Date Published: March 23, 2017
Publisher: Public Library of Science
Author(s): Artuela Çaku, Nabil G. Seidah, Audrey Lortie, Nancy Gagné, Patrice Perron, Jean Dubé, Francois Corbin, Barbara Bardoni.
Fragile 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.
Anthropometric 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.
FXS 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. Our 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.
Fragile X Syndrome (FXS) is a genetic condition caused by an expansion mutation of a CGG repeat sequence in the FMR1 gene resulting in the methylation of the promoter; the silencing of the gene leads to a failure to express the fragile X mental retardation protein (FMRP) [1, 2]. FMRP is an ubiquitous protein, mostly expressed in neurons where it regulates the postsynaptic protein synthesis required for synaptic plasticity . The lack of this protein leads to an alteration of cognitive functions and hence to a typical phenotype characterized by varying degrees of intellectual disability (ID). The FXS individuals also present anatomical abnormalities associated with a vast variety of medical conditions including neurologic, cardiac, gastrointestinal, ophthalmologic and/ or ear-nose-throat problems .
In this cohort of French Canadian individuals with SXF, total cholesterol originating from both alpha and beta lipoproteins was lower as compared to the reference French Canadian population adjusted for age and sex. Results suggest that males across all ages are affected. However results in female are not conclusive considering the small sample size.