Abstract
Fragile X syndrome (FXS) is caused by the full mutation (>200 CGG repeats) in the Fragile X Mental Retardation 1 (FMR1) gene. It is the most common inherited cause of intellectual disability (ID) and autism. This review focuses on neuropsychiatric disorders frequently experienced by premutation carriers with 55 to 200 CGG repeats and the pathophysiology involves elevated FMR1 mRNA levels, which is different from the absence or deficiency of fragile X mental retardation protein (FMRP) seen in FXS. Neuropsychiatric disorders are the most common problems associated with the premutation, and they affect approximately 50% of individuals with 55 to 200 CGG repeats in the FMR1 gene. Neuropsychiatric disorders in children with the premutation include anxiety, ADHD, social deficits, or autism spectrum disorders (ASD). In adults with the premutation, anxiety and depression are the most common problems, although obsessive compulsive disorder, ADHD, and substance abuse are also common. These problems are often exacerbated by chronic fatigue, chronic pain, fibromyalgia, autoimmune disorders and sleep problems, which are also associated with the premutation. Here we review the clinical studies, neuropathology and molecular underpinnings of RNA toxicity associated with the premutation. We also propose the name Fragile X-associated Neuropsychiatric Disorders (FXAND) in an effort to promote research and the use of fragile X DNA testing to enhance recognition and treatment for these disorders.
Highlights
Mutations in the Fragile X Mental Retardation 1 (FMR1) gene are relatively common in the general population and create a spectrum of disorders, ranging from neurodevelopmental problems in childhood to neurodegenerative problems in aging
Fragile X-associated Neuropsychiatric Disorders (FXAND) refers to the neuropsychiatric problems that typically occur at an earlier age than FXTAS, and examples of these problems are described below
Hunter et al [53] evaluated the effect of single nucleotide polymorphisms (SNPs) of the corticotropin releasing hormone receptor 1 locus (CRHR1), which controls the hypothalamicpituitary axis (HPA) axis and the response to stress, the stress of raising a child with Fragile X syndrome (FXS). They did not find a correlation with depression, they did find 2 SNPs of CRHR1 that significantly correlated with social phobia in mothers of children with FXS; this correlation was not found in premutation carriers without children with FXS
Summary
Mutations in the FMR1 gene are relatively common in the general population and create a spectrum of disorders, ranging from neurodevelopmental problems in childhood to neurodegenerative problems in aging. The full mutation, which has >200 CGG repeats in the 5’ untranslated region of FMR1, typically causes methylation leading to silencing of FMR1 such that little or no FMR1 mRNA and FMRP are produced. This leads to FXS, which is characterized by ID in 85% of males and 25% of females [1]. FXTAS and FXPOI are commonly recognized, but the most common problems of premutation carriers are psychiatric These psychiatric problems are not typically recognized as related to the premutation because they do not have a fragile X- associated name. This paper describes the fragile X-associated Neuropsychiatric Disorders (FXAND), bringing recognition to these problems by naming them
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