Fragile X and autism: Intertwined at the molecular level leading to targeted treatments

Fragile X syndrome (FXS) is an important subtype of autism, both because of its frequency and because knowledge of the molecular mechanisms involved in its pathogenesis has facilitated the development of targeted treatments with the potential to reverse or dramatically improve both behavioral and cognitive deficits. Because FXS is the most common single gene cause of autism, responsible for 2% to 6% of all cases of autism, it is clinically recommended that all individuals diagnosed with autism or ASD should have the FX DNA test (both PCR and Southern blot) when the etiology of their autism is not known [1-4]. FXS is nearly always caused by a trinucleotide (CGG) repeat expansion, located in the 5' untranslated region of the FMR1 gene, to a length of greater than 200 repeats (full mutation range). Full mutation expansions typically lead to methylation of the gene, reduced or absent transcription, and consequent decreased reduction in translation of the FMR1 protein (FMRP), the proximal basis of FXS. FMRP levels are correlated with the degree of clinical involvement including physical, cognitive and structural/functional brain involvement [5-10].Approximately 30% of males with FXS have full autism, as determined by the standardized criteria of the Autism Diagnostic Observation Scale (ADOS) and the Autism Diagnostic Interview (ADI-R) [11-15]. An additional 30% of boys have pervasive developmental disorder, not otherwise specified (PDD-NOS) [11]. Among the remaining patients with FXS, of those who do not meet the criteria for an autism spectrum disorder (ASD) diagnosis, the majority have one or more autistic features, such as hand flapping, poor eye contact and tactile defensiveness [11].A premutation CGG-repeat range (55 to 200 repeats) was initially defined in terms of an increased frequency of expansion of the CGG repeat to the full mutation range when transmitted by a premutation (carrier) woman. All children with the full mutation have a carrier mother, although a f