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Journal of Pediatric Biochemistry 2016; 06(01): 011-018
DOI: 10.1055/s-0036-1582237
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Hyperphenylalaninemia: From Diagnosis to Therapy

Daniela Procopio
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Italia Mascaro
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Stefania Ferraro
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Ferdinando Ceravolo
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Maria Teresa Moricca
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Vincenzo Salpietro
2   Department of Pediatrics, University of Messina, Messina, Italy
3   Institute of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College, London Hospitals, London, United Kingdom
,
Agata Polizzi
4   National Centre for Rare Diseases, Istituto Superiore di Sanità, Roma, Italy
,
Martino Ruggieri
5   Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy
,
Giuseppe Bonapace
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
,
Daniela Concolino
1   Department of Medical and Surgical Sciences, Pediatrics Unit, University “Magna Graecia,” Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

10 December 2015

20 January 2016

Publication Date:
26 April 2016 (online)

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Abstract

Hyperphenylalaninemia (HPA) is a biochemical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine (Phe) in the blood. HPA is commonly diagnosed by newborn screening. The primary cause of HPA is phenylketonuria (PKU), an inborn error of metabolism characterized by persistently elevated plasma concentrations of Phe secondary to a total or partial deficiency of the liver enzyme phenylalanine hydroxylase. The treatment of babies affected with PKU is based on a Phe-restricted diet, aiming to maintain blood Phe concentrations within a range of 120 to 360 μmol/L to prevent the spectrum of neurological disorders associated with PKU, that is, microcephaly, learning disability, epilepsy, pyramidal and extrapyramidal signs, and behavioral changes. This metabolic disorder mainly affects the white matter (e.g., dysmyelination, demyelination, and hypomyelination) and the cortical-subcortical structures. A delay in starting the dietary treatment, or an inadequate Phe-restricted diet, may relentlessly lead to brain damage.

Keywords

hyperphenylalaninemia - phenylalanine - phenylketonuria - PKU - phenylalanine hydroxylase - diet - neurological
 

  • References

  • 1 Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, et al., eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw-Hill; 2001: 1667-1724
    Search in Google Scholar
  • 2 BIOPKU: International Database Available at: http://www.biopku.org/home/home.asp
    PubMed
  • 3 Santos LL, Fonseca CG, Starling AL , et al. Variations in genotype-phenotype correlations in phenylketonuria patients. Genet Mol Res 2010; 9 (1) 1-8
    CrossrefPubMedSearch in Google Scholar
  • 4 Guzzetta V, Bonapace G, Dianzani I , et al. Phenylketonuria in Italy: distinct distribution pattern of three mutations of the phenylalanine hydroxylase gene. J Inherit Metab Dis 1997; 20 (5) 619-624
    CrossrefPubMedSearch in Google Scholar
  • 5 Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency. Genet Med 2011; 13 (8) 697-707
    CrossrefPubMedSearch in Google Scholar
  • 6 Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab 2011; 104 (Suppl): S2-S9
    CrossrefPubMedSearch in Google Scholar
  • 7 Camp KM, Parisi MA, Acosta PB , et al. Phenylketonuria Scientific Review Conference: state of the science and future research needs. Mol Genet Metab 2014; 112 (2) 87-122
    CrossrefPubMedSearch in Google Scholar
  • 8 Williams RA, Mamotte CD, Burnett JR. Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev 2008; 29 (1) 31-41
    PubMedSearch in Google Scholar
  • 9 Abita JP, Dorche C, Kaufman S. Futher studies on the nature of phenylalanine hydroxylation in brain. Pediatr Res 1974; 8 (7) 714-717
    CrossrefPubMedSearch in Google Scholar
  • 10 Kaufman S. A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients. Proc Natl Acad Sci U S A 1999; 96 (6) 3160-3164
    CrossrefPubMedSearch in Google Scholar
  • 11 Donlon J, Levy H, Scriver CR. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. In: Valle D, Beaudet AL, Vogelstein B, et al, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill; 2014: Chapter 77 . Available at http://ommbid.mhmedical.com . Accessed July 7, 2015
    Search in Google Scholar
  • 12 Brosco JP, Sanders LM, Seider MI, Dunn AC. Adverse medical outcomes of early newborn screening programs for phenylketonuria. Pediatrics 2008; 122 (1) 192-197
    CrossrefPubMedSearch in Google Scholar
  • 13 Hennermann JB, Loui A, Weber A, Mönch E. Hyperphenylalaninemia in a premature infant with heterozygosity for phenylketonuria. J Perinat Med 2004; 32 (4) 383-385
    PubMedSearch in Google Scholar
  • 14 Chace DH, Sherwin JE, Hillman SL, Lorey F, Cunningham GC. Use of phenylalanine-to-tyrosine ratio determined by tandem mass spectrometry to improve newborn screening for phenylketonuria of early discharge specimens collected in the first 24 hours. Clin Chem 1998; 44 (12) 2405-2409
    PubMedSearch in Google Scholar
  • 15 Blau N, Thony B, Cotton RGH, Hyland K. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Kaufman S, Eisensmith E, Woo SLC, Vogelstein B, Childs B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York, NY: McGraw Hill; 2001: Chapter 78
    Search in Google Scholar
  • 16 Ponzone A, Ferraris S, Baglieri S, Spada M. Treatment of tetrahydrobiopterin deficiencies. In: Blau N, ed. PKU and BH4 Advances in Phenylketonuria and Tetrahydrobiopterin. Heilbronn, Germany: SPS Verlagsgesellschaft; 2006: 612-637
    Search in Google Scholar
  • 17 Ahring K, Bélanger-Quintana A, Dokoupil K , et al. Dietary management practices in phenylketonuria across European centres. Clin Nutr 2009; 28 (3) 231-236
    CrossrefPubMedSearch in Google Scholar
  • 18 Giovannini M, Verduci E, Salvatici E, Fiori L, Riva E. Phenylketonuria: dietary and therapeutic challenges. J Inherit Metab Dis 2007; 30 (2) 145-152
    CrossrefPubMedSearch in Google Scholar
  • 19 Yi S, Singh RH. Protein substitute for children and adults with phenylketonuria. Cochrane Database Syst Rev 2008; 4 (4) CD004731
    PubMedSearch in Google Scholar
  • 20 Pietz J, Dunckelmann R, Rupp A , et al. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 1998; 157 (10) 824-830
    CrossrefPubMedSearch in Google Scholar
  • 21 National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference Statement: phenylketonuria: screening and management, October 16-18, 2000. Pediatrics 2001; 108 (4) 972-982
    CrossrefPubMedSearch in Google Scholar
  • 22 Waisbren SE, Noel K, Fahrbach K , et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab 2007; 92 (1–2) 63-70
    CrossrefPubMedSearch in Google Scholar
  • 23 Strisciuglio P, Concolino D. New Strategies for the Treatment of Phenylketonuria (PKU). Metabolites 2014; 4 (4) 1007-1017
    CrossrefPubMedSearch in Google Scholar
  • 24 Feillet F, Agostoni C. Nutritional issues in treating phenylketonuria. J Inherit Metab Dis 2010; 33 (6) 659-664
    CrossrefPubMedSearch in Google Scholar
  • 25 Beblo S, Reinhardt H, Demmelmair H, Muntau AC, Koletzko B. Effect of fish oil supplementation on fatty acid status, coordination, and fine motor skills in children with phenylketonuria. J Pediatr 2007; 150 (5) 479-484
    CrossrefPubMedSearch in Google Scholar
  • 26 MacLeod EL, Clayton MK, van Calcar SC, Ney DM. Breakfast with glycomacropeptide compared with amino acids suppresses plasma ghrelin levels in individuals with phenylketonuria. Mol Genet Metab 2010; 100 (4) 303-308
    CrossrefPubMedSearch in Google Scholar
  • 27 Matalon R, Michals-Matalon K, Bhatia G , et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis 2007; 30 (2) 153-158
    CrossrefPubMedSearch in Google Scholar
  • 28 Schindeler S, Ghosh-Jerath S, Thompson S , et al. The effects of large neutral amino acid supplements in PKU: an MRS and neuropsychological study. Mol Genet Metab 2007; 91 (1) 48-54
    CrossrefPubMedSearch in Google Scholar
  • 29 Cerone R, Andria G, Giovannini M, Leuzzi V, Riva E, Burlina A. Testing for tetrahydrobiopterin responsiveness in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. Adv Ther 2013; 30 (3) 212-228
    CrossrefPubMedSearch in Google Scholar
  • 30 Blau N, Bélanger-Quintana A, Demirkol M , et al. Optimizing the use of sapropterin (BH(4)) in the management of phenylketonuria. Mol Genet Metab 2009; 96 (4) 158-163
    CrossrefPubMedSearch in Google Scholar
  • 31 Fiege B, Blau N. Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr 2007; 150 (6) 627-630
    CrossrefPubMedSearch in Google Scholar
  • 32 Trefz FK, Burton BK, Longo N , et al; Sapropterin Study Group. Efficacy of sapropterin dihydrochloride in increasing phenylalanine tolerance in children with phenylketonuria: a phase III, randomized, double-blind, placebo-controlled study. J Pediatr 2009; 154 (5) 700-707
    CrossrefPubMedSearch in Google Scholar
  • 33 Scala I, Concolino D, Della Casa R , et al. Long-term follow-up of patients with phenylketonuria treated with tetrahydrobiopterin: a seven years experience. Orphanet J Rare Dis 2015; 10: 14
    CrossrefPubMedSearch in Google Scholar
  • 34 Blau N. Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias. Expert Opin Drug Metab Toxicol 2013; 9 (9) 1207-1218
    PubMedSearch in Google Scholar
  • 35 Longo N, Harding CO, Burton BK , et al. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial. Lancet 2014; 384 (9937) 37-44
    CrossrefPubMedSearch in Google Scholar
  • 36 Kang TS, Wang L, Sarkissian CN, Gámez A, Scriver CR, Stevens RC. Converting an injectable protein therapeutic into an oral form: phenylalanine ammonia lyase for phenylketonuria. Mol Genet Metab 2010; 99 (1) 4-9
    CrossrefPubMedSearch in Google Scholar
  • 37 Rebuffat A, Harding CO, Ding Z, Thöny B. Comparison of adeno-associated virus pseudotype 1, 2, and 8 vectors administered by intramuscular injection in the treatment of murine phenylketonuria. Hum Gene Ther 2010; 21 (4) 463-477
    CrossrefPubMedSearch in Google Scholar
  • 38 Van der Knaap M, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. 3rd ed. Berlin: Springer-Verlag; 2005
    CrossrefSearch in Google Scholar
  • 39 Patay Z. Metabolic disorders. In: Tortori-Donati P. Pediatric Neuroradiology. Brain. Berlin: Springer-Verlag; 2005. : pp. 543-722
    CrossrefSearch in Google Scholar
  • 40 Barkovich AJ. Pediatric Neuroradiology. 5th ed. Baltimore: Lippincott Wliiams & Wilkins; 2012
    Search in Google Scholar
  • 41 Pavone P, Spalice A, Polizzi A, Parisi P, Ruggieri M. Ohtahara syndrome with emphasis on recent genetic discovery. Brain Dev 2012; 34 (6) 459-468
    CrossrefPubMedSearch in Google Scholar
  • 42 Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev 2014; 36 (9) 739-751
    CrossrefPubMedSearch in Google Scholar
  • 43 Pavone P, Incorpora G, Fiumara A, Parano E, Trifiletti RR, Ruggieri M. Epilepsy is not a prominent feature of primary autism. Neuropediatrics 2004; 35 (4) 207-210
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR. Meta-analysis of neuropsychological symptoms of adolescents and adults with PKU. Neuropsychol Rev 2007; 17 (2) 91-101
    CrossrefPubMedSearch in Google Scholar
  • 45 Burton BK, Leviton L, Vespa H , et al. A diversified approach for PKU treatment: routine screening yields high incidence of psychiatric distress in phenylketonuria clinics. Mol Genet Metab 2013; 108 (1) 8-12
    CrossrefPubMedSearch in Google Scholar
  • 46 Hanley WB. Adult phenylketonuria. Am J Med 2004; 117 (8) 590-595
    CrossrefPubMedSearch in Google Scholar
  • 47 Channon S, Goodman G, Zlotowitz S, Mockler C, Lee PJ. Effects of dietary management of phenylketonuria on long-term cognitive outcome. Arch Dis Child 2007; 92 (3) 213-218
    CrossrefPubMedSearch in Google Scholar
  • 48 Fonnesbeck CJ, McPheeters ML, Krishnaswami S, Lindegren ML, Reimschisel T. Estimating the probability of IQ impairment from blood phenylalanine for phenylketonuria patients: a hierarchical meta-analysis. J Inherit Metab Dis 2013; 36 (5) 757-766
    CrossrefPubMedSearch in Google Scholar
  • 49 Koch R, Burton B, Hoganson G , et al. Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 2002; 25 (5) 333-346
    CrossrefPubMedSearch in Google Scholar
  • 50 Phillips MD, McGraw P, Lowe MJ, Mathews VP, Hainline BE. Diffusion-weighted imaging of white matter abnormalities in patients with phenylketonuria. AJNR Am J Neuroradiol 2001; 22 (8) 1583-1586
    PubMedSearch in Google Scholar
  • 51 Anderson PJ, Wood SJ, Francis DE , et al. Neuropsychological functioning in children with early-treated phenylketonuria: impact of white matter abnormalities. Dev Med Child Neurol 2004; 46 (4) 230-238
    PubMedSearch in Google Scholar
  • 52 Karimzadeh P. Approach to neurometabolic diseases from a pediatric neurological point of view. Iran J Child Neurol 2015; 9 (1) 1-16
    PubMedSearch in Google Scholar
  • 53 Ruggieri M, Tigano G, Mazzone D, Tiné A, Pavone L. Involvement of the white matter in hypomelanosis of Ito (incontinentia pigmenti achromiens). Neurology 1996; 46 (2) 485-492
    CrossrefPubMedSearch in Google Scholar
  • 54 Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in children with measles infection and selective, reversible thalamic involvement. Pediatrics 1998; 101 (1 Pt 1) 112-119
    CrossrefPubMedSearch in Google Scholar
  • 55 Abdel-Salam GMH, Abdel-Kader AA, Effat L, Gouda A, Hindawy A, El-Gammal MA. Clinical, Electroencephalographic (EEG), Neuroradiological and Molecular Correlations in Late-Detected Phenylketonuria (PKU) Patients. Egypt J Neurol Psychiat Neurosurg 2005; 42 (2) 391-406
    PubMedSearch in Google Scholar
  • 56 Karimzadeh P, Ahmadabadi F, Jafari N , et al. Study on MRI changes in phenylketonuria in patients referred to mofid hospital/iran. Iran J Child Neurol 2014; 8 (2) 53-56
    PubMedSearch in Google Scholar
  • 57 Antenor-Dorsey JAV, Hershey T, Rutlin J , et al. White matter integrity and executive abilities in individuals with phenylketonuria. Mol Genet Metab 2013; 109 (2) 125-131
    CrossrefPubMedSearch in Google Scholar
  • 58 White DA, Connor LT, Nardos B , et al. Age-related decline in the microstructural integrity of white matter in children with early- and continuously-treated PKU: a DTI study of the corpus callosum. Mol Genet Metab 2010; 99 (Suppl. 01) S41-S46
    PubMedSearch in Google Scholar
  • 59 White DA, Antenor-Dorsey JA, Grange DK , et al. White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. Mol Genet Metab 2013; 110 (3) 213-217
    CrossrefPubMedSearch in Google Scholar
  • 60 Waisbren SE, Rohr F, Anastasoaie V , et al. Maternal Phenylketonuria: Long-term Outcomes in Offspring and Post-pregnancy Maternal Characteristics. JIMD Rep 2015; 21: 23-33
    PubMedSearch in Google Scholar
  • 61 Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of untreated and treated pregnancies. N Engl J Med 1980; 303 (21) 1202-1208
    CrossrefPubMedSearch in Google Scholar
  • 62 Anderson PJ, Wood SJ, Francis DE, Coleman L, Anderson V, Boneh A. Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels?. Dev Neuropsychol 2007; 32 (2) 645-668
    CrossrefPubMedSearch in Google Scholar
  • 63 Diamond A, Prevor MB, Callender G, Druin DP. Prefrontal cortex cognitive deficits in children treated early and continuously for PKU. Monogr Soc Res Child Dev 1997; 62 (4) i-v , 1–2008
    PubMedSearch in Google Scholar
  • 64 Smith M, Klim P, Hanley W. Executive function in school-aged children with phenylketonuria. J Dev Phys Disabil 2000; 12: 317-332
    CrossrefPubMedSearch in Google Scholar
  • 65 Harding CO, Gibson KM. Therapeutic liver repopulation for phenylketonuria. J Inherit Metab Dis 2010; 33 (6) 681-687
    CrossrefPubMedSearch in Google Scholar