Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study

Abstract

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.

Effect of Omega-3 Long Chain Polyunsaturated Fatty Acids (n-3 LCPUFA) Supplementation on Cognition in Children and Adolescents: A Systematic Literature Review with a Focus on n-3 LCPUFA Blood Values and Dose of DHA and EPA

“…Of the 33 studies included in this review, 13 studies had no reported blood fatty acid concentrations [ 29 , 31 , 33 , 35 , 36 , 38 , 43 , 44 , 45 , 49 , 52 , 53 , 55 ]. In 20 studies, fatty acid concentrations were reported, and the fatty acid concentrations were analyzed in a variety of bodily tissues and blood fractions (note that in some studies multiple fractions were utilized): plasma fatty acids [ 27 , 32 , 33 , 56 ], phospholipids in erythrocyte membranes [ 28 , 41 ], plasma phosphatidylcholine [ 30 ], erythrocyte phosphatidylcholine [ 30 ], erythrocyte phosphatidylethanolamine [ 30 ], cheek cells [ 37 , 48 ], capillary whole blood [ 40 , 46 , 47 , 50 ], serum phospholipids [ 42 , 57 , 58 ], total fatty acids in erythrocyte membrane [ 39 , 56 , 59 ], glycerol-phospholipids in plasma [ 51 ] and erythrocytes [ 54 ]. Unfortunately, recalculation formulae to the O3I equivalence are only available for a limited number of blood fractions [ 60 ].…”

“…Unfortunately, recalculation formulae to the O3I equivalence are only available for a limited number of blood fractions [ 60 ]. The recalculation to the O3I equivalence was thus not possible for seven studies because they used a blood fraction for which no recalculation formula is available: erythrocyte and plasma phosphatidylcholine [ 30 ], erythrocyte phosphatidylethanolamine [ 30 ], cheek cells [ 37 ], serum phospholipids [ 42 ], cheek cells [ 48 ], glycerol-phospholipids in plasma [ 51 ] or serum phospholipids [ 57 , 58 ]. Moreover, in three studies only DHA levels were reported and recalculation to the O3I equivalence was thus not possible [ 39 , 40 , 54 ].…”

“…There were two studies with an O3I equivalence >6% after supplementation in the active group, however, there were no significant effects of supplementation on cognitive measures [ 28 , 32 ]. The notion that an increase in O3I equivalence is related to improved cognition, is supported by the fact that six [ 30 , 37 , 39 , 46 , 57 , 59 ] out of the 10 studies [ 30 , 37 , 39 , 46 , 47 , 51 , 56 , 57 , 58 , 59 ] that related blood values to cognitive outcomes showed significant positive associations or correlations between (change in) DHA and/or EPA blood values and cognitive tests used.…”

Effects of LC-PUFA Supplementation in Patients with Phenylketonuria: A Systematic Review of Controlled Trials

“…Twenty-four articles were excluded after revision of the abstract. Of the 33 articles considered for evaluation of the complete text, nine articles were ultimately included in the systematic review [27,28,29,30,31,32,33,34,35].…”

“…The combined study population of the nine clinical trials included in this review was 419 individuals, 365 (87.1%) of whom had phenylketonuria. Only two studies included a healthy control group [29,33] and the remaining seven, a PKU control group [27,28,30,31,32,34,35]. Ages ranged from 2.1 weeks to 47 years.…”