings of the disease.