Fragile X-Associated Neuropsychiatric Disorders (FXAND)

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.

Using the tools of genetic epidemiology to understand sex differences in neuropsychiatric disorders

“…In addition to being the most common inherited cause for ASD and intellectual disability, deletion of the FMR1 gene is also associated with a broad range of neuropsychiatric outcomes in both youth and adults ranging from anxiety disorders to substance abuse. 53 Studies of female carriers of the Fragile X mutation have also informed sex differences in the influence of these mutations. 54 Premutation carriers of the FMR1 gene have a lesser number of repeats (55-200 CGG repeats) than those who manifest FXS (>200 CGG repeats), and increased prevalence of anxiety, depression, ASD, ADHD, intellectual and learning disabilities, substance use problems, and personality disorders have been reported.…”

“…54 Premutation carriers of the FMR1 gene have a lesser number of repeats (55-200 CGG repeats) than those who manifest FXS (>200 CGG repeats), and increased prevalence of anxiety, depression, ASD, ADHD, intellectual and learning disabilities, substance use problems, and personality disorders have been reported. 53,55 In addition, a number of X chromosome genes and copy number variants (CNV) have been associated with intellectual disability, 56 developmental delay, 57 and schizophrenia, 58 but the risk of incurring a mutation associated with intellectual disability on the X chromosome is the same for males and females. Figure 2 by light gray for males and dark gray for females.…”

Cardiovascular Problems in the Fragile X Premutation

“…Finally, since neuropsychiatric disorders in carriers called FXAND are very common ( Hagerman et al, 2018 ) and a long history of emotional intensity can lead to enhanced catecholamine release which could aggravate cardiovascular problems including cardiomyopathy ( Wittstein et al, 2005 ), hypertension ( Hamlin et al, 2012 ), and SCAD ( McKenzie et al, 2020 ), therefore, treatment of FXAND should be kept in mind.…”

“…In addition, psychiatric problems are common, particularly anxiety, depression, obsessive-compulsive disorder, mood disorder, and they fall under the umbrella term of fragile X-associated neuropsychiatric disorders (FXAND). One or more of these psychiatric problems can affect up to 50% of carriers ( Wheeler et al, 2014 ; Hagerman et al, 2018 ).…”

Cortical gyrification and its relationships with molecular measures and cognition in children with the FMR1 premutation

“…To understand neurobiological bases for cognitive development and neuropsychiatric conditions in PM carriers, we examined cortical folding in children with the PM and its relationships with FMR1 molecular measurements and cognitive functioning. Given the variability found in the phenotype of children with the PM 4 , we explored gyrification analyses at both group and individual levels to account for potential spatial and directional (i.e., hyper-or hypo-gyrification) variations in gyrification. Gyrification was quantified using local gyrification index (LGI) 33 , the ratio of total surface area (both hidden within the sulci and exposed on the outer surface of the brain) and exposed surface area.…”