New insights of altered lipid profile in Fragile X Syndrome

Abstract

BackgroundFragile X Syndrome (FXS) is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP). Clinical picture is characterized by cognitive impairment associated with a broad spectrum of psychiatric comorbidities including autism spectrum disorders and attention-deficit/hyperactivity disorders. Some of these disorders have been associated with lipid abnormalities and lower cholesterol levels. Since lipids are important for neuronal development, we aim to investigate the lipid profile of French Canadian-FXS individuals and to identify the altered components of cholesterol metabolism as well as their association with clinical profile.MethodsAnthropometric data were collected from 25 FXS individuals and 26 controls. Lipid assessment included: total cholesterol (TC), triglycerides, LDL, HDL, ApoB, ApoA1, PCSK9, Lp(a) and lipoprotein electrophoresis. Aberrant and adaptive behaviour of affected individuals was respectively assessed by the ABC-C and ABAS questionnaires.ResultsFXS participants had a higher body mass index as compared to controls while 38% of them had TC<10th percentile. Lower levels of LDL, HDL and apoA1 were observed in FXS group as compared to controls. However, PCSK9 levels did not differ between the two groups. As expected, PCSK9 levels correlated with total cholesterol (rs = 0.61, p = 0.001) and LDL (rs = 0.46, p = 0.014) in the control group, while no association was present in the FXS group. An inverse relationship was observed between total cholesterol and aberrant behaviour as determined by ABC-C total score.ConclusionOur results showed the presence of hypocholesterolemia in French Canadian-FXS population, a condition that seems to influence their clinical phenotype. We identified for the first time a potential underlying alteration of PCSK9 function in FXS that could result from the absence of FMRP. Further investigations are warranted to better understand the association between cholesterol metabolism, PCSK9, FMRP and clinical profile.

Implication of hypocholesterolemia in autism spectrum disorder and its associated comorbidities: A retrospective case–control study

“…We found no SLOS patients among our 79 ASD individuals, suggesting an association of ASD with other disorders of the cholesterol homeostasis. Furthermore, high incidence of hypocholesterolemia (23%) has also been reported in FXS [Berry-Kravis et al, 2015;Caku et al, 2017]. Regardless the presence of several risk factors such as ethnicity, nonobserved diet, or psychoactive treatment, the authors suggest that FXS males have lower TC, lower LDL, and higher incidence of hypocholesterolemia (23%), the same as reported from the present study when compared to the normative population [Caku et al, 2017].…”

“…Furthermore, high incidence of hypocholesterolemia (23%) has also been reported in FXS [Berry-Kravis et al, 2015;Caku et al, 2017]. Regardless the presence of several risk factors such as ethnicity, nonobserved diet, or psychoactive treatment, the authors suggest that FXS males have lower TC, lower LDL, and higher incidence of hypocholesterolemia (23%), the same as reported from the present study when compared to the normative population [Caku et al, 2017]. An alternation of the PCSK9 function was suggested as a plausible underlying mechanism of hypocholesterolemia in FXS.…”

“…Since many psychoactive drugs could alter lipid metabolism, we further reviewed clinical data of this subgroup. Most treated participants were taking antipsychotics associated with higher cholesterol levels (risperidone, olanzapine, or quetiapine) [Rummel-Kluge et al, 2010] and only three participants were taking antipsychotics associated with lower cholesterol (aripiprazole, haloperidol, or trazodone) [Canfran-Duque et al, 2013;Korade et al, 2017]. Indeed, the prevalence of hypocholesterolemia in the ASD group was still high regardless the presence of latter drugs.…”

“…Lipid profile abnormalities have been recently reported in FXS with 26%-35% of individuals having total cholesterol (TC) <10th centile [Berry-Kravis et al, 2015] while more than 20% individuals fulfilling the criteria of hypocholesterolemia [Caku et al, 2017]. The latter, defined as a plasma TC level below the fifth percentile of the normal population adjusted for age, sex, and ethnic origin [Berry-Kravis et al, 2015;Elmehdawi, 2008].…”

Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome

“…To study possible peripheral consequences of FMR1deficiency, some authors have compared the levels of serum and plasma biomarkers between FXS patients and healthy controls. Prior studies have focused on metabolic markers and have highlighted reduced levels of cholesterol [11][12][13] and abnormal abundances of the metabolic hormones leptin and adiponectin [14]. In a translational study addressing metabolic consequences of FMR1-deficiency both in a FXS mouse model and in FXS patients, we have recently shown that FXS patients display reductions in circulating glucose and increases in both free fatty acids and insulin, underlining metabolic anomalies in FXS [15].…”