Vitamin/mineral and micronutrient status in patients with classical phenylketonuria

  • Engin Kose
    Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey
    Search for articles by this author
  • Nur Arslan
    Corresponding author. Dokuz Eylul University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Izmir Biomedicine and Genome Center (iBG-izmir), Izmir, Turkey. Fax: +90 2324126005.
    Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey
    Search for articles by this author
Published:February 02, 2018DOI:


      Background & aims

      Strict low-phenylalanine diet is associated with an increased risk of developing micronutrient deficiencies in patients with phenylketonuria (PKU). The primary objective of this single-center, case–control study was to assess the nutritional parameters of patients with PKU on strict low-phenylalanine diet without vitamin and mineral supplementation compared to a healthy control group. Secondary objective was to identify the adequacy of vitamin/mineral supplementation in phenylalanine-free (Phe-free) amino acid formulas.


      A total of 112 age- and sex-matched patients with PKU and 36 controls who did not take vitamin or mineral supplementation at least for the last 6 months were enrolled in the study. Biochemical and hematological markers including hemoglobin, serum vitamin B12, folic acid, iron, ferritin, transferrin saturation, copper, prealbumin, albumin, total protein, phosphorus, calcium, 25-hydroxy vitamin D, zinc, vitamin A and vitamin E levels were screened from fasting morning blood samples.


      One hundred and twelve patients with classical PKU (53 females, 47.3%) and 36 healthy controls (18 females, 50.0%) were enrolled in the study. The mean age of patients with PKU was 136.8 ± 82.1 months (18–377). Median serum vitamin B12 level of patients with PKU was found to be higher than the control group (p = 0.002). Vitamin B12 deficiency was 15.2% and 30.6% in patients with PKU and healthy controls, respectively (p = 0.040). Mean serum folic acid level was higher in patients with PKU than the control group (p < 0.0001). In 55.4% of patients with PKU, and 2.8% of the control group, serum folic acid level was above the reference range (p < 0.0001). The frequency of ferritin and prealbumin values above the reference range was found to be higher in patients with PKU compared to the control group (44.4% vs 16.9%, p = 0.001; 38.8% vs 22.1%, p = 0.020, respectively). 25-Hydroxy vitamin D deficiency was detected in 53.6% and 47.2% of patients with PKU and the control group, respectively. Mean serum copper level was higher in the well-controlled (114.3 ± 26.7 μg/dL) group than the poorly controlled group (101.0 ± 29.1 μg/dL) (p = 0.022).


      Phe-free amino acid formulas provide adequate vitamin A and zinc levels in patients with PKU, and result in excess folic acid, vitamin B12, copper and vitamin E values that are higher than required levels. Our results demonstrate a high percentage of vitamin D deficiency in patients with classical PKU and also in healthy controls in Turkey.


      To read this article in full you will need to make a payment
      Subscribe to Clinical Nutrition
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Crujeiras V.
        • Aldámiz-Echevarría L.
        • Dalmau J.
        • Vitoria I.
        • Andrade F.
        • Roca I.
        • et al.
        Vitamin and mineral status in patients with hyperphenylalaninemia.
        Mol Genet Metab. 2015; 115: 145-150
      1. Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly SW, Valle D, editors; Childs B, Kinzler KW, Vogelstein B, assoc editors. The metabolic and molecular bases of inherited disease. 8th ed. New York, NY: McGraw-Hill; 2001. p. 1667–1724.

        • Williams R.A.
        • Mamotte C.D.
        • Burnett J.R.
        Phenylketonuria: an inborn error of phenylalanine metabolism.
        Clin Biochem Rev. 2008; 29: 31-41
        • Shayeghi M.
        • Latunde-Dada G.O.
        • Oakhill J.S.
        • Laftah A.H.
        • Takeuchi K.
        • Halliday N.
        • et al.
        Identification of an intestinal heme transporter.
        Cell. 2005; 122: 789-801
        • Fairweather-Tait S.
        • Hurrell R.F.
        Bioavailability of minerals and trace elements.
        Nutr Res Rev. 1996; 9: 295-324
        • Lammardo A.M.
        • Robert M.
        • Rocha J.C.
        • van Rijn M.
        • Ahring K.
        • Bélanger-Quintana A.
        • et al.
        Main issues in micronutrient supplementation in phenylketonuria.
        Mol Genet Metab. 2013; 110: S1-S5
        • Vockley J.
        • Andersson H.C.
        • Antshel K.M.
        • Braverman N.E.
        • Burton B.K.
        • Frazier D.M.
        • et al.
        • American College of Medical Genetics and Genomics Therapeutics Committee
        Phenylalanine hydroxylase deficiency: diagnosis and management guideline.
        Genet Med. 2014; 16: 188-200
        • de Romana D.L.
        • Olivares M.
        • Uauy R.
        • Araya M.
        Risks and benefits of copper in light of new insights of copper homeostasis.
        J Trace Elem Med Biol. 2011; 25: 3-13
        • Lin C.N.
        • Wilson A.
        • Church B.B.
        • Ehman S.
        • Roberts W.L.
        • McMillin G.A.
        Pediatric reference intervals for serum copper and zinc.
        Clin Chim Acta. 2012; 413: 612-615
        • Raizman J.E.
        • Cohen A.H.
        • Teodoro-Morrison T.
        • Wan B.
        • Khun-Chen M.
        • Wilkenson C.
        • et al.
        Pediatric reference value distributions for vitamins A and E in the CALIPER cohort and establishment of age-stratified reference intervals.
        Clin Biochem. 2014; 47: 812-815
        • Roberts W.L.
        • McMillin G.A.
        • Burtis C.A.
        • Bruns D.E.
        Reference information for the clinical laboratory.
        in: Burtis C.A. Ashwood E.R. Burns D.E. Tietz textbook of clinical chemistry and molecular diagnostics. 4th ed. Elsevier Saunders, St. Louis, Mo2006: 2251-2318
        • Evans S.
        • Daly A.
        • MacDonald J.
        • Preece M.A.
        • Santra S.
        • Vijay S.
        • et al.
        The micronutrient status of patients with phenylketonuria on dietary treatment: an ongoing challenge.
        Ann Nutr Metab. 2014; 65: 42-48
        • Fisberg R.M.
        • Da Silva-Femandes M.E.
        • Fisberg M.
        • Schmidt B.J.
        Plasma zinc, copper, and erythrocyte superoxide dismutase in children with phenylketonuria.
        Nutrition. 1999; 15: 449-452
        • MacDonald A.
        • Lee P.
        • Davies P.
        • Daly A.
        • Lilburn M.
        • Gokmen Ozel H.
        • et al.
        Long-term compliance with a novel vitamin and mineral supplement in older people with PKU.
        J Inherit Metab Dis. 2008; 31: 718-723
        • Arnold G.L.
        • Kirby R.
        • Preston C.
        • Blakely E.
        Iron and protein sufficiency and red cell indices in phenylketonuria.
        J Am Coll Nutr. 2001; 20: 65-70
        • Verkerk P.H.
        • van Spronsen F.J.
        • Smit G.P.
        • Sengers R.C.
        Impaired prenatal and postnatal growth in Dutch patients with phenylketonuria. The National PKU Steering Committee.
        Arch Dis Child. 1994; 71: 114-118
        • van Spronsen F.J.
        • Verkerk P.H.
        • van Houten M.
        • Smit G.P.
        • van der Meer S.B.
        • Bakker H.D.
        • et al.
        Does impaired growth of PKU patients correlate with the strictness of dietary treatment? National Dutch PKU Steering Committee.
        Acta Paediatr. 1997; 86: 816-818
        • Walter J.H.
        Vitamin B12 deficiency and phenylketonuria.
        Mol Genet Metab. 2011; 104: S52-S54
        • Robinson M.
        • White F.J.
        • Cleary M.A.
        • Wraith E.
        • Lam W.K.
        • Walter J.H.
        Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet.
        J Pediatr. 2000; 136: 545-547
        • MacDonald A.
        • Rocha J.C.
        • van Rijn M.
        • Feillet F.
        Nutrition in phenylketonuria.
        Mol Genet Metab. 2011; 104: S10-S18
        • Dizdar O.S.
        • Baspınar O.
        • Kocer D.
        • Dursun Z.B.
        • Avcı D.
        • Karakükcü C.
        • et al.
        Nutritional risk, micronutrient status and clinical outcomes: a prospective observational study in an infectious disease clinic.
        Nutrients. 2016; 8: 124
        • Baltaci D.
        • Deler M.H.
        • Turker Y.
        • Ermis F.
        • Iliev D.
        • Velioglu U.
        Evaluation of serum Vitamin B12 level and related nutritional status among apparently healthy obese female individuals.
        Niger J Clin Pract. 2017; 20: 99-105
        • Halicioglu O.
        • Sutcuoglu S.
        • Koc F.
        • Ozturk C.
        • Albudak E.
        • Colak A.
        • et al.
        Vitamin B12 and folate statuses are associated with diet in pregnant women, but not with anthropometric measurements in term newborns.
        J Matern Fetal Neonatal Med. 2012; 25: 1618-1621
        • Gunduz M.
        • Cakar S.
        • Kuyum P.
        • Makay B.
        • Arslan N.
        Comparison of atherogenic risk factors among poorly-controlled and well-controlled adolescent phenylketonuria patients.
        Cardiol Young. 2016; 26: 901-908
        • Winkler M.F.
        • Gerrior S.A.
        • Pomp A.
        • Albina J.E.
        Use of retinol-binding protein and prealbumin as indicators of the response to nutrition therapy.
        J Am Diet Assoc. 1989; 89: 684-687
        • Acosta P.B.
        Nutrition studies in treated infants and children with phenylketonuria: vitamins, minerals, trace elements.
        Eur J Pediatr. 1996; 155: S136-S139
        • Arnold G.L.
        • Vladutiu C.J.
        • Kirby R.S.
        • Blakely E.M.
        • Deluca J.M.
        Protein insufficiency and linear growth restriction in phenylketonuria.
        J Pediatr. 2002; 141: 243-246
        • Rocha J.C.
        • Almeida M.F.
        • Carmona C.
        • Cardoso M.L.
        • Borges N.
        • Soares I.
        • et al.
        The use of prealbumin concentration as a biomarker of nutritional status in treated phenylketonuric patients.
        Ann Nutr Metab. 2010; 56: 207-211
        • Dobbelaere D.
        • Michaud L.
        • Debrabander A.
        • Vanderbecken S.
        • Gottrand F.
        • Turck D.
        • et al.
        Evaluation of nutritional status and pathophysiology of growth retardation in patients with phenylketonuria.
        J Inherit Metab Dis. 2003; 26: 1-11
        • Schulpis K.H.
        • Karakonstantakis T.
        • Bartzeliotou A.
        • Karikas G.A.
        • Papassotiriou I.
        The association of serum lipids, lipoproteins and apolipoproteins with selected trace elements and minerals in phenylketonuric patients on diet.
        Clin Nutr. 2004; 23: 401-407
        • Barretto J.R.
        • Silva L.R.
        • Leite M.E.
        • Boa-Sorte N.
        • Pimentel H.
        • Purificação A.C.
        • et al.
        Poor zinc and selenium status in phenylketonuric children and adolescents in Brazil.
        Nutr Res. 2008; 28: 208-211
        • Longhi R.
        • Rottoli A.
        • Vittorelli A.
        • Zecchini G.
        • Bonabitacola T.
        • Bertassi F.
        • et al.
        Trace elements nutriture in hyperphenylalaninemic patients. Long-term follow up study.
        Eur J Pediatr. 1987; 146: A32-A37
        • McMurry M.P.
        • Chan G.M.
        • Leonard C.O.
        • Ernst S.L.
        Bone mineral status in children with phenylketonuria–relationship to nutritional intake and phenylalanine control.
        Am J Clin Nutr. 1992; 55: 997-1004
        • Taylor C.J.
        • Moore G.
        • Davidson D.C.
        The effect of treatment on zinc, copper and calcium status in children with phenylketonuria.
        J Inherit Metab Dis. 1984; 7: 160-164
        • Acosta P.B.
        • Fernhoff P.M.
        • Warshaw H.S.
        • Hambidge K.M.
        • Ernest A.
        • McCabe E.R.
        • et al.
        Zinc and copper status of treated children with phenylketonuria.
        J Parenter Enteral Nutr. 1981; 5: 406-409
        • Lowe N.M.
        • Fekete K.
        • Decsi T.
        Methods of assessment of zinc status in humans: a systematic review.
        Am J Clin Nutr. 2009; 89: 2040-2051
        • Gibson R.S.
        • Hess S.Y.
        • Hotz C.
        • Brown K.H.
        Indicators of zinc status at the population level: a review of the evidence.
        Br J Nutr. 2008; 99: S14-S23
        • Gropper S.S.
        • Acosta P.B.
        • Clarke-Sheehan N.
        • Wenz E.
        • Cheng M.
        • Koch R.
        Trace element status of children with PKU and normal children.
        J Am Diet Assoc. 1988; 88: 459-465
        • Fisberg M.
        • Castillo Durán C.
        • Egaña J.I.
        • Uauy Dagach R.
        Plasma zinc and copper in infants with protein-calorie malnutrition.
        Arch Latinoam Nutr. 1984; 34: 568-577
        • Modan-Moses D.
        • Vered I.
        • Schwartz G.
        • Anikster Y.
        • Abraham S.
        • Segev R.
        • et al.
        Peak bone mass in patients with phenylketonuria.
        J Inherit Metab Dis. 2007; 30: 202-208
        • Gülez P.
        • Korkmaz H.A.
        • Özkök D.
        • Can D.
        • Özkan B.
        Factors influencing serum vitamin D concentration in Turkish children residing in İzmir: a single- center experience.
        J Clin Res Pediatr Endocrinol. 2015; 7: 294-300
        • Colomé C.
        • Artuch R.
        • Vilaseca M.A.
        • Sierra C.
        • Brandi N.
        • Lambruschini N.
        • et al.
        Lipophilic antioxidants in patients with phenylketonuria.
        Am J Clin Nutr. 2003; 77: 185-188
        • Schulpis K.H.
        • Tsakiris S.
        • Karikas G.A.
        • Moukas M.
        • Behrakis P.
        Effect of diet on plasma total antioxidant status in phenylketonuric patients.
        Eur J Clin Nutr. 2003; 57: 383-387
        • Schulpis K.H.
        • Papastamataki M.
        • Stamou H.
        • Papassotiriou I.
        • Margeli A.
        The effect of diet on total antioxidant status, ceruloplasmin, transferrin and ferritin serum levels in phenylketonuric children.
        Acta Paediatr. 2010; 99: 1565-1570
        • Robert M.
        • Rocha J.C.
        • van Rijn M.
        • Ahring K.
        • Bélanger-Quintana A.
        • MacDonald A.
        • et al.
        Micronutrient status in phenylketonuria.
        Mol Genet Metab. 2013; 110: S6-S17