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The Neurobiology of Mental Retardation: Fragile X Syndrome

Deborah Silvis

In my previous paper, I wrote on the topic of the nature-nurture debate and the ways it related to the brain-equals-behavior dilemma. In this paper, I will continue this investigation into the link between genes and neurobiology, but I will focus in on a particular aspect of the relationship: neurological disease caused by genetic aberration. There are many well studied and well documented (thought not necessarily well understood) disorders associated with the X chromosome, and a large number of these have neurobiological roots and behavioral manifestations. One such disease is fragile X syndrome. Fragile X syndrome is the most common inherited form of learning disabilities and mental retardation known (1). The disease shows an x-linked inheritance pattern and is characterized by a host of symptoms ranging from impaired learning abilities to severe retardation and autistic behaviors (1). An understanding of the disease is vital on several levels. Fragile X syndrome (FXS) not only bears scientific significance for the fields of molecular genetics, transmission genetics, neurophysiology, and abnormal psychology. It also provides one with a vantage point from which to view the particular set of behaviors known as mental retardation as well as those afflicted by retardation who are too often stigmatized and marginalized in our society.

Before analyzing the neurobiological basis of FXS, it is pertinent to examine the genetics underlying the disease. As stated before, FXS is known to be x-linked which means that the disease will appear roughly in twice as many male cases as female. This is because males, who have only a single copy of x-linked genes which they inherit on their mothers X chromosome, are hemizygous for all genes on that chromosome. The consequence of this is that if a male inherits an X chromosome with mutant alleles at any locus, he lacks the second dose of paternal X which may counter the deleterious effects of those mutation. Men who exhibit the behaviors associated with FXS, then have inherited the disease from their mothers. To continue with the transmission genetics pertaining to this syndrome, it is also known that there are more than twice as many female carriers of the disease than male carriers (1). Of the approximately 1 in 259 women in the population who are carriers of the fragile x mutation, some are pre-mutation carriers and others are full mutation carriers. The former class is generally unaffected by the disease. The full mutation carriers, however, exhibit a range of mild to moderate behaviors associated with learning disabilities and retardation. Thus, the disease can vary in severity, a behavioral characteristic attributable to the varying degrees of expressivity of the mutant gene responsible for the disease.

What is known of this elusive mutant gene which is thought to cause fragile X syndrome? The gene is called Fragile X Mental Retardation 1 (FMR1) and is normally transmitted stably from parent to offspring in humans as well as in divergent organisms. The mutation consists of excessive copies of the CGG triplicate (which codes for the amino acid arginine) at the 5 end of the FMR1 gene. This expansive repeat results in the inability of FMR1 to be expressed (2). Through cloning, it has been found that the FMR1 protein is involved in RNA binding, however, its precise function and the way in which a mutant FMR1 gene leads to mental retardation remains unclear. It appears that the expansive CGG repeat sequence is one key to understanding the degrees of severity of fragile x syndrome across individuals. Normal, unaffected individuals have between 6 and 54 CGG repeats in the region of the FMR1 gene, while affected individuals can have over 200 CGG repeats in this region. FXS carriers can have anywhere between 50 and 200 repeats; it is this subclass of individuals which is said to have the pre-mutation and to exhibit varying levels of severity of the disease. Furthermore, genetic mosaicism, which in the case of FXS means that different cells of the affected individual have differing numbers of CGG repeats in FMR1 region, has been noted and also leads to varying degrees of mental retardation.

The ways in which these genetic phenomena relate to the particular neural state associated with fragile x syndrome is more ambiguous than the cytological evidence which has been presented. The behaviors of the mentally retarded vary between diseases and within single diseases which cause the retardation. Some of these variable clinical manifestations of FXS are cognitive and others are behavioral. Among the cognitive are delayed speech, attention problems, and hyperactivity. Behavioral characteristics of FXS include hand flapping, eye contact aversion, and a fascination with spinning objects; many such attributes are also associated with autism (1). What, though, is the link between these behaviors and a FMR1-linked neurological deficit? It has been stated before that fragile X syndrome occurs as the result of an inborn error of metabolism or Mendelian disorder (3) which prohibits the expression of the FMR1 gene in FMR protein (FMRP). The question, therefore, becomes: what is the functional or structural purpose of FMRP?

On this vital point, the information available on the web is scarce. Perhaps this is because little is known about the essential utility of FMRP in facilitating the development of proper mental functioning. Some sources do point to FMRPs role in RNA binding, though it is unclear from the research how this RNA binding problem may relate to complex behavioral attributes such as a fascination with spinning objects or hyperactivity. Typically, when encountering this problem of extrapolating directly from the cytological level to the behavioral level, biologists fall back on the polygeneity explanation- that not one, but many genes must be responsible for the behavior in question. In the case of fragile X syndrome and its associated mental retardation, however, the web-based evidence points to the contrary; by all accounts to date, a mutation in the single FMR1 gene is the causative agent underlying the disease (3). It would seem, given this, that it is indeed the different dosages of CGG repeats that is leading to the complex variety of behaviors involved in the disorder. Perhaps the root of the neurobiological aspects of the disease lies in some combination of amount of excess arginine and deficiency in RNA binding.

The National Fragile X Foundation does vaguely claim that FMRP has an important function within the cell [and that] these functions particularly impact the way the brain cells work, and when FMRP is not present in the brain the result is mental retardation (1). Unfortunately, no supplementary information is provided about the specific ways in which neurons are affected by problems with RNA binding which are caused by the mutated FMR1 gene. At a recent conference held by the National Fragile X Foundation, an intriguing lecture was given on brain imaging conducted on affected FXS individuals. The imaging is focused on the regions of the brain associated with temporal lobe structures known to be involved in mediating learning and memory, such as the amygdala and the hippocampus. One reported study showed that magnetic resonance imaging of the brain of fragile X patients has revealed abnormalities in the size of specific brain structures, including the cerebellar vermis, the hippocampus, and the ventricular system (1). This link between the hippocampus and the disease was supported by another study which analyzed the volumes of the hippocampus in affected versus non-affected individuals. It found the volume of the right hippocampus to be 10% larger in girls with fragile X and 8.3% larger in fragile X boys (1).

Despite these hopeful findings, there is still much uncertainty surrounding the link between gene and behavior in the case of fragile X syndrome. Mental retardation is characterized by a complex set of behaviors with a myriad of manifestations. Quite contrarily, FMR1 is a single gene whose mutation has a single result: the inability to properly bind RNA. It is understandable, then, that the links between these two seemingly opposed elements of the disease have not yet been fully elucidated. The imaging data may present one connection, but there are likely many more which lie between cytological issues and MRI evidence on one side of the chain and between MRI evidence and mentally retarded behavior on the other side of the chain. Furthermore, there remains the chance that the abnormal behaviors and cognitive problems associated with fragile X syndrome are all aspects of different diseases, and the FMR1 mutation is associative- not causative; this would explain the wide variety and complexity of behaviors exhibited by the mentally retarded. This possibility is supported by the fact that not all of what is clinically classified as mental retardation is due to FXS. Fetal alcohol syndrome and Downs Syndrome are also forms of mental retardation, the latter of which is not even an inborn error of metabolism- it is a chromosomal disorder. And yet the particular subset of behaviors in question is all called mental retardation. Thus, more cytological and neuro-imaging research must be conducted to fully elucidate the complexities of FXS. For the time being, I think, it is safe to assume that the link between a single gene and a complex class of behaviors is strong for fragile X syndrome.

WWW Sources

1)National Fragil X Foundation

2)Neurosciences on the Internet

3)Genetic Causes of Mental Retardation

4)Online Mendelian Inheritance in Man