Purpose of review: This review will describe recent developments in the neurobiology of fragile X syndrome (FXS), the association between FXS and autism, and involvement in premutation carriers.
Recent findings: Metabotropic glutamate receptor 5 (mGluR5)-coupled pathways are dysregulated in individuals with FXS and this is thought to relate to the FXS phenotype. The mGluR5 model suggests that mGluR5 antagonists, including downstream effectors such as lithium, could be useful for treating FXS. Two forms of clinical involvement associated with the fragile X mental retardation 1 (FMR1) gene, autism and fragile X-associated tremor/ataxia syndrome (FXTAS), have received additional attention during the past year. One study has found that approximately 30% of individuals with FXS have autism; those with autism have lowered cognitive abilities, language problems, and behavioral difficulties compared to those with FXS alone. Furthermore, evidence is mounting that autism also occurs in some young males who have premutation alleles. Finally, males and occasional females with premutation alleles may develop a neurological syndrome with aging that consists of tremor, ataxia, peripheral neuropathy, and cognitive deficits. Significant brain atrophy and white-matter disease is usually seen. This new disorder (FXTAS) is thought to be related to elevated levels of abnormal FMR1 mRNA.
Summary: Full-mutation forms of the gene (> 200 repeats) can cause autism, learning disabilities, anxiety disorders, and mental retardation. Disorders associated with premutation forms of the gene (55-200 repeats) include, in addition to autism, FXTAS in older males and females, and premature ovarian failure.