Fragile X syndrome
Fragile X syndrome is one of the most common forms of inherited intellectual disability, affecting 1 in 5,000 males1. The vast majority of cases are caused by the expansion of a CGG-trinucleotide repeat in the 5' untranslated region of the X-linked FMR1 gene2. This results in the gene not being expressed and the absence of the encoded FMRP protein. The lack of FMRP leads to defects in synaptic transmission.
The syndrome gets its name from the fact that when chromosomes from individuals with the syndrome are observed in metaphase spreads, they appear to contain a gap or constriction at the end of the long arm of the X chromosome. In the past, cytogeneticists diagnosed the syndrome by the presence of this fragile site, but this has since been superseded by molecular techniques.
The length of the CGG repeat in the 5' untranslated region of FMR1 is polymorphic in the healthy population and ranges from 6 to 54 repeats. Some individuals carry alleles with an intermediate number (55 – 200) of repeats. These are referred to as pre-mutation alleles, as they do not result in a fragile X syndrome phenotype. However, premutation alleles are prone to expand to a larger number of repeats during meiosis, especially in females. When the number of repeats exceeds 200, the expansion is referred to as a full mutation allele and results in the full syndrome.
At the molecular level, the large number of CGG repeats results in epigenetic changes in the promoter and 5' untranslated region of FMR1, which in turn cause the gene not to be transcribed. Although most known cases are caused by the expansion of the CGG repeat to a full mutation, a small number of deletions, splice site and missense mutations in the FMR1 gene have also been reported.
The most prominent symptom of fragile X syndrome is mild to severe intellectual disability. The average intelligence quotient (IQ) of adult males with the most severe mutation is 40, although those with less severe mutations can have IQs in the borderline to normal range. Full mutation females, of whom only about half are affected, typically have less severe intellectual disability, often demonstrating normal to borderline IQ. Individuals with the syndrome also display a wide variety of autism-like features (see below). Other neurological symptoms include developmental delay and increased susceptibility to seizures.
The most prominent physical symptom is enlarged testes in males, which usually develops just before puberty. More subtle physical symptoms can include a long, narrow face with prominent ears, joint laxity and flat feet. It is now standard of care to test all children presenting with developmental delay, intellectual disability or autism for fragile X syndrome, although only one to three percent of children tested are diagnosed with the syndrome.
Relevance to autism:
Fully 90 percent of males with fragile X syndrome display some autism-like features3, including hand flapping, hand biting, avoidance of eye contact, tactile defensiveness and hyperarousal to sensory stimuli4. Approximately 30 percent of males meet the formal diagnostic criteria for autism spectrum disorder. In fact, fragile X syndrome is one of the leading known causes of autism and is estimated to account for up to five percent of all cases of autism. Research into the molecular mechanisms of the syndrome may very well provide insight into some of the underlying causes of autism.
Current therapies for fragile X syndrome focus on treating the symptoms associated with the syndrome. Stimulants, selective serotonin reuptake inhibitors and antipsychotics have all been used to manage various behavioral symptoms. Non-pharmaceutical interventions include speech therapy, customized educational plans, behavioral interventions and ensuring a structured environment for the patient5. No treatment targeting the underlying causes of fragile X syndrome exists, however several candidate drugs, based upon the known molecular mechanisms of the syndrome (below), are in clinical trials6,7.
The FMRP protein plays a critical role in allowing dendrites to respond to synaptic activity. Under steady-state conditions, FMRP prevents a subset of dendritic messenger RNAs from being translated into protein. Upon activation of specific postsynaptic receptors, FMRP allows its target mRNAs to be translated. This burst of protein synthesis is specific in both time and location, allowing the dendrites to respond precisely to synaptic signals.
In the absence of FMRP, these same proteins are constitutively over-expressed resulting in persistent activation of certain signaling pathways, reducing surface AMPA receptor density and thereby weakening the synapse. These defects ultimately are believed to cause the cognitive and behavioral symptoms seen in individuals with the syndrome.
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Jacquemont S. et al. Sci. Transl. Med. 3, 64ra1 (2011) (7)