Cardiovascular Problems in the Fragile X Premutation

Abstract

There is a dearth of information about cardiovascular problems in fragile X premutation carriers who have 55–200 CGG repeats in fragile X mental retardation 1 ( FMR1 ) gene. The FMR1 expansion in the premutation range leads to toxic RNA gain-of-function resulting in cellular dysregulation. The mechanism of RNA toxicity underlies all of the premutation disorders including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X-associated neuropsychiatric disorder. Cardiovascular problems particularly autonomic dysfunction, hypertension, and cardiac arrhythmias are not uncommon in premutation carriers. Some arterial problems and valvular heart diseases have also been reported. This article reviews cardiovascular problems in premutation carriers and discusses possible contributing mechanisms including RNA toxicity and mild fragile X mental retardation protein deficiency. Further research studies are needed in order to prove a direct association of the cardiovascular problems in fragile X premutation carriers because such knowledge will lead to better preventative treatment.

Genetic mouse models of autism spectrum disorder present subtle heterogenous cardiac abnormalities

“…More specifically, our findings of altered anterior wall thickness and thickening, HR and fractional shortening can be effects of Tetralogy of Fallot, pulmonary atresia or aortic valve abnormalities, all reported in the literature (Pierpont et al, 2018). Fmr1, has the second most abnormalities, both structural (LV chamber diameter, anterior wall) and functional (anterior wall thickening) which can be anticipated by the range of abnormalities reported in literature along with the fact that CHD has been reported (<10% of cases; Berry‐Kravis et al, 2019; Ciaccio et al, 2017; Ornoy et al, 2016; Pierpont et al, 2018; Tassanakijpanich et al, 2020). In the Chd8 (+/−) group, we observed increase in the LV anterior wall.…”

“…Fragile X syndrome results from a mutation in the FMR1 gene and is one of the syndromes with high ASD comorbidity (30%; Hagerman et al, 2010). Additionally, cardiac abnormalities have been reported in FMR1 patients, primarily mitral valve prolapse (MVP), aortic root dilation, and arrhythmias (Berry-Kravis et al, 2019;Ciaccio et al, 2017;Ornoy et al, 2016;Pierpont et al, 2018;Tassanakijpanich et al, 2020). An occurrence rate of congenital heart disease <10% has also been reported (Pierpont et al, 2018).…”

“…In Rett syndrome ( MECP2 mutation; 95% ASD prevalence) severe cardiac arrythmias, abnormal ventricular repolarisation and systo‐diastolic biventricular myocardial dysfunction are reported (Acampa & Guideri, 2006; de Felice et al, 2012). Finally, morphological cardiac abnormalities have been reported in (and Fragile X syndrome ( FMR1 mutation) including mitral valve anomalies, aortic root dilation, and arrhythmias (Berry‐Kravis et al, 2019; Ciaccio et al, 2017; Ornoy et al, 2016; Pierpont et al, 2018; Tassanakijpanich et al, 2020; Tables S1 and S2).…”

Case Reports of Aortic Aneurism in Fragile X Syndrome

“…FXS presents genetically through the emergence of CGG repeats in the 5′ untranslated region of the fragile X messenger ribonucleoprotein 1 ( FMR1 ) gene located on chromosome Xq27.3 [ 3 ]. The CGG repeat size is variable between people, and usually healthy people have less than 45 repeats [ 4 ]. Affected individuals possess 200 CGG repeats or greater [ 5 ].…”

Fragile X Premutation: Medications, Therapy and Lifestyle Advice

“… 6 Additional medical conditions associated with the premutation include connective tissue problems, endocrine dysfunction particularly thyroid problems, immune mediated disorders such as fibromyalgia, multiple sclerosis, autoimmune thyroid disease, and other health problems including hypertension, migraine, restless legs syndrome, insomnia and sleep apnea. 3 , 7 …”