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

Hans Demmelmair, Anita MacDonald, Urania Kotzaeridou, Peter Burgard, Domingo Gonzalez-Lamuno, Elvira Verduci, Melike Ersoy, Gulden Gokcay, Behiye Alyanak, Eva Reischl, Wolfgang Müller-Felber, Fabienne Lara Faber, Uschi Handel, Sabrina Paci, Berthold Koletzko, Hans Demmelmair, Anita MacDonald, Urania Kotzaeridou, Peter Burgard, Domingo Gonzalez-Lamuno, Elvira Verduci, Melike Ersoy, Gulden Gokcay, Behiye Alyanak, Eva Reischl, Wolfgang Müller-Felber, Fabienne Lara Faber, Uschi Handel, Sabrina Paci, Berthold Koletzko

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.

Keywords: cognitive function; docosahexaenoic acid; motor skills; neurological function; phenylketonuria.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
Participant flow chart according to CONSORT.
Figure 2
Figure 2
Association of the latency of visually evoked potentials with pattern size 15′ (VEP15 latency), the Ravens score (RPM), and the Lincoln-Oseretzky score (LOS) with the percentage of DHA in plasma glycerophospholipids before (pre) and after (post) intervention.
Figure 3
Figure 3
Association of the latency of visually evoked potentials with pattern size 15′ (VEP15 latency), the Ravens score (RPM), and the Lincoln-Oseretzky score (LOS) with the plasma phenylalanine (Phe) concentrations (µmol/L) before (pre) and after (post) intervention.
Figure 4
Figure 4
Linear relationship between DHA intake (mg/kg&day) and post intervention phosphoglycerid bound DHA concentration (□) and percentage contribution of DHA to total analysed glycerophospholipid fatty acids (■).
Figure 5
Figure 5
(a) Pre study arachidonic acid (%-ARA) percentages versus linoleic acid (%-LA) percentages in glycerophospholipids according to the individual alleles of rs174548; (b) Pre study docosahexaenoic acid (%-DHA) percentages versus α-linolenic acid (%-ALA) percentages in glycerophospholipids according to the individual alleles of rs174548.

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