Plasma cholesterol in adults with phenylketonuria

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine (Phe) catabolism resulting from a deficiency of L-phenylalanine hydroxylase (PAH). An association between hyperphenylalaninaemia (HPA) and hypocholesterolaemia has been reported in children. However, controversy exists as to whether this is due to the low protein diet or to a disruption to cholesterol biosynthesis inherent to those with PKU. We investigated the relationship between blood Phe and plasma cholesterol in 41 apparently healthy adults with PKU (26 female, 15 male, age 18-57 years, median age 26 years) attending a PKU outpatient clinic at an adult tertiary care hospital. Of these patients, 33 (80%) were compliant with a Phe-restricted diet with amino acid supplementation, whereas eight (20%) were not. The PKU subjects had a mean body mass index (BMI) of 30.3 ± 1.8 kg/m2; 72% were obese, 14% overweight, with only 14% having normal BMI. The mean blood Phe was 1194±522μmol/L with plasma total cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol and apolipoprotein (apo) B concentrations of 4.3 ± 0.8 mmol/L, 1.6 ± 0.8 mmol/L, 1.2 ± 0.3 mmol/L, 2.3±0.8mmol/L, and 0.83 ±0.21 g/L, respectively. The mean LDL-cholesterol was 19% lower in PKU females than that of 8944 age-matched females from a community population (2.5±0.8mmol/L vs 3.1 ±0.9mmol/L, p<0.001). Similarly, the mean LDL-cholesterol was 32% lower in PKU males than 3786 age-matched males (2.1 ± 0.7 mmol/L vs 3.1 ± 1.0 mmol/L, p< 0.0001). No correlations were observed between Phe and total cholesterol, LDL-cholesterol or apoB in the PKU cohort. Adults with PKU had low-normal cholesterol concentrations, with no correlation observed between Phe and cholesterol levels. Our findings support the concept that the HPA found in PKU, rather than an effect of a low-protein diet, leads to hypocholesterolaemia. Studies are required to determine whether this cholesterol-lowering effect confers cardioprotection.