Phenylketonuria (PKU) was discovered and described by Folling in 1934. It is the most common inborn error of amino acid metabolism. Deficiency of the enzyme phenylalanine hydroxylase (PAH) leads to accumulation of phenylalanine (Phe) 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. Phe 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, phenylketonuria is detected by screening newborns. Patients treated with a diet low in Phe can lead a normal life.
In most patients, the classic type of phenylketonuria (PKU) is caused by a deficiency of PAH, resulting in increased levels of Phe in body fluids. PAH catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the oxidative degradation of Phe. 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 phenylketonuria reveals that some of the most frequent mutations are located at the interface of the catalytic and tetramerization domains.
Other types of phenylketonuria include phenylketonuria 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 Phe.
The learning disabilities in patients with phenylketonuria who are adequately treated may result from reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membranes.
The incidence of classic phenylketonuria (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 phenylketonuria (PKU). A high incidence is reported in Turkey (approximately 1 case in 2,600 births), the Yemenite Jewish population (1:5,300), Scotland (1:5,300), Estonia (1:8,090),[1] Iceland (1:8,400), Hungary (1:11,000), Denmark (1:12,000), France (1:13,500), United Kingdom (1:14,300), Norway (1:14,500), China (1:17,000), Italy (1:17,000), Chile (1:18,916), Canada (1:20,000), Minas Gerais State in Brazil (1:20,000),[2] and former Yugoslavia (1:25,042).[3] A low incidence is reported in African Americans (1:50,000), Finland (< 1:100,000),[4] and Japan (1:125,000).[5]
Mortality/Morbidity
Patients with phenylketonuria (PKU) who have not been treated have severe mental retardation. Psychological problems, including agoraphobia and other disorders, have been reported in individuals both on and off dietary treatment.
Race
Phenylketonuria (PKU) is common in whites and Asians and is rare in blacks.
Sex
No sexual predilection exists for phenylketonuria (PKU). Untreated maternal PKU increases the risk for developmental problems in offspring.
Age
Phenylketonuria (PKU) can commonly be recognized in newborns with the help of newborn screening programs.
Clinical manifestations of phenylketonuria (PKU) are largely of historical interest, because the damaging features of the disease are usually prevented through early diagnosis and treatment.
Skin findings are as follows:
Fair skin and hair (most characteristic skin manifestation resulting from impairment of melanin synthesis; striking in black and Japanese persons
Note image below.
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Fair skin and hair resulting from impairment of melanin synthesis.
Eczema (including atopic dermatitis)
Light sensitivity
Increased incidence of pyogenic infections
Increased incidence of keratosis pilaris
Decreased number of pigmented nevi
Sclerodermalike plaques
Hair loss[6]
Other manifestations are as follows:
Mental retardation
Musty odor
Epilepsy (50%)[7]
Extrapyramidal manifestations (eg, parkinsonism)
Eye abnormalities (eg, hypopigmentation)
Psychological and psychiatric problems - Attentional problems, school problems, lower achievement motivation, decreased social competence, decreased autonomy, low-self-esteem[8]
Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene, which is located on band 12q23.2, spans about 171 kb, and contains 13 exons. More than 500 different mutations in the PAH gene have been identified. The PAH gene shows great allelic variation, and pathogenic mutations have been described in all 13 exons of the PAH gene and its flanking region. The mutations can be of various types, including missense mutations (62% of PAH alleles), small or large deletions (13%), splicing defects (11%), silent polymorphisms (6%), nonsense mutations (5%), and insertions (2%).[5]
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. Additionally, PKU displays a marked genotypic heterogeneity, both within populations and between different populations.
Three methods of newborn screening are currently in use: Guthrie card bacterial inhibition assay, fluorometric analysis, and tandem mass spectrometry. 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 Phe concentrations in a 24-hour period in children with phenylketonuria (PKU) may require repeat screening.
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.[9]
Perform cranial magnetic resonance spectroscopy to determine brain metabolite concentrations and brain compartmentation.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling at about 10-12 weeks' gestation.
Treatment of phenylketonuria (PKU) with a diet low in Phe and with tyrosine supplementation is required for normal psychomotor development. The diet should not be terminated after adolescence because strong evidence indicates hyperphenylalaninemia can have detrimental effects in adult patients.
As a result of the lack of internationally accepted guidelines, the management of phenylketonuria (PKU) varies among countries. Instruct patients to do the following:
Selectively restrict Phe 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, chewing gum, 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).
Supplement the diet with sufficient nutrients (eg, vitamins, long-chain polyunsaturated fatty acids) - Restricted diets in patients with PKU may alter antioxidant status as a result of deficiency of selenium or coenzyme Q10 deficiency.[10]
Advice on 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.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. An alternative enzyme therapy for phenylketonuria (PKU) has undergone trials, which involve the substitution of PAH with Phe ammonialyase, a non-cofactor – dependent plant protein involved in Phe degradation. It is currently under investigation for the potential treatment of patients with PKU who do not respond to BH4.
Research into gene therapy for the treatment of PKU has been ongoing over the last 2 decades. The focus has been on replacement of the human PAH mutant gene in somatic cells of PKU patients, because germ-line therapy, which is the most desirable and ultimate solution, still faces ethical and technical barriers.[11]
Clinical Context:
Synthetic form of (BH4), the cofactor for the enzyme PAH. PAH hydroxylates Phe through an oxidative reaction to form tyrosine. PAH activity is absent or deficient in patients with PKU. Treatment with BH4 can activate residual PAH enzyme, improve normal oxidative metabolism of Phe, and decrease Phe levels in some patients. Indicated to reduce blood Phe levels in patients with hyperphenylalaninemia caused by BH4 -responsive PKU. Used in conjunction with a Phe-restricted diet.
Clinical Context:
Tab contains essential amino acids (LNAAs), including high dosages of tyrosine and tryptophan. Too much tyrosine can cause headaches, which limits the numbers of tabs that can be consumed. Furthermore, by competitive inhibition, they also counteract uptake of Phe across the blood-brain barrier, thus reducing its impairing effect on neurotransmitter production.
The main purpose of the tabs is to create a Phe-blocking effect.
May be ideal for young adults, when compliance is poor, and for late-diagnosed patients, in whom compliance is low and in whom drinking formula can be a burden for the patient and caretakers.
Young women of childbearing age need to realize this drug does not protect their fetus from the teratogenic effects of Phe.
Tabs must be combined with a certain amount of natural protein in order for the diet to contain sufficient protein.
Because some patients are not able to adhere rigorously to the Phe-restricted diet during life, alternative treatment regimens have been developed.[12]
Phe levels are monitored twice per week in neonates, weekly in infants, biweekly or every 3 weeks in toddlers, and monthly thereafter, even during adult life. The recommended Phe treatment targets are as follows[13] :
Birth to age 4 years - Phe level of 100-350 μmol/L
Older children and adults - Phe level of greater than 600 μmol/L
Attention should be given to variability in blood Phe levels and to maintenance within the recommended range.[14]
During pregnancy, a weekly sampling test is recommended.
The prognosis for normal intelligence is good when patients have been put on a diet low in Phe in the first month of life.
A quantitative, proportional relationship exists between blood Phe levels and intelligence quotient (IQ) for early-treated patients with phenylketonuria (PKU), assessed during critical, early childhood years (age 0–12 y) or by a lifetime Index of Dietary Control. A 100-μmol/l increase in Phe has resulted in a 1.3- to 4.1-point reduction in IQ.[15]
Patients with PKU who are treated early and continuously can have a normal health-related quality of life and course of life.[16]
Zeljko P Mijuskovic, MD, PhD, Associate Professor of Dermatology, Department of Dermatology and Venereology, Military Medical Academy, Serbia
Disclosure: Nothing to disclose.
Coauthor(s)
Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro
Disclosure: Nothing to disclose.
Ljubomir Stojanov, MD, PhD, Lecturer in Metabolism and Clinical Genetics, University of Belgrade School of Medicine, Serbia
Disclosure: Nothing to disclose.
Specialty Editors
Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine
Disclosure: Nothing to disclose.
David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
Disclosure: Nothing to disclose.
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School
Disclosure: Nothing to disclose.
Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York
Disclosure: Nothing to disclose.
Acknowledgments
The authors and editors of eMedicine gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.
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