PHENYLKETONURIA DIET:EFFECT ON CARDIOVASCULAR RISK FACTORS AND FECAL SHORT CHAIN FATTY ACIDS

Phenylketonuria (PKU) is a genetic disorder, caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). PAH catalyzes the hydroxylation of phenylalanine (Phe) to tyrosine. Loss of PAH activity results in increased concentrations of phenylalanine in the blood and fluids throughout the body and toxic concentrations in the brain (Blau 2016). Despite continuing progress in the treatment, the restriction of dietary Phe remains the mainstay of PKU management (Giovannini et al. 2012). Various combinations of PAH mutations result in a full spectrum of metabolic phenotypes ranging from mild hyperphenylalaninemia (MHP), in which dietary restriction is not necessary to mild, moderate and classical phenylketonuria, which require dietary management (Regier, Greene 2000). PKU diet is mainly made up of low-protein natural foods (vegetables, fruits), special low protein products (low-protein variants of some foods such as bread, pasta and biscuits) and Phe-free protein substitutes, which provide amino acids in suitable proportions (Giovannini et al. 2012). Because PKU children have to start a Phe restricted diet as soon as possible and to follow this throughout life, the long-term safety of this dietary treatment and its potential impact on later non-communicable diseases risk need to be better evaluated. The general aim of this PhD thesis was to investigate the impact of phenylketonuric diet, principally carbohydrates quality, on cardiovascular risk factors and fecal short chain fatty acids (SCFA) production in children with phenylketonuria. The key findings were: 1) in PKU children the dietary treatment could be associated with higher overall glycemic index and load, fiber and carbohydrate intakes and lower protein intakes than healthy children. Moreover, in PKU children a relationship between the quality of carbohydrates consumed and the triglyceride glucose index, that seems to reflect mainly peripheral insulin resistance, may exist. 2) Regarding cardiovascular risk factors, PKU children showed a thinner intima media thickness, lower total cholesterol, LDL cholesterol and homocysteine levels than healthy children. Conversely, PKU children had higher triglyceride levels, atherogenic index of plasma and higher triglycerides/HDL ratio than healthy children. In PKU group, no associations of intima media thickness with overall glycemic index and glycemic load were observed. 3) Comparing gut microbiota biodiversity and its production of SCFA in PKU children and MHP children, PKU children showed a lower degree of microbial diversity in gut microbiota and minor total fecal SCFA and butyrate production than MHP children. In conclusion, a greater attention should be paid to the management of dietary carbohydrate quality in PKU diet, with focus on special low protein products. Longitudinal, adequately powered studies are needed to clarify the interrelationships between the diet and cardiovascular risk factors/metabolic profile of PKU children. Moreover, further studies using innovative sequencing techniques are needed to better investigate gut microbiota dysbiosis in PKU children and to eventually pave the way for pre/probiotic supplementations in this population.