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Phenylketonuria(PKU)

MedGen UID:
19244
Concept ID:
C0031485
Disease or Syndrome
Synonyms: Classic phenylketonuria; Folling disease; Oligophrenia phenylpyruvica; Phenylalanine Hydroxylase Deficiency; Phenylalanine hydroxylase deficiency; Phenylketonurias; PKU
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
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 homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): PAH (12q23.2)
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 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  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
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

Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Finding
Aggressive behavior can denote verbal aggression, physical aggression against objects, physical aggression against people, and may also include aggression towards oneself.
Anxiety
MedGen UID:
1613
Concept ID:
C0003467
Finding
Fear and anxiety are part of life. You may feel anxious before you take a test or walk down a dark street. This kind of anxiety is useful - it can make you more alert or careful. It usually ends soon after you are out of the situation that caused it. But for millions of people in the United States, the anxiety does not go away, and gets worse over time. They may have chest pains or nightmares. They may even be afraid to leave home. These people have anxiety disorders. Types include. -Panic disorder . -Obsessive-compulsive disorder . -Post-traumatic stress disorder . -Phobias . -Generalized anxiety disorder . Treatment can involve medicines, therapy or both. NIH: National Institute of Mental Health .
Scleroderma
MedGen UID:
3770
Concept ID:
C0011644
Finding
Scleroderma means hard skin. It is a group of diseases that cause abnormal growth of connective tissue. Connective tissue is the material inside your body that gives your tissues their shape and helps keep them strong. In scleroderma, the tissue gets hard or thick. It can cause swelling or pain in your muscles and joints. Symptoms of scleroderma include . - Calcium deposits in connective tissues. - Raynaud's phenomenon, a narrowing of blood vessels in the hands or feet. - Swelling of the esophagus, the tube between your throat and stomach. - Thick, tight skin on your fingers. - Red spots on your hands and face . No one knows what causes scleroderma. It is more common in women. It can be mild or severe. Doctors diagnose scleroderma using your medical history, a physical exam, lab tests, and a skin biopsy. There is no cure, but various treatments can control symptoms and complications. . NIH: National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Eczematous rash
MedGen UID:
3968
Concept ID:
C0013595
Finding
Eczema is a term for several different types of skin swelling. Eczema is also called dermatitis. It is not dangerous, but most types cause red, swollen and itchy skin. Factors that can cause eczema include other diseases, irritating substances, allergies and your genetic makeup. Eczema is not contagious. The most common type of eczema is atopic dermatitis. It is an allergic condition that makes your skin dry and itchy. It is most common in babies and children. Eczema is a chronic disease. You can prevent some types of eczema by avoiding irritants, stress, and the things you are allergic to.
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Finding
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Finding
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Microcephalus
MedGen UID:
44422
Concept ID:
C0025958
Finding
A congenital abnormality in which the CEREBRUM is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (Desk Reference for Neuroscience, 2nd ed.)
Psychosis
MedGen UID:
19568
Concept ID:
C0033975
Finding
Psychotic disorders are severe mental disorders that cause abnormal thinking and perceptions. People with psychoses lose touch with reality. Two of the main symptoms are delusions and hallucinations. Delusions are false beliefs, such as thinking that someone is plotting against you or that the TV is sending you secret messages. Hallucinations are false perceptions, such as hearing, seeing, or feeling something that is not there. Schizophrenia is one type of psychotic disorder. People with bipolar disorder may also have psychotic symptoms. Other problems that can cause psychosis include alcohol and some drugs, brain tumors, brain infections, and stroke. Treatment depends on the cause of the psychosis. It might involve drugs to control symptoms and talk therapy. Hospitalization is an option for serious cases where a person might be dangerous to himself or others.
Self-mutilation
MedGen UID:
19925
Concept ID:
C0036601
Finding
Deliberate self-injurious behavior causing tissue damage with the intent of causing nonfatal injury to attain relief of tension
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Finding
A cataract is a clouding of the lens in your eye. It affects your vision. Cataracts are very common in older people. By age 80, more than half of all Americans either have a cataract or have had cataract surgery. A cataract can occur in either or both eyes. It cannot spread from one eye to the other. Common symptoms are. -Blurry vision. -Colors that seem faded. -Glare - headlights, lamps or sunlight may seem too bright. You may also see a halo around lights. -Not being able to see well at night. -Double vision . -Frequent prescription changes in your eye wear . Cataracts usually develop slowly. New glasses, brighter lighting, anti-glare sunglasses or magnifying lenses can help at first. Surgery is also an option. It involves removing the cloudy lens and replacing it with an artificial lens. Wearing sunglasses and a hat with a brim to block ultraviolet sunlight may help to delay cataracts. NIH: National Eye Institute.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Dry skin
MedGen UID:
56250
Concept ID:
C0151908
Finding
Skin characterized by the lack of natural or normal moisture.
Aminoaciduria
MedGen UID:
116067
Concept ID:
C0238621
Finding
An increased concentration of an amino acid in the urine.
Blonde hair
MedGen UID:
116090
Concept ID:
C0239801
Finding
A lesser degree of hair pigmentation than would otherwise be expected.
Cerebral calcification
MedGen UID:
124360
Concept ID:
C0270685
Finding
The presence of calcium deposition within brain structures.
Impaired cognition
MedGen UID:
90932
Concept ID:
C0338656
Finding
a condition where a person has problems with the ability to think and learn
Blue irides
MedGen UID:
108297
Concept ID:
C0578626
Finding
A markedly blue coloration of the iris.
Obsessive-compulsive behavior
MedGen UID:
109373
Concept ID:
C0600104
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).
Phenylketonuria
MedGen UID:
199655
Concept ID:
C0751434
Finding
A reduction in phenylalanine 4-monooxygenase activity.
Hyperphenylalaninemia, non-pku
MedGen UID:
155558
Concept ID:
C0751435
Finding
An increased concentration of L-phenylalanine in the blood.
Attention deficit hyperactivity disorder
MedGen UID:
220387
Concept ID:
C1263846
Finding
Is it hard for your child to sit still? Does your child act without thinking first? Does your child start but not finish things? If so, your child may have attention deficit hyperactivity disorder (ADHD). Nearly everyone shows some of these behaviors at times, but ADHD lasts more than 6 months and causes problems in school, at home and in social situations. ADHD is more common in boys than girls. It affects 3-5 percent of all American children. The main features of ADHD are. -Inattention. -Hyperactivity. -Impulsivity. No one knows exactly what causes ADHD. It sometimes runs in families, so genetics may be a factor. There may also be environmental factors. A complete evaluation by a trained professional is the only way to know for sure if your child has ADHD. Treatment may include medicine to control symptoms, therapy, or both. Structure at home and at school is important. Parent training may also help. NIH: National Institute of Mental Health .
Generalized hypopigmentation
MedGen UID:
340426
Concept ID:
C1849923
Finding
Phenylpyruvic acidemia
MedGen UID:
376669
Concept ID:
C1849926
Finding
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Finding
A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medical condition.
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.

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; 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. [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

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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

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Cochrane Database Syst Rev 2015 Mar 27;3:CD008005. doi: 10.1002/14651858.CD008005.pub4. PMID: 25812600
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Cochrane Database Syst Rev 2015 Feb 27;2:CD004731. doi: 10.1002/14651858.CD004731.pub4. PMID: 25723866
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Gynecol Endocrinol 2014 Oct;30(10):691-3. Epub 2014 Jun 13 doi: 10.3109/09513590.2014.928688. [Epub ahead of print] PMID: 24927077

Diagnosis

Wyrwich KW, Auguste P, Yu R, Zhang C, Dewees B, Winslow B, Yu S, Merilainen M, Prasad S
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Indian Pediatr 2015 May;52(5):397-401. PMID: 26061925
Seki M, Takizawa T, Suzuki S, Shimizu T, Shibata H, Ishii T, Hasegawa T, Suzuki N
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Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N
Eur J Hum Genet 2015 Mar;23(3):302-9. Epub 2014 Jun 18 doi: 10.1038/ejhg.2014.114. [Epub ahead of print] PMID: 24939588Free PMC Article
Aldámiz-Echevarría L, Couce ML, Llarena M, Andrade F
Gynecol Endocrinol 2014 Oct;30(10):691-3. Epub 2014 Jun 13 doi: 10.3109/09513590.2014.928688. [Epub ahead of print] PMID: 24927077

Therapy

Wyrwich KW, Auguste P, Yu R, Zhang C, Dewees B, Winslow B, Yu S, Merilainen M, Prasad S
Value Health 2015 Jun;18(4):404-12. Epub 2015 Apr 4 doi: 10.1016/j.jval.2015.01.008. [Epub ahead of print] PMID: 26091594
Somaraju UR, Merrin M
Cochrane Database Syst Rev 2015 Mar 27;3:CD008005. doi: 10.1002/14651858.CD008005.pub4. PMID: 25812600
Yi SH, Singh RH
Cochrane Database Syst Rev 2015 Feb 27;2:CD004731. doi: 10.1002/14651858.CD004731.pub4. PMID: 25723866
Aldámiz-Echevarría L, Couce ML, Llarena M, Andrade F
Gynecol Endocrinol 2014 Oct;30(10):691-3. Epub 2014 Jun 13 doi: 10.3109/09513590.2014.928688. [Epub ahead of print] PMID: 24927077
Grange DK, Hillman RE, Burton BK, Yano S, Vockley J, Fong CT, Hunt J, Mahoney JJ, Cohen-Pfeffer JL; Phenylketonuria Demographics Outcomes and Safety (PKUDOS) registry; Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry
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Prognosis

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Eur J Hum Genet 2015 Mar;23(3):302-9. Epub 2014 Jun 18 doi: 10.1038/ejhg.2014.114. [Epub ahead of print] PMID: 24939588Free PMC Article
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Pimentel FB, Alves RC, Costa AS, Torres D, Almeida MF, Oliveira MB
Food Chem 2014 Apr 15;149:144-50. Epub 2013 Oct 31 doi: 10.1016/j.foodchem.2013.10.099. [Epub ahead of print] PMID: 24295688
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

Clinical prediction guides

Wyrwich KW, Auguste P, Yu R, Zhang C, Dewees B, Winslow B, Yu S, Merilainen M, Prasad S
Value Health 2015 Jun;18(4):404-12. Epub 2015 Apr 4 doi: 10.1016/j.jval.2015.01.008. [Epub ahead of print] PMID: 26091594
Soleymani Z, Keramati N, Rohani F, Jalaei S
Indian Pediatr 2015 May;52(5):397-401. PMID: 26061925
Seki M, Takizawa T, Suzuki S, Shimizu T, Shibata H, Ishii T, Hasegawa T, Suzuki N
J Clin Neurosci 2015 Aug;22(8):1361-3. Epub 2015 Apr 23 doi: 10.1016/j.jocn.2015.02.011. [Epub ahead of print] PMID: 25913748
Wettstein S, Underhaug J, Perez B, Marsden BD, Yue WW, Martinez A, Blau N
Eur J Hum Genet 2015 Mar;23(3):302-9. Epub 2014 Jun 18 doi: 10.1038/ejhg.2014.114. [Epub ahead of print] PMID: 24939588Free PMC Article
Grange DK, Hillman RE, Burton BK, Yano S, Vockley J, Fong CT, Hunt J, Mahoney JJ, Cohen-Pfeffer JL; Phenylketonuria Demographics Outcomes and Safety (PKUDOS) registry; Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry
Mol Genet Metab 2014 May;112(1):9-16. Epub 2014 Mar 12 doi: 10.1016/j.ymgme.2014.02.016. [Epub ahead of print] PMID: 24667082

Recent systematic reviews

Somaraju UR, Merrin M
Cochrane Database Syst Rev 2015 Mar 27;3:CD008005. doi: 10.1002/14651858.CD008005.pub4. PMID: 25812600
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Cochrane Database Syst Rev 2015 Feb 27;2:CD004731. doi: 10.1002/14651858.CD004731.pub4. PMID: 25723866
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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
Webster D, Wildgoose J
Cochrane Database Syst Rev 2013 Jun 5;6:CD001507. doi: 10.1002/14651858.CD001507.pub3. PMID: 23737086
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