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Phenylketonuria(PKU)

MedGen UID:
19244
Concept ID:
C0031485
Disease or Syndrome
Synonyms: Classic phenylketonuria; Deficiency Disease, Phenylalanine Hydroxylase; Folling disease; Folling's Disease; Oligophrenia phenylpyruvica; PAH deficiency; Phenylalanine Hydroxylase Deficiency; Phenylalanine hydroxylase deficiency; Phenylketonurias; PKU
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
 
Gene: PAH
Cytogenetic location: 12q23.2
OMIM: 261600

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 including phenylketonuria (PKU), non-PKU hyperphenylalaninemia (non-PKU HPA), and variant PKU. Classic PKU is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity; without dietary restriction of phenylalanine, most children with PKU develop profound and irreversible intellectual disability. Non-PKU HPA is associated with a much lower risk of impaired cognitive development in the absence of treatment.  [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References
Authors:
John J Mitchell   view full author information

Additional descriptions

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
From GHR
Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners. If PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems. The signs and symptoms of PKU vary from mild to severe. The most severe form of this disorder is known as classic PKU. Infants with classic PKU appear normal until they are a few months old. Without treatment, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders are also common. Untreated individuals may have a musty or mouse-like odor as a side effect of excess phenylalanine in the body. Children with classic PKU tend to have lighter skin and hair than unaffected family members and are also likely to have skin disorders such as eczema. Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a smaller risk of brain damage. People with very mild cases may not require treatment with a low-phenylalanine diet. Babies born to mothers with PKU and uncontrolled phenylalanine levels (women who no longer follow a low-phenylalanine diet) have a significant risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth. These infants may also have a low birth weight and grow more slowly than other children. Other characteristic medical problems include heart defects or other heart problems, an abnormally small head size (microcephaly), and behavioral problems. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.  http://ghr.nlm.nih.gov/condition/phenylketonuria

Clinical features

Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an `amino acid` (CHEBI:33709 ) in the `urine` (FMA:12274).
Blue irides
MedGen UID:
500890
Concept ID:
CN000597
Finding
A markedly blue coloration of the iris.
Irritability
MedGen UID:
5898
Concept ID:
C0022107
Finding
Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience.
Psychosis
MedGen UID:
504566
Concept ID:
CN000666
Finding
A condition characterized by changes of personality and thought patterns often accompanied by hallucinations and delusional beliefs.
Obsessive-compulsive behavior
MedGen UID:
504572
Concept ID:
CN000679
Finding
Recurrent obsessions or compulsions that are severe enough to be time consuming (i.e., they take more than 1 hour a day) or cause marked distress or significant impairment (DSM-IV).
Attention deficit hyperactivity disorder
MedGen UID:
506017
Concept ID:
CN006126
Finding
Attention deficit hyperactivity disorder (ADHD) manifests at age 2-3 years or by first grade at the latest. The main symptoms are distractibility, impulsivity, hyperactivity, and often trouble organizing tasks and projects, difficulty going to sleep, and social problems from being aggressive, loud, or impatient.
Maternal hyperphenylalaninemia
MedGen UID:
451908
Concept ID:
CN117502
Finding
A medical history of exposure during the fetal period to hyperphenylalaninemia because the mother had phenylketonuria with inadequate control during pregnancy.
Eczema
MedGen UID:
504663
Concept ID:
CN000902
Finding
Eczema is a form of dermatitis. The term eczema is broadly applied to a range of persistent skin conditions and can be related to a number of underlying conditions. Manifestations of eczema can include dryness and recurring skin rashes with redness, skin edema, itching and dryness, crusting, flaking, blistering, cracking, oozing, or bleeding.
Fair hair
MedGen UID:
500923
Concept ID:
CN002075
Finding
A lesser degree of hair pigmentation than would otherwise be expected.
Scleroderma
MedGen UID:
451684
Concept ID:
CN117220
Finding
A chronic autoimmune phenomenon characterized by fibrosis (or hardening) and vascular alterations of the skin.
Malformation of the heart and great vessels
MedGen UID:
428300
Concept ID:
CN002327
Finding
Congenital malformation of the heart or great vessels (i.e., the large blood vesslesentering and leaving the heart: aorta, the pulmonary arteries and veins, and the superior and inferior vena cava).
Aminoaciduria
MedGen UID:
425142
Concept ID:
CN003029
Finding
An increased concentration of an `amino acid` (CHEBI:33709 ) in the `urine` (FMA:12274).
Hyperphenylalaninemia
MedGen UID:
505720
Concept ID:
CN004366
Finding
An increased concentration of `L-phenylalanine` (CHEBI:17295) in the `blood` (FMA:9670).
Reduced phenylalanine hydroxylase activity
MedGen UID:
428606
Concept ID:
CN005271
Finding
A reduction in `phenylalanine 4-monooxygenase activity` (GO:0004505).
Maternal hyperphenylalaninemia
MedGen UID:
451908
Concept ID:
CN117502
Finding
A medical history of exposure during the fetal period to hyperphenylalaninemia because the mother had phenylketonuria with inadequate control during pregnancy.

Professional guidelines

PubMed

Singh RH, Rohr F, Frazier D, Cunningham A, Mofidi S, Ogata B, Splett PL, Moseley K, Huntington K, Acosta PB, Vockley J, Van Calcar SC
Genet Med 2014 Feb;16(2):121-31. Epub 2014 Jan 2 doi: 10.1038/gim.2013.179. [Epub ahead of print] PMID: 24385075Free PMC Article
Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA
Genet Med 2014 Feb;16(2):188-200. Epub 2013 Oct 10 doi: 10.1038/gim.2013.157. [Epub ahead of print] PMID: 24385074
Zschocke J, Haverkamp T, Møller LB
Eur J Hum Genet 2012 Feb;20(2) Epub 2011 Sep 14 doi: 10.1038/ejhg.2011.172. [Epub ahead of print] PMID: 21915151Free PMC Article
US Preventive Services Task Force
Ann Fam Med 2008 Mar-Apr;6(2):166. doi: 10.1370/afm.820. PMID: 18332411Free PMC Article

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. [Epub ahead of print] PMID: 24667081

Recent clinical studies

Etiology

Walkowiak J, Cofta S, Mozrzymas R, Siwinska-Mrozek Z, Nowak J, Kaluzny L, Banasiewicz T
Eur Rev Med Pharmacol Sci 2013 Nov;17(22):3056-9. PMID: 24302186
Procházková D, Jarkovský J, Vinohradská H, Konečná P, Machačová L, Doležel Z
Biol Trace Elem Res 2013 Aug;154(2):178-84. Epub 2013 Jun 15 doi: 10.1007/s12011-013-9724-6. [Epub ahead of print] PMID: 23771645
Webster D, Wildgoose J
Cochrane Database Syst Rev 2013 Jun 5;6:CD001507. doi: 10.1002/14651858.CD001507.pub3. PMID: 23737086
Somaraju UR, Merrin M
Cochrane Database Syst Rev 2012 Dec 12;12:CD008005. doi: 10.1002/14651858.CD008005.pub3. PMID: 23235653
Kanzelmeyer N, Tsikas D, Chobanyan-Jürgens K, Beckmann B, Vaske B, Illsinger S, Das AM, Lücke T
Amino Acids 2012 May;42(5):1765-72. Epub 2011 Apr 7 doi: 10.1007/s00726-011-0892-4. [Epub ahead of print] PMID: 21472412

Diagnosis

Liu X, Guo H, Dahal M, Shi B
BMJ Case Rep 2013 Sep 24;2013 doi: 10.1136/bcr-2013-010270. PMID: 24068375
Murad H, Dabboul A, Moassas F, Alasmar D, Al-Achkar W
Gene 2013 Oct 10;528(2):241-7. Epub 2013 Jul 12 doi: 10.1016/j.gene.2013.07.001. [Epub ahead of print] PMID: 23856132
Webster D, Wildgoose J
Cochrane Database Syst Rev 2013 Jun 5;6:CD001507. doi: 10.1002/14651858.CD001507.pub3. PMID: 23737086
Jeong JS, Kim SK, Park SR
Anal Bioanal Chem 2013 Oct;405(25):8063-72. Epub 2013 May 15 doi: 10.1007/s00216-013-6999-6. [Epub ahead of print] PMID: 23673571
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Therapy

Cleary M, Trefz F, Muntau AC, Feillet F, van Spronsen FJ, Burlina A, Bélanger-Quintana A, Giżewska M, Gasteyger C, Bettiol E, Blau N, MacDonald A
Mol Genet Metab 2013 Dec;110(4):418-23. Epub 2013 Sep 9 doi: 10.1016/j.ymgme.2013.09.001. [Epub ahead of print] PMID: 24090706
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Procházková D, Jarkovský J, Vinohradská H, Konečná P, Machačová L, Doležel Z
Biol Trace Elem Res 2013 Aug;154(2):178-84. Epub 2013 Jun 15 doi: 10.1007/s12011-013-9724-6. [Epub ahead of print] PMID: 23771645
Webster D, Wildgoose J
Cochrane Database Syst Rev 2013 Jun 5;6:CD001507. doi: 10.1002/14651858.CD001507.pub3. PMID: 23737086
Somaraju UR, Merrin M
Cochrane Database Syst Rev 2012 Dec 12;12:CD008005. doi: 10.1002/14651858.CD008005.pub3. PMID: 23235653

Prognosis

Jahja R, Huijbregts SC, de Sonneville LM, van der Meere JJ, van Spronsen FJ
J Pediatr 2014 Apr;164(4):895-899.e2. Epub 2014 Jan 30 doi: 10.1016/j.jpeds.2013.12.015. [Epub ahead of print] PMID: 24485821
White DA, Antenor-Dorsey JA, Grange DK, Hershey T, Rutlin J, Shimony JS, McKinstry RC, Christ SE
Mol Genet Metab 2013 Nov;110(3):213-7. Epub 2013 Jul 19 doi: 10.1016/j.ymgme.2013.07.010. [Epub ahead of print] PMID: 23928118Free PMC Article
Murad H, Dabboul A, Moassas F, Alasmar D, Al-Achkar W
Gene 2013 Oct 10;528(2):241-7. Epub 2013 Jul 12 doi: 10.1016/j.gene.2013.07.001. [Epub ahead of print] PMID: 23856132
Burton BK, Leviton L, Vespa H, Coon H, Longo N, Lundy BD, Johnson M, Angelino A, Hamosh A, Bilder D
Mol Genet Metab 2013 Jan;108(1):8-12. Epub 2012 Nov 15 doi: 10.1016/j.ymgme.2012.11.003. [Epub ahead of print] PMID: 23266195
Fonnesbeck CJ, McPheeters ML, Krishnaswami S, Lindegren ML, Reimschisel T
J Inherit Metab Dis 2013 Sep;36(5):757-66. Epub 2012 Nov 30 doi: 10.1007/s10545-012-9564-0. [Epub ahead of print] PMID: 23197105

Clinical prediction guides

Jahja R, Huijbregts SC, de Sonneville LM, van der Meere JJ, van Spronsen FJ
J Pediatr 2014 Apr;164(4):895-899.e2. Epub 2014 Jan 30 doi: 10.1016/j.jpeds.2013.12.015. [Epub ahead of print] PMID: 24485821
Walkowiak J, Cofta S, Mozrzymas R, Siwinska-Mrozek Z, Nowak J, Kaluzny L, Banasiewicz T
Eur Rev Med Pharmacol Sci 2013 Nov;17(22):3056-9. PMID: 24302186
Murad H, Dabboul A, Moassas F, Alasmar D, Al-Achkar W
Gene 2013 Oct 10;528(2):241-7. Epub 2013 Jul 12 doi: 10.1016/j.gene.2013.07.001. [Epub ahead of print] PMID: 23856132
Gramer G, Förl B, Springer C, Weimer P, Haege G, Mackensen F, Müller E, Völcker HE, Hoffmann GF, Lindner M, Krastel H, Burgard P
Mol Genet Metab 2013 Jan;108(1):1-7. Epub 2012 Oct 30 doi: 10.1016/j.ymgme.2012.10.021. [Epub ahead of print] PMID: 23219290
Fonnesbeck CJ, McPheeters ML, Krishnaswami S, Lindegren ML, Reimschisel T
J Inherit Metab Dis 2013 Sep;36(5):757-66. Epub 2012 Nov 30 doi: 10.1007/s10545-012-9564-0. [Epub ahead of print] PMID: 23197105

Recent systematic reviews

Lohner S, Fekete K, Decsi T
Nutr Res 2013 Jul;33(7):513-20. Epub 2013 Jun 10 doi: 10.1016/j.nutres.2013.05.003. [Epub ahead of print] PMID: 23827125
Webster D, Wildgoose J
Cochrane Database Syst Rev 2013 Jun 5;6:CD001507. doi: 10.1002/14651858.CD001507.pub3. PMID: 23737086
Eijgelshoven I, Demirdas S, Smith TA, van Loon JM, Latour S, Bosch AM
Mol Genet Metab 2013 Jul;109(3):237-42. Epub 2013 May 10 doi: 10.1016/j.ymgme.2013.05.003. [Epub ahead of print] PMID: 23731533
Fonnesbeck CJ, McPheeters ML, Krishnaswami S, Lindegren ML, Reimschisel T
J Inherit Metab Dis 2013 Sep;36(5):757-66. Epub 2012 Nov 30 doi: 10.1007/s10545-012-9564-0. [Epub ahead of print] PMID: 23197105
Somaraju UR, Merrin M
Cochrane Database Syst Rev 2012 Dec 12;12:CD008005. doi: 10.1002/14651858.CD008005.pub3. PMID: 23235653

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