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Dermatology > PEDIATRIC DISEASES
Phenylketonuria
Article Last Updated: Sep 20, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Zeljko P Mijuskovic, MD, Consulting Staff, Department of Dermatology and Venereology, Military Medical Academy, Belgrade, Serbia
Zeljko P Mijuskovic is a member of the following medical societies: European Academy of Dermatology and Venereology and International Society of Dermatology
Coauthor(s):
Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro;
Ljubomir Stojanov, MD, PhD, Mother and Child Health Care Institute, Professor, Department of Metabolic and Genetic, University of Belgrade School of Medicine, Serbia
Editors: Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
PKU, phenylalanine hydroxylase, PAH, phenylalanine, phenylpyruvic acid, phenylacetic acid, hyperphenylalaninemia type I, Folling disease, Folling's disease, phenylpyruvic oligophrenia
Background
Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine in the plasma (>1200 µmol/L; reference range, 35-90 µmol/L) and to excretion of phenylpyruvic acid (approximately 1 g/d) and phenylacetic acid in the urine. Phenylalanine has ketogenic and gluconeogenic intermediates that contribute to the glucose pool, which can play a role in normal brain development and function. In many countries, PKU is detected by screening newborns. Patients treated with a diet low in phenylalanine can lead a normal life.
Pathophysiology
In most patients, the classic type of PKU is caused by a deficiency of PAH, resulting in increased levels of phenylalanine in body fluids. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of phenylalanine. PAH requires a nonprotein cofactor termed tetrahydrobiopterin (BH4), and the rate-limiting step in the synthesis of BH4 is guanosine triphosphate cyclohydrolase I (GTP-CH I). PAH crystallizes as a tetramer with each monomer consisting of a catalytic domain and a tetramerization domain. Examination of the mutations causing PKU reveals that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains.
Other types of PKU include PKU caused by impaired synthesis of BH4, GTP-CH I, 6-pyruvoyl tetrahydropterin (6-PTS), or dihydropteridine reductase (DHPR). Patients with the BH4 cofactor deficiency have more severe neurologic problems that are not completely corrected by the dietary reduction of phenylalanine.
The learning disabilities in patients with PKU who are adequately treated may result from reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes.
Frequency
United States
The incidence of classic PKU is approximately 1 case per 15,000 births.
International
The prevalence in the general population is approximately 4 cases per 100,000 individuals, and the incidence is 350 cases per million live births. Approximately 0.04-1% of the residents in mental retardation clinics are affected by PKU. A high incidence is reported in Turkey (approximately 1 case in 2600 births), regions of northern and eastern Europe, the Yemenite Jewish population, Italy, Estonia (1 case in 8090 births), China (1 case in 11,144 births), France (1 case in 17,000 births), and former Yugoslavia (1 case in 25,042 births). A low prevalence is reported in Finland (<1 case per 100,000 births).
Mortality/Morbidity
- Patients with PKU who are not treated have severe mental retardation.
- Psychologic problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment.
Race
PKU is common in whites and Asians and is rare in blacks.
Sex
No sexual predilection exists for PKU. Untreated maternal PKU increases the risk for developmental problems in offspring.
Age
PKU can commonly be recognized in newborns with the help of newborn-screening programs.
History
- Most patients appear healthy at birth.
- In adult patients who stop dietary treatment, neurologic dysfunction may occur.
Physical
Clinical manifestations of PKU are largely of historical interest, because the damaging features of the disease are usually prevented through early diagnosis and treatment.
- Skin
- Fair skin and hair (most characteristic skin manifestation resulting from impairment of melanin synthesis; striking in black and Japanese persons [see Image 1])
- Eczema (including atopic dermatitis)
- Light sensitivity
- Increased incidence of pyogenic infections
- Increased incidence of keratosis pilaris
- Decreased number of pigmented nevi
- Sclerodermalike plaques
- Other manifestations
- Mental retardation
- Musty odor
- Epilepsy (50%)
- Extrapyramidal manifestations, such as parkinsonism
- Eye abnormalities, such as hypopigmentation
Causes
- PKU is an autosomal recessive disorder caused by mutations at the PAH locus on bands 12q22-24.1. The PAH gene includes approximately 90 kilobase pairs and contains 13 exons. Until now, more than 400 different mutations in the PAH gene have been identified.
- Other causes of PKU include BH4 deficiency and DHPR deficiency. The former is caused by mutated alleles at 3 other loci (bands 11q22.3-23.3, 10q22, and 2p13). The latter involves abnormalities localized to bands 4p15.1-16.1.
- PKU displays a marked genotypic heterogeneity, both within populations and between different populations.
Other Problems to be Considered
Hyperphenylalaninemia
Tetrahydrobiopterin deficiency
Tyrosinemia
Liver disease
Other diseases with mental retardation
Tyrosinemia type II (Richner-Hanhart syndrome)
Childhood systemic sclerosis
Lab Studies
- Screening (enzymatic determination of phenylalanine, the standard amino acid analysis by means of ion exchange chromatography, and the Guthrie test as a bacterial inhibition assay)
- Perform screening on blood samples during the first week of life.
- Results of urine tests (ie, ferric chloride test) may be negative in the first month of life.
- Perform urinalysis of biopterin and neoptrins to exclude defects of biopterin synthesis or recycling.
- Wide variability in phenylalanine concentrations in a 24-hour period in children with PKU may require repeat screening.
Imaging Studies
- Perform cranial MRI in adults who have neurologic dysfunction; the most severely affected brain structures regarding volume loss are the cerebrum, corpus callosum, hippocampus, and pons.
- Perform cranial magnetic resonance (MR) spectroscopy to determine brain metabolite concentrations and brain compartmentation.
Other Tests
- Prenatal diagnosis is experimental. Prenatal diagnosis can be made in families at risk with the help of a combination of DNA analysis, enzyme activity, and amniotic fluid metabolite levels.
- Abnormal EEG findings may be present.
Medical Care
- Treatment with a diet low in phenylalanine and with tyrosine supplementation is required for normal psychomotor development.
- The diet should not be terminated after adolescence because strong indications exist that hyperphenylalaninemia can have detrimental effects in adult patients.
- BH4 supplementation (5-20 mg/kg) has been applied in PKU treatment, resulting in successful control of blood phenylalanine concentrations. The main problem with BH4 treatment is finding an optimal dosage at different ages and in persons with special conditions such as those with infectious diseases. It is not yet approved by US Food and Drug Association.
Consultations
- Consult a psychologist for assessment and management of mental disorders.
- Consult a nutritionist for dietary instructions.
Diet
As a result of the lack of internationally accepted guidelines, the management of PKU varies among countries. Instruct patients to do the following:
- Selectively restrict phenylalanine consumption (ie, approximately 250-550 mg/d or 40-60 mg/kg/d in newborns).
- Supplement the diet with tyrosine. However, tyrosine supplementation does not appear to alter neuropsychologic performance in individuals with PKU.
- Avoid the use of products containing aspartame (artificial sweetener). Aspartame is used widely in medicines, vitamins, beverages, and many other products.
- Eliminate all high-protein foods (eg, meat and meat products, milk and dairy products, nuts, legumes), and introduce low-protein foods (eg, fruits, vegetables, breads).
- Help with specific diet recommendations can be found at many Web sites devoted to PKU. The Web site National PKU News has extensive dietary recommendations. Links to a variety of international organizations for PKU can be found under "Related Links." Some languages available include German, Danish, Dutch, and Spanish. Food companies distributing products useful for low-protein diets are also listed.
Activity
Advise continuation of normal activity in patients who are adequately treated.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Amino acids
Tyrosine is a precursor of several neurotransmitters, including levodopa, dopamine, norepinephrine, and epinephrine.
| Drug Name | Tyrosine |
|---|
| Description | Nonessential amino acid that the body makes from phenylalanine. |
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| Adult Dose | 100 mg/kg/d PO |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | None reported |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Tyrosine supplementation does not appear to alter neuropsychologic performance in PKU |
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Further Inpatient Care
- Phenylalanine is monitored twice per week in neonates, weekly in infants, biweekly or every 3 weeks in toddlers, and monthly thereafter, even during adult life.
- During pregnancy, a weekly sampling test is recommended.
Complications
- Agoraphobia is a complication.
- For other complications, see Physical.
Prognosis
- The prognosis for normal intelligence is good when patients have been put on a diet low in phenylalanine in the first month of life.
Patient Education
- Teach patients how to initiate and continue the diet.
- Educate women with PKU about the risks of untreated pregnancy and the benefits of dietary treatment.
- The organization National PKU News is a nonprofit entity dedicated to providing up-to-date, accurate news and information to families and professionals dealing with PKU. This site contains excellent articles and links to other information sources. Information on how to subscribe to a PKU newsletter and on how to contact support groups is available. Numerous other PKU Web sites are available to assist families in search of additional information.
Medical/Legal Pitfalls
- Failure to provide an adequate phenylalanine blood level
- Failure to diagnose PKU correctly in a child with mental retardation
- Failure to perform testing for biopterin defects
- Failure to diagnose PKU correctly in a child with normal phenylalanine blood levels in only 1 sample
- Failure of the patient to comply with the diet may result in neurologic dysfunction
Special Concerns
- Surveys have revealed that maternal phenylalanine blood concentrations greater than 1200 µmol/L are associated with fetal microcephaly, congenital heart defects, and intrauterine growth retardation. Maintain maternal blood phenylalanine levels in the range of 120-360 µmol/L using dietary control. The diet should provide adequate energy, protein, vitamin, and mineral intake. Treatment at any time during pregnancy may reduce the severity of developmental delay.
| Media file 1:
Fair skin and hair resulting from impairment of melanin synthesis. |
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Media type: Photo
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Phenylketonuria excerpt Article Last Updated: Sep 20, 2006
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