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Phenylketonuria(PKU)

MedGen UID:
19244
Concept ID:
C0031485
Disease or Syndrome
Synonyms: Folling disease; Oligophrenia phenylpyruvica; Phenylalanine Hydroxylase Deficiency; Phenylketonurias; PKU
SNOMED CT: Phenylketonuria (190687004); PKU - phenylketonuria (190687004); PAH (phenylalanine hydroxylase) deficiency (190687004); Phenylalanine hydroxylase deficiency (190687004); Folling disease (190687004); Oligophrenia phenylpyruvica (190687004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PAH (12q23.2)
Related gene: QDPR
 
Monarch Initiative: MONDO:0009861
OMIM®: 261600
Orphanet: ORPHA716

Disease characteristics

Excerpted from the GeneReview: Phenylalanine Hydroxylase Deficiency
Phenylalanine hydroxylase (PAH) deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The risk of adverse outcome varies based on the degree of PAH deficiency. Without effective therapy, most individuals with severe PAH deficiency, known as classic PKU, develop profound and irreversible intellectual disability. Affected individuals on an unrestricted diet who have phenylalanine levels above normal but below 1,200 μmol/L (20 mg/dL) are at much lower risk for impaired cognitive development in the absence of treatment. [from GeneReviews]
Authors:
Debra S Regier  |  Carol L Greene   view full author information

Additional description

From OMIM
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; 612349), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (Zurfluh et al., 2008). See Scriver (2007) and Blau et al. (2010) for detailed reviews of PKU.  http://www.omim.org/entry/261600

Clinical features

From HPO
Increased level of hippuric acid in urine
MedGen UID:
1640306
Concept ID:
C4703632
Finding
An increase in the level of hippuric acid in the urine.
Elevated urinary phenylpyruvic acid level
MedGen UID:
1841861
Concept ID:
C5826407
Finding
An abnormally increased amount of phenylpyruvic acid in the urine.
Elevated urinary gamma-glutamylphenylalanine level
MedGen UID:
1053903
Concept ID:
CN377092
Finding
The amount of gamma-glutamylphenylalanine level in the urine, when normalized for urine concentration, is above the upper limit of normal.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Psychotic disorder
MedGen UID:
19568
Concept ID:
C0033975
Mental or Behavioral Dysfunction
A condition characterized by changes in personality and thought patterns, often accompanied by hallucinations and delusional beliefs, is known as psychosis.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Self-mutilation
MedGen UID:
19925
Concept ID:
C0036601
Injury or Poisoning
Deliberate harm to one's body resulting in tissue damage, without a conscious intent to die.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Hyperactivity
MedGen UID:
98406
Concept ID:
C0424295
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
Compulsive behaviors
MedGen UID:
109373
Concept ID:
C0600104
Mental or Behavioral Dysfunction
Behavior that consists of repetitive acts, characterized by the feeling that one "has to" perform them, while being aware that these acts are not in line with one's overall goal.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Mental or Behavioral Dysfunction
Attention-deficit/hyperactivity disorder (ADHD) is a behavioral disorder that typically begins in childhood and is characterized by a short attention span (inattention), an inability to be calm and stay still (hyperactivity), and poor impulse control (impulsivity). Some people with ADHD have problems with only inattention or with hyperactivity and impulsivity, but most have problems related to all three features.\n\nIn people with ADHD, the characteristic behaviors are frequent and severe enough to interfere with the activities of daily living such as school, work, and relationships with others. Because of an inability to stay focused on tasks, people with inattention may be easily distracted, forgetful, avoid tasks that require sustained attention, have difficulty organizing tasks, or frequently lose items.\n\nHyperactivity is usually shown by frequent movement. Individuals with this feature often fidget or tap their foot when seated, leave their seat when it is inappropriate to do so (such as in the classroom), or talk a lot and interrupt others.\n\nImpulsivity can result in hasty actions without thought for the consequences. Individuals with poor impulse control may have difficulty waiting for their turn, deferring to others, or considering their actions before acting.\n\nMore than two-thirds of all individuals with ADHD have additional conditions, including insomnia, mood or anxiety disorders, learning disorders, or substance use disorders. Affected individuals may also have autism spectrum disorder, which is characterized by impaired communication and social interaction, or Tourette syndrome, which is a disorder characterized by repetitive and involuntary movements or noises called tics.\n\nIn most affected individuals, ADHD continues throughout life, but in about one-third of individuals, signs and symptoms of ADHD go away by adulthood.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a tendency to become easily bothered or annoyed.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within the cerebrum.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Eczema
MedGen UID:
3968
Concept ID:
C0013595
Disease or Syndrome
Eczema is a form of dermatitis that is characterized by scaly, pruritic, erythematous lesions located on flexural surfaces.
Hyperphenylalaninemia
MedGen UID:
155558
Concept ID:
C0751435
Disease or Syndrome
An increased concentration of L-phenylalanine in the blood.
Phenylpyruvic acidemia
MedGen UID:
376669
Concept ID:
C1849926
Finding
Maternal hyperphenylalaninemia
MedGen UID:
867625
Concept ID:
C4022014
Finding
A medical history of exposure during the fetal period to hyperphenylalaninemia because the mother had phenylketonuria with inadequate control during pregnancy.
Reduced phenylalanine hydroxylase level
MedGen UID:
892453
Concept ID:
C4025094
Finding
A reduction in phenylalanine 4-monooxygenase level.
Scleroderma
MedGen UID:
3770
Concept ID:
C0011644
Disease or Syndrome
A chronic autoimmune phenomenon characterized by fibrosis (or hardening) and vascular alterations of the skin.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Sign or Symptom
Skin characterized by the lack of natural or normal moisture.
Fair hair
MedGen UID:
336542
Concept ID:
C1849221
Finding
A lesser degree of hair pigmentation than would otherwise be expected.
Generalized hypopigmentation
MedGen UID:
340426
Concept ID:
C1849923
Finding
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
A markedly blue coloration of the iris.

Professional guidelines

PubMed

van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ
Orphanet J Rare Dis 2017 Oct 12;12(1):162. doi: 10.1186/s13023-017-0685-2. PMID: 29025426Free PMC Article
van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefz FK, van Rijn M, Walter JH, MacDonald A
Lancet Diabetes Endocrinol 2017 Sep;5(9):743-756. Epub 2017 Jan 10 doi: 10.1016/S2213-8587(16)30320-5. PMID: 28082082
Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA; American College of Medical Genetics and Genomics Therapeutics Committee
Genet Med 2014 Feb;16(2):188-200. Epub 2013 Oct 10 doi: 10.1038/gim.2013.157. PMID: 24385074

Curated

Zschocke J, Haverkamp T, Møller LB
Eur J Hum Genet 2012 Feb;20(2) Epub 2011 Sep 14 doi: 10.1038/ejhg.2011.172. PMID: 21915151Free PMC Article

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Phenylalanine, Phenylalanine hydroxylase deficiency (PAH), 2022

American College of Medical Genetics and Genomics, Algorithm, PAH deficiency: Elevated Phenylalanine, 2022

PKU Nutrition Management Guidelines

American College of Medical Genetics and Genomics, Adult Genetics Disease ACT Sheet, Adult Phenylketonuria (PKU), 2012

Suggested Reading

PubMed

Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, Brown CS, Burlina AB, Burton BK, Chang CS, Coates PM, Cunningham AC, Dobrowolski SF, Ferguson JH, Franklin TD, Frazier DM, Grange DK, Greene CL, Groft SC, Harding CO, Howell RR, Huntington KL, Hyatt-Knorr HD, Jevaji IP, Levy HL, Lichter-Konecki U, Lindegren ML, Lloyd-Puryear MA, Matalon K, MacDonald A, McPheeters ML, Mitchell JJ, Mofidi S, Moseley KD, Mueller CM, Mulberg AE, Nerurkar LS, Ogata BN, Pariser AR, Prasad S, Pridjian G, Rasmussen SA, Reddy UM, Rohr FJ, Singh RH, Sirrs SM, Stremer SE, Tagle DA, Thompson SM, Urv TK, Utz JR, van Spronsen F, Vockley J, Waisbren SE, Weglicki LS, White DA, Whitley CB, Wilfond BS, Yannicelli S, Young JM
Mol Genet Metab 2014 Jun;112(2):87-122. Epub 2014 Mar 6 doi: 10.1016/j.ymgme.2014.02.013. PMID: 24667081

Recent clinical studies

Etiology

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Int J Mol Sci 2023 Dec 13;24(24) doi: 10.3390/ijms242417428. PMID: 38139256Free PMC Article
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U
Mol Genet Metab 2011;104 Suppl:S2-9. Epub 2011 Aug 26 doi: 10.1016/j.ymgme.2011.08.017. PMID: 21937252
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948
Hanley WB
Am J Med 2004 Oct 15;117(8):590-5. doi: 10.1016/j.amjmed.2004.03.042. PMID: 15465508
Purnell H
Breastfeed Rev 2001 Jul;9(2):19-21. PMID: 11550601

Diagnosis

van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ
Orphanet J Rare Dis 2017 Oct 12;12(1):162. doi: 10.1186/s13023-017-0685-2. PMID: 29025426Free PMC Article
Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U
Mol Genet Metab 2011;104 Suppl:S2-9. Epub 2011 Aug 26 doi: 10.1016/j.ymgme.2011.08.017. PMID: 21937252
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948
Blau N, van Spronsen FJ, Levy HL
Lancet 2010 Oct 23;376(9750):1417-27. doi: 10.1016/S0140-6736(10)60961-0. PMID: 20971365
Yu JS
Postgrad Med J 1970 Jul;46(537):430-6. doi: 10.1136/pgmj.46.537.430. PMID: 4920277Free PMC Article

Therapy

Rondanelli M, Porta F, Gasparri C, Barrile GC, Cavioni A, Mansueto F, Mazzola G, Patelli Z, Peroni G, Pirola M, Razza C, Tartara A, Perna S
Clin Nutr 2023 May;42(5):732-763. Epub 2023 Mar 21 doi: 10.1016/j.clnu.2023.03.007. PMID: 37001196
Elhawary NA, AlJahdali IA, Abumansour IS, Elhawary EN, Gaboon N, Dandini M, Madkhali A, Alosaimi W, Alzahrani A, Aljohani F, Melibary EM, Kensara OA
Hum Genomics 2022 Jul 19;16(1):22. doi: 10.1186/s40246-022-00398-9. PMID: 35854334Free PMC Article
Grisch-Chan HM, Schwank G, Harding CO, Thöny B
Hum Gene Ther 2019 Oct;30(10):1274-1283. Epub 2019 Sep 9 doi: 10.1089/hum.2019.111. PMID: 31364419Free PMC Article
Thomas J, Levy H, Amato S, Vockley J, Zori R, Dimmock D, Harding CO, Bilder DA, Weng HH, Olbertz J, Merilainen M, Jiang J, Larimore K, Gupta S, Gu Z, Northrup H; PRISM investigators
Mol Genet Metab 2018 May;124(1):27-38. Epub 2018 Mar 31 doi: 10.1016/j.ymgme.2018.03.006. PMID: 29653686
Mitchell JJ, Trakadis YJ, Scriver CR
Genet Med 2011 Aug;13(8):697-707. doi: 10.1097/GIM.0b013e3182141b48. PMID: 21555948

Prognosis

De Giorgi A, Nardecchia F, Manti F, Campistol J, Leuzzi V
Mol Genet Metab 2023 Jun;139(2):107588. Epub 2023 Apr 25 doi: 10.1016/j.ymgme.2023.107588. PMID: 37149991
Guerra IMS, Ferreira HB, Neves B, Melo T, Diogo LM, Domingues MR, Moreira ASP
Arch Biochem Biophys 2020 Jul 30;688:108431. Epub 2020 May 24 doi: 10.1016/j.abb.2020.108431. PMID: 32461102
Leuzzi V, Chiarotti F, Nardecchia F, van Vliet D, van Spronsen FJ
J Med Genet 2020 Mar;57(3):145-150. Epub 2019 Sep 4 doi: 10.1136/jmedgenet-2019-106278. PMID: 31484718
Isabella VM, Ha BN, Castillo MJ, Lubkowicz DJ, Rowe SE, Millet YA, Anderson CL, Li N, Fisher AB, West KA, Reeder PJ, Momin MM, Bergeron CG, Guilmain SE, Miller PF, Kurtz CB, Falb D
Nat Biotechnol 2018 Oct;36(9):857-864. Epub 2018 Aug 13 doi: 10.1038/nbt.4222. PMID: 30102294
Blau N
Hum Mutat 2016 Jun;37(6):508-15. Epub 2016 Mar 18 doi: 10.1002/humu.22980. PMID: 26919687

Clinical prediction guides

Coşkun T, Çoker M, Mungan NÖ, Özel HG, Sivri HS
Turk J Pediatr 2022;64(3):413-434. doi: 10.24953/turkjped.2021.4098. PMID: 35899555
de Almeida BNF, Laufer JA, Mezzomo TR, Shimada NC, Furtado IHF, Dias MRMG, Pereira RM
Clin Nutr ESPEN 2020 Jun;37:44-49. Epub 2020 Apr 15 doi: 10.1016/j.clnesp.2020.03.024. PMID: 32359754
Leuzzi V, Chiarotti F, Nardecchia F, van Vliet D, van Spronsen FJ
J Med Genet 2020 Mar;57(3):145-150. Epub 2019 Sep 4 doi: 10.1136/jmedgenet-2019-106278. PMID: 31484718
Isabella VM, Ha BN, Castillo MJ, Lubkowicz DJ, Rowe SE, Millet YA, Anderson CL, Li N, Fisher AB, West KA, Reeder PJ, Momin MM, Bergeron CG, Guilmain SE, Miller PF, Kurtz CB, Falb D
Nat Biotechnol 2018 Oct;36(9):857-864. Epub 2018 Aug 13 doi: 10.1038/nbt.4222. PMID: 30102294
Blau N
Hum Mutat 2016 Jun;37(6):508-15. Epub 2016 Mar 18 doi: 10.1002/humu.22980. PMID: 26919687

Recent systematic reviews

Ubaldi F, Frangella C, Volpini V, Fortugno P, Valeriani F, Romano Spica V
Int J Mol Sci 2023 Dec 13;24(24) doi: 10.3390/ijms242417428. PMID: 38139256Free PMC Article
Pinto A, Ilgaz F, Evans S, van Dam E, Rocha JC, Karabulut E, Hickson M, Daly A, MacDonald A
Nutrients 2023 Aug 8;15(16) doi: 10.3390/nu15163506. PMID: 37630696Free PMC Article
De Giorgi A, Nardecchia F, Manti F, Campistol J, Leuzzi V
Mol Genet Metab 2023 Jun;139(2):107588. Epub 2023 Apr 25 doi: 10.1016/j.ymgme.2023.107588. PMID: 37149991
Rondanelli M, Porta F, Gasparri C, Barrile GC, Cavioni A, Mansueto F, Mazzola G, Patelli Z, Peroni G, Pirola M, Razza C, Tartara A, Perna S
Clin Nutr 2023 May;42(5):732-763. Epub 2023 Mar 21 doi: 10.1016/j.clnu.2023.03.007. PMID: 37001196
Demirdas S, Coakley KE, Bisschop PH, Hollak CE, Bosch AM, Singh RH
Orphanet J Rare Dis 2015 Feb 15;10:17. doi: 10.1186/s13023-015-0232-y. PMID: 25758373Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
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      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Phenylalanine, Phenylalanine hydroxylase deficiency (PAH), 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, PAH deficiency: Elevated Phenylalanine, 2022
    • GMDI/SERN, 2022
      PKU Nutrition Management Guidelines
    • ACMG ACT, 2012
      American College of Medical Genetics and Genomics, Adult Genetics Disease ACT Sheet, Adult Phenylketonuria (PKU), 2012
    • EuroGenetest, 2011
      Clinical utility gene card for: Phenylketonuria.

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