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Genotype-Phenotype Relationships in Fragile X Families

State/Province Full: 
United States

Fragile X syndrome (FXS) is the most common heritable form of mental retardation and is a frequent cause of autism. Specifically, up to 30 percent of people with FXS have autism and 2 to 8 percent of children with autism are also diagnosed with FXS. Over the past several years Dr. Hagerman and his colleagues have found a more specific association between the two disorders. Their work indicates that people with a certain subtype of FXS, termed “fragile X premutation” are at increased risk for autism and attention deficit hyperactivity disorder. In addition, these people show elevated levels of the genetic material that produces a protein called Fragile X Mental Retardation Protein—FMR1 mRNA. Increases in FMR1 mRNA in turn, correlate with emotional problems and a disruption in attending to social stimuli. Dr. Hagerman and his team speculate that FMR1 may prove toxic to brain systems and that then lead to autism in people with the premutation. This grant will provide bridge funding to compare twenty young men, between 8 and 16, with the premutation with 20 young men without the premutation. Each subject will undergo a thorough evaluation for autism and ADHD, in addition to a molecular analysis for fragile X. This study will allow Dr. Hagerman's group to continue NIH-sponsored research at the MIND Institute to study whether autism in young males with the premutation is related to FMR1 mRNA toxicity. What this means for people with autism:Due to the concordance of Fragile X Syndrome and autism, FXS is considered an excellent genetic model for autism spectrum disorders. In fact, the American Academy of Pediatrics recommends routine screening for FMR1 in the medical evaluation of autism. It is likely that the pathways leading to autism in FXS are related to pathways that lead to other subgroups of autism. This study will allow Dr. Hagerman's group to focus on the cause and consequences of a specific mutation of the Fragile X gene that causes an increase in FMR1 mRNA. The outcome will lead to better treatment interventions and pharmacotherapies both for FXS and autism.