Abstract
Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria
(PKU); however, the functional implications in adolescents and adults are unknown.
This pilot study investigated the effect of supplemental DHA on cognitive performance
in 33 females with PKU ages 12–47 years. Participants were randomly assigned to receive
DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and
executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat
and per protocol analyses were performed. At follow up, biomarkers of DHA status were
significantly higher in the DHA-supplemented group. Performance on the cognitive tasks
and reported treatment-related adverse events did not differ. While no evidence of
cognitive effect was seen, a larger sample size is needed to be conclusive, which
may not be feasible in this population. Supplementation was a safe and effective way
to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Prostaglandins, Leukotrienes and Essential Fatty AcidsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Influence of phenylalanine intake on phenylketonuria.Lancet. 1953; 265: 812-813
- The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria).Pediatrics. 1957; 20: 290-302
- Trace element status of children with PKU and normal children.J. Am. Diet. Assoc. 1988; 88: 459-465
- Nutrient intake and food consumption of adolescents and young adults with phenylketonuria.Acta Paediatr. 1995; 84: 743-748
- Diet and compliance in phenylketonuria.Eur. J. Pediatr. 2000; 159: S136-S141
- National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16–18, 2000.Pediatrics. 2001; 108: 972-982
- A neuropsychological profile of off-diet adults with phenylketonuria.J. Clin. Exp. Neuropsychol. 2007; 29: 436-441
- Effects of dietary management of phenylketonuria on long-term cognitive outcome.Arch. Dis. Child. 2007; 92: 213-218
- Phenylketonuria: diet for life or not?.Acta Paediatr. 1999; 88: 664-666
- Phenylketonuric patients decades after diet.J. Inherit. Metab. Dis. 1995; 18: 347-353
- Agoraphobia in phenylketonuria.J. Inherit. Metab. Dis. 1991; 14: 755-764
- Personality disorder in young women with treated phenylketonuria.J. Inherit. Metab. Dis. 1994; 17: 584-592
- Executive functioning and speed of processing in phenylketonuria.Neuropsychology. 2005; 19: 679-686
- Review of neuropsychological functioning in treated phenylketonuria: an information processing approach.Acta Paediatr. Suppl. 1994; 407: 98-103
- Frontal lobe-dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults.J. Inherit. Metab. Dis. 2005; 28: 445-455
- Neuropsychological outcome of subjects participating in the PKU adult collaborative study: a preliminary review.J. Inherit. Metab. Dis. 2004; 27: 549-566
- Twenty-five years of research on neurocognitive outcomes in early-treated phenylketonuria: intelligence and executive function.Dev. Neuropsychol. 2008; 33: 474-504
- Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU.Neuropsychol. Rev. 2007; 17: 91-101
- Reduced plasma C-20 and C-22 polyunsaturated fatty acids in children with phenylketonuria during dietary intervention.J. Pediatr. 1991; 119: 562-567
- Lipid status and long-chain polyunsaturated fatty acid concentrations in adults and adolescents with phenylketonuria on phenylalanine-restricted diet.J. Inherit. Metab. Dis. 2002; 25: 56-64
- The essential fatty acid status in phenylketonuria patients under treatment.J. Nutr. Biochem. 2000; 11: 543-547
- Fatty acids in the stability of neuronal membrane: relevance to PKU.Int. Pediatr. 1996; 11: 56-60
- Impaired arachidonic (20:4n-6) and docosahexaenoic (22:6n-3) acid synthesis by phenylalanine metabolites as etiological factors in the neuropathology of phenylketonuria.Mol. Genet. Metab. 2001; 72: 185-198
- Does dietary DHA improve neural function in children? Observations in phenylketonuria.Prostaglandins Leukot. Essent. Fatty Acids. 2009; 81: 159-164
- The relationship between age and the fatty acid composition of cerebral cortex and erythrocytes in human subjects.Brain Res. Bull. 2001; 56: 79-85
- Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain.J. Mol. Neurosci. 2001; 16 (discussion 215–21): 159-165
- Docosahexaenoic acid domains: the ultimate non-raft membrane domain.Chem. Phys. Lipids. 2008; 153: 57-63
- 2H nuclear magnetic resonance order parameter profiles suggest a change of molecular shape for phosphatidylcholines containing a polyunsaturated acyl chain.Biophys. J. 1995; 68: 2396-2403
- Role of docosahexaenoic acid in determining membrane structure and function.in: Mostofsky D. Yehuda S. Salem Jr., N. Fatty Acids: Physiological and Behavioral Functions. Human Press Inc., Totowa1999: 41-62
- Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection.Prostaglandins Leukot. Essent. Fatty Acids. 2009; 81: 205-211
- Mechanisms of action of docosahexaenoic acid in the nervous system.Lipids. 2001; 36: 945-959
- Effect of fish oils containing different amounts of EPA, DHA, and antioxidants on plasma and brain fatty acids and brain nitric oxide synthase activity in rats.Ups. J. Med. Sci. 2009; 114: 206-213
- The influence of orally administered docosahexaenoic acid on monoamine neurotransmitter, nerve growth factor, and brain-derived neurotrophic factor in aged mice..Pharmaceut. Biol. (Formerly International Journal of Pharmacognosy). 2009; : 584-59147. 2009; : 584-591
- Docosahexaenoic acid: a positive modulator of Akt signaling in neuronal survival.Proc. Natl. Acad. Sci. USA. 2005; 102: 10858-10863
- Omega-3 fatty acids upregulate adult neurogenesis.Neurosci. Lett. 2007; 415: 154-158
- PUFA induce antidepressant-like effects in parallel to structural and molecular changes in the hippocampus.Psychoneuroendocrinology. 2009; 34: 199-211
- A possible essential role for dietary linolenic acid in the development of the young rat.J. Nutr. 1976; 106: 86-93
- Effect of dietary alpha-linolenate/linoleate balance on brain lipid compositions and learning ability of rats.J. Lipid. Res. 1987; 28: 144-151
- Effect of the dietary alpha-linolenate/linoleate balance on lipid compositions and learning ability of rats. II. Discrimination process, extinction process, and glycolipid compositions.J. Lipid Res. 1988; 29: 1013-1021
- Effect of the long-term feeding of dietary lipids on the learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in adult mice: a comparison of sardine oil diet with palm oil diet.Mech. Ageing Dev. 1998; 101: 119-128
- Visual attention in infant monkeys: effects of dietary fatty acids and age.Dev. Psychol. 1997; 33: 387-395
- Fish oil supplementation of control and (n-3) fatty acid-deficient male rats enhances reference and working memory performance and increases brain regional docosahexaenoic acid levels.J. Nutr. 2008; 138: 1165-1171
- A systemic review of the roles of n-3 fatty acids in health and disease.J. Am. Diet. Assoc. 2009; 109: 668-679
- Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia.J. Pediatr. 2000; 137: 504-509
- The effects of n-3 and n-6 polyunsaturated fatty acids on plasma lipids and fatty acids of treated phenylketonuric children.Prostaglandins Leukot. Essent. Fatty Acids. 1995; 53: 401-404
- Effect of fish oil supplementation on fatty acid status, coordination, and fine motor skills in children with phenylketonuria.J. Pediatr. 2007; 150: 479-484
- Fish oil supplementation improves visual evoked potentials in children with phenylketonuria.Neurology. 2001; 57: 1488-1491
- A randomized trial of long-chain polyunsaturated fatty acid supplementation in infants with phenylketonuria.Dev. Med. Child. Neurol. 2006; 48: 207-212
- Bioequivalence of docosahexaenoic acid from different algal oils in capsules and in a DHA-fortified food.Lipids. 2007; 42: 1011-1024
- Amino acid analysis of physiological samples.in: Hommos F. Techniques in Diagnostic Human Biochemical Genetics. Wiley Liss, New York1991
- Blood phenylalanine monitoring for dietary compliance among patients with phenylketonuria: comparison of methods.Genet. Med. 2007; 9: 761-765
National Institute of Standards and Technology (NIST), NIST Chemistry WebBook, 2008.
- Quantitative determination of plasma c8-c26 total fatty acids for the biochemical diagnosis of nutritional and metabolic disorders.Mol. Genet. Metab. 2001; 73: 38-45
- Examiner’s Manual for the Peabody Picture Vocabulary Test—Third Edition (PPVT-III).American Guidance Service, Circle Pines, MN1997
- Delis–Kaplan Executive Function System: Technical Manual.The Psychological Corporation, San Antonio, TX2001
- Woodcock-Johnson III Technical Manual.The Riverside Publishing Company, Itasca, IL2001
- Technical Abstract (Assessment Service Bulletin No. 2).Riverside Publishing, Itasca2001
Yi, S.H. The impact of docosahexaenoic acid status and phenylalanine control on cognitive performance in females of reproductive age with phenylketonuria. 2010. Ph.D. dissertation, 353 pages doi: 〈http://pid.emory.edu/ark:/25593/7r08v〉.
- Studies of interference in serial verbal reactions.J. Exp. Psychol. 1935; 18: 643-662
- Executive functioning in children and adolescents with phenylketonuria.Clin. Genet. 2007; 72: 13-18
- Long term effects of long chain polyunsaturated fats in hyperphenylalaninemic children.Arch. Dis. Child. 2003; 88: 582-583
Lenth, R.V. Java Applets for Power and Sample Size [Computer software]. 2006 March 20, 2007]; available from: 〈http://www.stat.uiowa.edu/~rlenth/Power〉.
- The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials.Lancet. 2001; 357: 1191-1194
- The revised CONSORT statement for reporting randomized trials: explanation and elaboration.Ann. Intern. Med. 2001; 134: 663-694
- Assessing the effect of docosahexaenoic acid on cognitive functions in healthy, preschool children: a randomized, placebo-controlled, double-blind study.Clin. Pediatr. (Phila). 2008; 47: 355-362
- Effect of maternal docosahexaenoic acid supplementation on postpartum depression and information processing.Am. J. Obstet. Gynecol. 2003; 188: 1348-1353
- Effect of fish oil on cognitive performance in older subjects: a randomized, controlled trial.Neurology. 2008; 71: 430-438
- Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women.Nutr. Neurosci. 2008; 11: 75-83
- Alpha-linolenic acid supplementation during human pregnancy does not effect cognitive functioning.Prostaglandins Leukot. Essent. Fatty Acids. 2004; 70: 41-47
- Exploratory study into the relation between plasma phospholipid fatty acid status and cognitive performance.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 76: 165-172
- Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study.Am. J. Clin. Nutr. 2010; 91: 1060-1067
- A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria.J. Inherit. Metab. Dis. 2011; 34: 455-463
- Physiological compartmental analysis of alpha-linolenic acid metabolism in adult humans.J. Lipid Res. 2001; 42: 1257-1265
- Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk.Am. J. Clin. Nutr. 2003; 77: 226-233
- Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans.J. Nutr. 2006; 136: 83-87
- Effect of alpha-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome.Am. J. Clin. Nutr. 2004; 79: 251-260
- Formula 18:2(n-6) and 18:3(n-3) content and ratio influence long-chain polyunsaturated fatty acids in the developing piglet liver and central nervous system.J. Nutr. 1994; 124: 289-298
- Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men.J. Nutr. 2007; 137: 945-952
- Optimizing DHA levels in piglets by lowering the linoleic acid to alpha-linolenic acid ratio.J. Lipid Res. 2002; 43: 1537-1543
- Randomised controlled trial of essential fatty acid supplementation in phenylketonuria.Eur. J. Clin. Nutr. 2006; 60: 915-920
- The Omega-3 Index: a new risk factor for death from coronary heart disease?.Prev. Med. 2004; 39: 212-220
- Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: current status, future directions, and dietary recommendations.Prostaglandins Leukot. Essent. Fatty Acids. 2009; 81: 223-231
- Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee.Circulation. 2006; 114: 82-96
- Recommendations for intake of polyunsaturated fatty acids in healthy adults, in Report on Dietary Intake of Essential Fatty Acids.International Society for the Study of Fatty Acids and Lipids. 2004; : 1-22
- The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations.J. Perinat. Med. 2008; 36: 5-14
- Workshop on the essentiality of and recommended dietary intakes for omega-6 and omega-3 fatty acids.J. Am. Coll. Nutr. 1999; 18: 487-489
Article info
Publication history
Published online: October 17, 2011
Accepted:
September 11,
2011
Received in revised form:
September 7,
2011
Received:
April 24,
2011
Footnotes
☆Ethics approval: Approval was obtained to conduct this study from the Emory University Institutional Review Board. Informed consent was obtained from all participants and a parent and/or guardian if the participant was under age 18 years.
☆☆Source(s) of support: This research was supported in part by grants from United to Support Metabolic Disorders (USMD-PKU) in America; and PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program and PHS Grant M01 RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources. Study supplements were provided by Martek Biosciences Corporation. This material is also the result of work supported with resources at the Atlanta VA Medical Center.
Identification
Copyright
© 2011 Published by Elsevier Inc.
