Phenotypic variability to medication management: an update on fragile X syndrome

Abstract

This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome’s variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene’s promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS’s variable expressivity by regulating the pathophysiological mechanisms related to the syndrome’s behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Behavioral and Psychiatric Disorders in Syndromic Autism

“…The premutation occurs when the repeats are in the range of 55 to 200 and can result in either early menopause (fragile X-associated primary ovarian insufficiency), fragile X-associated tremor ataxia syndrome (FXTAS, which is a progressive neurodegenerative disorder occurring later in life), or fragile X-associated neuropsychiatric disorder (FXAND). It should be noted that lesser degrees of functional impairment typically noted in females with FXS are due to the protective factor of having one normal FMR1 allele on their second X chromosome [25,26].…”

Clinical Epidemiology and APOE Gene Etiology: An Update on Alzheimer’s Disease.

“…Recent discoveries in modifier genes in various brain cell types have opened up new avenues for treating and halting the advancement of numerous neurological [65][66][67] and neurodegenerative conditions, including AD 62,68 . These modifier genes can alter the expression of other target genes and influence the penetrance, severity, or other clinically important features of diseases caused by rare mutations in target genes.…”

Synaptic cell adhesion molecules contribute to the pathogenesis and progression of fragile X syndrome

“…Fragile X syndrome affects approximately 1 in 3,600 males and 1 in 4,000–6,000 females ( Tassone et al, 2012 ; Sitzmann et al, 2018 ; Protic et al, 2022 ; Elhawary et al, 2023 ). Approximately 60% of males with FXS meet criteria for ASD ( Hagerman and Hagerman, 2021 ; Marlborough et al, 2021 ) and have some symptoms of autism such as poor eye contact or repetitive behavior like hand flapping ( Roberts et al, 2007 ; McDuffie et al, 2015 ), 23% patients with FXS experience seizures ( Tondo et al, 2011 ; Hagerman et al, 2017 ; Hagerman and Hagerman, 2021 ).…”