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Phenylketonuria is a well-known and recognized autosomal recessive disorder of phenylalanine metabolism that if not detected early may lead to mental retardation. The disorder is characterized by high serum levels of phenylalanine.


The cardinal clinical feature is mental retardation. The patients are asymptomatic until the initiation of dietary phenylalanine. Currently the overt phenylketonuria is rare with the advent of widespread screening at birth. If missed the symptoms are insidious until early infancy, with delayed milestones. The children also suffer from the other neurological diseases such as epilepsy. There is also be a “mosy” smell in urine due to the metabolite phenylacetic acid.

Progressive Mental Retardation
  • Phenylketonuria (PKU) is characterized by phenylalanine accumulation and progressive mental retardation caused by an unknown mechanism.[ncbi.nlm.nih.gov]
  • If untreated, the disorder can cause brain damage and progressive mental retardation as a result of the accumulation of phenylalanine and its breakdown products. Link/Cite Link to this page Cite this page MLA Style "phenylketonuria."[yourdictionary.com]
  • Følling practiced, Borgny and Harry Egeland had two children, ages four and six, with progressive mental retardation in 1934. The children expressed physical debilitations beyond overt mental handicaps.[doi.org]
  • Abstract Phenylketonuria (PKU) is characterized by phenylalanine accumulation and progressive mental retardation caused by an unknown mechanism.[doi.org]
  • Untreated individuals have very fair hair, eczema, a mousy odor of the urine and skin, and progressive mental retardation. Treatment consists of a diet low in phenylalanine.[medical-dictionary.thefreedictionary.com]
  • This 2-year-old boy was first hospitalized for bilious vomiting and moderate back pain. Laboratory values included a lipase level of 1.142 U/L, a phenylalanine level of 10mg/dL, and computed tomography revealed Balthazar grade E pancreatitis.[ncbi.nlm.nih.gov]
  • Clinical description In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty[orpha.net]
  • . • Other symptoms include:  Eczema  Recurrent vomiting  Jerking movements in arms and legs  Tremors  Mood disorders  Microcephaly, 6.[slideshare.net]
  • Occasionally, because of the severity of the nausea and vomiting and lack of appetite associated with early pregnancy, women with PKU are hospitalized for nutrition. Usually, intravenous (I.V.) nutrition is administered.[web.archive.org]
  • ADVERSE REACTIONS The most common adverse reactions (at least 20% of patients in either treatment phase) were injection site reactions, arthralgia, hypersensitivity reactions, headache, generalized skin reaction lasting at least 14 days, pruritus, nausea[investors.biomarin.com]
  • The most common adverse events reported in the Palynziq trials included injection site reactions, joint pain, hypersensitivity reactions, headache, generalized skin reactions lasting at least 14 days, pruritus (itchy skin), nausea, dizziness, abdominal[fda.gov]
  • When maternal blood Phe levels fall below 2 mg/dL, anecdotal reports indicate that the mothers may suffer adverse effects, including headaches, nausea, hair loss, and general malaise.[en.wikipedia.org]
  • Clinical features in the untreated patient include mental retardation, defects in executive functioning, seizures, and eczema. Caused by a deficiency of hepatic phenylalanine hydroxylase activity.[bestpractice.bmj.com]
  • Clinical features in the untreated patient include intellectual disability, defects in executive functioning, seizures, and eczema. Caused by a deficiency of hepatic phenylalanine hydroxylase activity.[bestpractice.bmj.com]
  • The resulting buildup of phenylalanine in the body causes mental retardation, mental disturbances, eczema and skin pigmentation. Category › Disease Graphical[uniprot.org]
  • Clinical description In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty[orpha.net]
  • […] the accumulation of phenylalanine and its metabolites (as phenylpyruvic acid ) in the blood and their excess excretion in the urine, that is inherited as an autosomal recessive trait, and that causes usually severe intellectual disability, seizures, eczema[merriam-webster.com]
Blonde Hair
  • This may explain why persons with phenylketonuria generally have blond hair, blue eyes, and fair skin. Phenylketonuria is transmitted by an autosomal recessive gene, which is present in about 1 in every 60 people.[britannica.com]
  • As a result, children with PKU often will have pale skin, blond hair and blue eyes. Dry skin; eczema; and a "musty" odor resulting from the buildup of phenylalanine in hair, skin and urine are also common.[drugs.com]
  • hair Irritability, restlessness, hyperactivity Diagnosis Phenylketonuria is diagnosed by a blood test, usually as part of the routine screening tests given to a newborn within the first few days of life.[rarediseases.about.com]
  • It has been shown that almost 90% of affected people have light coloration such as blond hair and blue eyes. Signs also include skeletal changes such as a small head, short stature, and flat feet.[web.archive.org]
  • チュウスウシンケイケイシッカン, central nervous system disease, 054490, 濃度, ノウド, concentration(ratio), 001225, concentration, 度, ド, degree, 046047, 作用, サヨウ, action and effect, 046464, 免疫反応, メンエキハンノウ, immunological reaction, 012548, 反応, ハンノウ, reaction, 007110, 発疹, ホッシン, exanthema[togodb.biosciencedbc.jp]
  • Here we report an adult patient who developed generalized seizures later in life, despite strict dietary control, and whose seizures were aggravated by levetiracetam (LEV).[ncbi.nlm.nih.gov]
  • ˌfe-nᵊl-ˌkē-tᵊn-ˈu̇r-ē-ə, ˌfē-, -ˈyu̇r- \ Definition of phenylketonuria : an inherited metabolic disorder caused by an enzyme deficiency resulting in accumulation of phenylalanine and its metabolites in the blood causing usually severe intellectual disability and seizures[merriam-webster.com]
  • PKU should be considered as an important differential in the diagnosis of adult patients with learning difficulties, seizures and behavioural problems.[ncbi.nlm.nih.gov]
  • This can cause mental retardation, behavioral and movement problems, seizures, and delayed development.[icd9data.com]
  • Untreated PKU is associated with an abnormal phenotype which includes growth failure, poor skin pigmentation, microcephaly, seizures, global developmental delay and severe intellectual impairment.[ncbi.nlm.nih.gov]
  • Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety.[ncbi.nlm.nih.gov]
  • […] included hair hypopigmentation, microcephaly, severe mental retardation with absent development of verbal language and autistic symptoms in all three patients, whereas variable neurological signs such as seizures, spasticity, ataxia, aggressivity, and hyperactivity[ncbi.nlm.nih.gov]
  • Progressively, both sisters exhibited odd behaviour, accompanied by personality changes and altered sleep rhythm and then were diagnosed as attention deficit hyperactivity disorder.[ncbi.nlm.nih.gov]
  • He was previously observed as having severe challenging and self-injurious behaviour, sleeping disorder, hyperactivity, and masturbation.[ncbi.nlm.nih.gov]
  • ADHD (attention-deficit hyperactivity disorder) appears to be a common problem in those who do not stick to a very low-phenylalanine diet. Call your health care provider if your infant has not been tested for PKU.[nlm.nih.gov]
Profound Mental Retardation
  • This early detection and development of a PKU diet has saved many infants from the profound mental retardation that families like the Egelands suffered prior to Dr.[web.archive.org]
  • When PKU is not diagnosed until this late age, serious damage has usually already occurred. 4 Initial estimates of the frequency of PKU (one per 25,000 live births) were based on institutionalized populations with profound mental retardation caused by[aafp.org]
  • A 36-year-old male patient with PKU presented with signs of cerebellar disease including dysmetria, resting tremor, and intention tremor in the left upper extremity.[ncbi.nlm.nih.gov]
Tic Disorder
  • Compared to GP, PKU was associated with significantly higher prevalence for numerous neuropsychiatric conditions, most notably for intellectual disability (PR 7.9, 95% CI: 6.4-9.9), autism spectrum disorder (PR 6.1, 95% CI: 3.6-10.4), Tourette/tic disorders[ncbi.nlm.nih.gov]


Screening is usually done in the first week of life. This is done by checking the phenylalanine and tyrosine levels. Blood levels are typically high (>20g/dl), but the wide variability in the phenylalanine levels over a 24 hour period may necessitate repeat sampling [6].

Laboratory studies

The most useful method is via tandem-mass spectrometry, as this method can also measure other amino acid levels such as tyrosine. Any abnormal levels will require immediate action and appropriate referral


There is white matter injury apparent on phenylketonuria patients. The severity of the injury is related to the treatment status. There are new techniques that may be able to estimate the phenylalanine level on magnetic resonance spectroscopy.

Genetic testing

Molecular analysis may be used to identify mutations on the enzyme locus and predict enzyme activity in some cases. All patients with a diagnosis of phenylketonuria require genetic counselling.

Phenylalanine Increased
  • In a PKU pregnancy large quantities of phenylalanine metabolites were found in urine despite a modest elevation of serum phenylalanine.[doi.org]


Management of patients with phenylketonuria should be provided by an experienced team of nutritionists, social workers, psychologists, metabolic specialists, and pediatricians [7].


The mainstay of therapy is dietary restriction of phenylalanine. This requires use of feeds that are deficient in phenylalanine, (with tyrosine supplementation) but supply adequate nutrition. These substitutes have to meet the requirement for development and optimal growth. Phenylalanine level are followed closely from initially one to two times a week and once a month in the older children and adults (but this is subject to local guidelines). Normal levels being the desired targets. Compliance may be an issue in older children and adults due to the poor taste of these substitutes and supplements. The diet restriction are for life for optimal outcomes.

There are currently a number of other strategies are being developed especially for patients who cannot adhere to the strict diet. It has been noted that ingestion of large amounts of neutral amino acids maybe beneficial by competing with phenylalanine at the blood brain barrier [8].


Patients with residual activity may benefit from administration of tetrahydrobiopterin (BH4) cofactor [9]. Upcoming treatments include Phenylalanine ammonia lyase, which is injectable. It is currently in the testing phase, but the optimism is guarded currently and more testing will be required.


The prognosis is excellent if the condition is identified early and the correct management is instituted and maintained strictly. There is a direct relationship between the phenylalanine levels and IQ levels especially in the early years when there is brain development. If left untreated the intellectual disability can be substantial.


Deficiency of the hepatic enzyme phenylalanine hydroxylase causes accumulation of phenylalanine and its metabolites. Phenylalanine hydroxylase is required for the conversion of the amino acid phenylalanine to tyrosine with tetrahydrobiopterin (deficiency of tetrahydrobiopterin accounts for about 2% of phenylketonuria) being used as a co-factor necessary for the activity of phenylalanine hydroxylase.


The incidence of this condition is approximately 1 in every 13,550 to 19,000 births and is less common in individuals of African descent. Information from intellectual disability clinics show 0.04-1% of the patients are affected by phenylketonuria.

Sex distribution
Age distribution


The enzyme accounts for about two thirds of the disposal of the amino acid with the rest being used protein synthesis [2]. The tyrosine levels are usually normal to low. The extent of the deficiency depends on the enzyme activity, complete deficiency causes phenylketonuria, with residual enzyme activity causing mild phenylketonuria.

In total enzyme deficiency usual results in serum levels of phenylalanine above 20mg/dl. Residual activity lead to levels to of about 10 to 20mg/dl [3].
The mechanism of mental retardation of is not known, but a number of theories have been proposed including, oxidative stress, affecting neuronal development. Other theories postulate metabolites of phenylalanine (phenylacetate and phenylpyruvate) which may inhibit neuronal growth [4].


Individuals with a strong family history of this enzyme deficiency need be tested and get counselled (genetic) before conceiving. [10]


Phenylketonuria is an inborn error in the metabolism of the aromatic amino acid phenylalanine. It is caused by the deficiency of a liver enzyme that causes accumulation of the amino acid. The enzyme is called phenylalanine hydroxylase. If not identified early can lead to mental retardation [1].
It has autosomal recessive mode of inheritance, with mutations in the gene coding for phenylalanine hydroxylase located on chromosome 12. More than 400 mutations have been identified.

Patient Information

Definition: Phenylketonuria is a genetic disease that is caused by a deficiency in an enzyme that breaks down a dietary protein building block (amino acid) called phenylalanine. Lack of this enzyme means that body cannot break this amino acid down and it accumulates with the body causing symptoms, mostly to the brain.

Cause: It is caused by a deletion in the gene that gives the instruction for making the enzyme. This deletion is passed down from parents (who are carriers and sufferers) to their children.

Symptoms: Patients with phenylketonuria suffer from mental retardation due to the high levels of the phenylalanine hindering brain development, especially in the younger years when the brain is growing. The bones may also be affected. Patients may have delayed milestones, such as sitting, walking and speech development. They may also suffer from seizures and have behavioral problems.

Diagnosis: It is diagnosed by a blood test that is done during the first week of life.

Treatment and follow-up: Treatment involves many people, but the mainstay of treatment is total restriction of food that contain the amino acid phenylalanine. This is done by giving medical substitutes that contain all the other necessary proteins and nutrients required for optimal growth and deployment. If the diet is followed the patients are expected to have normal intellect and lives. Anybody diagnosed will require genetic testing and counselling before they can have a baby. Regular testing of the phenylalanine is required to monitor progress of the patients.



  1. Santos LL, Castro-Magalhaes M, Fonseca CG, et al. PKU in Minas Gerais State, Brazil: mutation analysis. Ann Hum Genet. Nov 2008;72:774-9.
  2. Bosch AM, Tybout W, van Spronsen FJ, de Valk HW, Wijburg FA, Grootenhuis MA. The course of life and quality of life of early and continuously treated Dutch patients with phenylketonuria. J Inherit Metab Dis. Feb 2007;30(1):29-34.
  3. Guldberg P, Henriksen KF, Sipila I, Guttler F, de la Chapelle A. Phenylketonuria in a low incidence population: molecular characterisation of mutations in Finland. J Med Genet. Dec 1995;32(12):976-8.
  4. Ounap K, Lillevali H, Metspalu A, Lipping-Sitska M. Development of the phenylketonuria screening programme in Estonia. J Med Screen. 1998;5(1):22-3.
  5. Bodamer OA. Screening for phenylketonuria. In: Phenylketonuria: Special Issue: Annales Nestle, English ed, Lentze MJ (Ed), S Karger Pub, 2010. Vol Vol 68, No 2, p.53.
  6. Cerone R, Schiaffino MC, Di Stefano S, Veneselli E. Phenylketonuria: diet for life or not? Acta Paediatr 1999; 88:664.
  7. Lambruschini N, Pérez-Dueñas B, Vilaseca MA, et al. Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy. Mol Genet Metab 2005; 86 Suppl 1:S54.
  8. Abadie V, Berthelot J, Feillet F, et al. [Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. Arch Pediatr 2005; 12:594.
  9. Shintaku H. Disorders of tetrahydrobiopterin metabolism and their treatment. Curr Drug Metab 2002; 3:123.
  10. Keil S, Anjema K, van Spronsen FJ, Lambruschini N, Burlina A, Bélanger-Quintana A, et al. Long-term Follow-up and Outcome of Phenylketonuria Patients on Sapropterin: A Retrospective Study. Pediatrics. Jun 2013;131(6):e1881-8.

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Last updated: 2019-07-11 21:49