As a result, the severe signs and symptoms of PKU are rarely seen. Symptoms of PKU range from mild to severe. Infants born with classic PKU appear normal for the first few months after birth. However, without treatment with a low-phenylalanine diet, these infants will develop mental retardation and behavioral problems. Other common symptoms of untreated classic PKU include seizures, developmental delay, and autism.
Boys and girls who have classic PKU may also have eczema of the skin and lighter skin and hair than their family members who do not have PKU.
Babies born with less severe forms of PKU moderate or mild PKU may have a milder degree of mental retardation unless treated with the special diet.
If the baby has only a very slight degree of PKU, often called mild hyperphenylalaninemia, there may be no problems and the special dietary treatment may not be needed. PKU is usually diagnosed through newborn screening testing that is done shortly after birth on a blood sample heel stick. However, PKU should be considered at any age in a person who has developmental delays or mental retardation.
This is because, rarely, infants are missed by newborn screening programs. PKU is treated by limiting the amount of protein that contains phenylalanine in the diet. Most cases of PKU are detected shortly after birth by newborn screening, and treatment is started promptly.
As a result, the severe signs and symptoms of classic PKU are rarely seen. Mutations in the PAH gene cause phenylketonuria. The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues.
Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage. Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent.
People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious health problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia. Changes in other genes may influence the severity of PKU, but little is known about these additional genetic factors.
This condition is inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice.
Contact a health care provider if you have questions about your health. From Genetics Home Reference. Description Phenylketonuria commonly known as PKU is an inherited disorder that increases the levels of a substance called phenylalanine in the blood.
Among 10 mutations reported only in Norway, Eiken et al. From the birth places of the proband's grandparents, each mutation seemed to have an individual geographic distribution within Norway, with patterns of local mutation clustering. The observations were compatible with multiple founder effects and genetic drift for the distribution of PKU mutations within Norway. Using mutation and haplotype analysis, Tyfield et al.
An enormous genetic diversity within the British Isles was demonstrated in the large number of different mutations characterized and in the variety of genetic backgrounds on which individual mutations were found. In Quebec, Carter et al. The PAH mutations stratified by geographic region and population, their distributions validating hypotheses about the European expansion to North America during 3 separate phases of immigration and demographic expansion in the Quebec region over the past 4 centuries.
Hutchesson et al. The incidence in this group was estimated to be 3. Of the 12 patients with tyrosinemia I in the West Midlands, 10 were of 'non-oriental Asian' origin. Zschocke et al. The mutation ile65 to thr In contrast, arg to trp No mutation was identified that could represent European Celtic populations, supporting the view that the adoption of Celtic culture and language in Ireland did not involve major migration from the continent. Several less common mutations could be traced to the Norwegian Atlantic coast and were probably introduced into Ireland by Vikings.
Iceland was settled during the late ninth and early tenth centuries A. Although it is generally acknowledged that the Vikings brought with them Celtic slaves, the relative contribution of these peoples to the modern Icelandic gene pool is uncertain. Most population genetics studies using classical markers indicated a large Irish genetic contribution. Haplotype data supported a common ancestral origin of the mutation, and genealogic examination extending back more than 5 generations showed that this mutation probably arose in an isolated part of southern Iceland and was enriched by founder effect.
At least 7 PKU mutations had originated outside Iceland. The almost exclusively Scandinavian background of these mutations and the complete absence of common Irish PKU mutations strongly supported historic and linguistic evidence of a predominant Scandinavian heritage of the Icelandic people.
Khoury et al. They also discussed ethical, legal, and social issues such as testing children for adult-onset disorders, and the finding of unanticipated information such as misattribution of paternity and the discovery of a disorder other than the one for which the screening was undertaken in the first place. Stojiljkovic et al. The results suggested that PKU in this population is heterogeneous and reflects numerous migrations over the Balkan peninsula.
Wang et al. Individuals with PKU from the Geauga County settlement were homozygous for a splice site mutation Among unrelated Iranian patients with classic PKU, 84 of whom were born to consanguineous families, Esfahani and Vallian identified 34 different mutations, the most prevalent being IVS10nt Woolf suggested that there may be a heterozygous advantage in PKU which operates through protection against the toxic effects of ochratoxin A.
This mycotoxin is produced by several species of Aspergillus and Penicillium infesting stored grains and other foods. The mild, wet climate of Ireland and West Scotland tends to encourage the growth of molds.
Furthermore, these areas have suffered repeated famines during which moldy food was eaten. Heterozygous women appear to have a lower spontaneous abortion rate. McDonald et al. By linkage mapping, they demonstrated that the disorder, which had other characteristics close to those of phenylketonuria, mapped to mouse chromosome 10 at or near the Pah locus.
McDonald and Charlton identified a mutation within the protein coding sequence of the Pah gene in each of 2 genetic mouse models for human phenylketonuria. The enu1 mutation, induced by the chemical mutagen N-ethyl-N-nitrosourea ENU , predicts a conservative valine-to-alanine amino acid substitution and is located in exon 3, a gene region where serious mutations are rare in humans.
The phenotype in mice is mild. The second ENU-induced mutation, enu2, predicts a radical phenylalanine-serine substitution and is located in exon 7, a gene region where serious mutations are common in humans. The phenotype of the second mutation is severe. Martynyuk et al. Tetrahydrobiopterin BH4 attenuated this triad by conformational stabilization augmenting the effective PAH concentration, which led to rescue of the biochemical phenotype and enzyme function in vivo.
Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH4 confined to the pathologic metabolic state. Folling in Norway first described PKU under the designation oligophrenica phenylpyruvica. Jervis localized the metabolic error as an inability to oxidize phenylalanine to tyrosine, and Jervis demonstrated deficiency of phenylalanine hydroxylase in the liver of a patient.
Guthrie gave a history of his introduction of newborn screening for PKU. A shift in his research from cancer research to the study of mental retardation had been prompted by the birth of his second child with mental retardation. He learned that the phenylalanine-restricted diet introduced for treatment of PKU required close monitoring of blood Phe levels for which the methods were then laborious.
He conceived of modifying the bacterial test he was using to screen for different substances in the blood of patients who were being treated for cancer. These tests relied on 'competitive inhibition;' a compound that normally prevented growth of bacteria in culture plates no longer inhibited the growth when large amounts of Phe was present in a blood spot that was added to the plate. The birth of a niece who was found to have PKU at the age of 15 months also had an influence on his research.
Since a positive ferric chloride urine test came too late to prevent her mental retardation, he became interested in developing a blood test for neonates. He had been using filter paper discs soaked in serum from the patient to be studied. He found, however, that whole blood worked equally well and facilitated newborn screening. Newborn screening with the heel stick began in and was reported by Guthrie and Susi In the first 2 years, , infants were tested in 29 states and 39 cases of PKU were found--an incidence of about 1 per 10, None was missed by screening.
Guthrie noted that the National Association for Retarded Children through its state chapters lobbied vigorously for laws for PKU screening despite much opposition by organized medical groups; 37 states had such laws by Fanconi instructed Bickel to perform the ferric chloride test in every retarded patient.
Later, on moving to the University Children's Hospital in Birmingham, he introduced the ferric chloride test there and found a patient whose mother urged him to find a way to help the daughter. Under the pressure of this mother, Bickel, Gerrard, and Hickmans Bickel et al.
The use of a Phe-restricted casein hydrolysate as the main protein source of the diet was considered. Early results were dramatic. Kamaryt et al. Combined data for linkage with the two amylase loci yielded a lod score of 4. Paul et al. Linkage with theta less than 0. They expressed reservations about the data of Kamaryt et al. In this study done in Indiana, no evidence of linkage heterogeneity between Amish and non-Amish families was found.
Rao et al. Cabalska was unable, however, to confirm the linkage of chromosome 1 markers. Knapp et al. They considered loose linkage unlikely. Genetic heterogeneity was considered a possible but unlikely explanation. Abadie, V. Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria.
CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics 5: , Agostoni, C. Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. Aoki, K. Hyperphenylalaninemia: disaggregation of brain polyribosomes in young rats.
Science , Arthur, L. Intelligent, small for dates baby born to oligophrenic phenylketonuric mother after low phenylalanine diet during pregnancy. Pediatrics , Auerbach, V. Phenylalaninemia: a study of the diversity of disorders which produce elevation of blood concentrations of phenylalanine.
In: Nyhan, W. New York: McGraw-Hill pub. Barat, P. The impact of the control of serum phenylalanine levels on osteopenia in patients with phenylketonuria. Bartholome, K. Compound heterozygotes in hyperphenylalaninaemia. Berg, K. A linkage study of phenylketonuria. Bickel, H. Influence of phenylalanine intake on phenylketonuria. Lancet , Note: Originally Volume II. The influence of phenylalanine intake on the chemistry and behavior of a phenylketonuric child. Acta Paediat.
The first treatment of phenylketonuria. Blau, N. Bowden, J. Possible biochemical model for phenylketonuria. Nature , Brenton, D. Maternal phenylketonuria: a study from the United Kingdom. Brumm, V. Psychiatric symptoms and disorders in phenylketonuria. Burgard, P. Phenylalanine hydroxylase genotypes, predicted residual enzyme activity and phenotypic parameters of diagnosis and treatment of phenylketonuria.
Cabalska, B. Personal Communication. Warsaw, Poland Carter, C. The birthplaces of parents and grandparents of a series of patients with phenylketonuria in southeast England.
Carter, K. Mutation at the phenylalanine hydroxylase gene PAH and its use to document population genetic variation: the Quebec experience. Centerwall, W. Phenylketonuria: a case report of children of Jewish ancestry. Chen, S. Study of restriction fragment length polymorphisms at the human phenylalanine hydroxylase locus and evaluation of its potential application in prenatal diagnosis of phenylketonuria in Chinese. Cipcic-Schmidt, S.
German maternal phenylketonuria study. Cohen, B. Phenylketonuria in Jews. Note: Originally Volume I. Coskun, T. Scleroderma-like skin lesions in two patients with phenylketonuria. Crujeiras, V. Vitamin and mineral status in patients with hyperphenylalaninemia.
Cunningham, G. Phenylalanine tolerance tests in families with phenylketonuria and hyperphenylalaninemia. Daiger, S. Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria. Dianzani, I. Haplotype distribution and molecular defects at the phenylalanine hydroxylase locus in Italy. DiLella, A. Screening for phenylketonuria mutations by DNA amplification with the polymerase chain reaction.
Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry , Drogari, E. Dworniczak, B. Phenylalanine hydroxylase gene: silent mutation uncovers evolutionary origin of different alleles. Eiken, H. Relative frequency, heterogeneity and geographic clustering of PKU mutations in Norway. Eisensmith, R. Multiple origins for phenylketonuria in Europe. Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene.
Updated listing of haplotypes at the human phenylalanine hydroxylase PAH locus. Letter Am. Gene therapy for phenylketonuria. Esfahani, M. A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients. Note: Electronic Article. Fisch, R. Gestational carrier--a reproductive haven for offspring of mothers with phenylketonuria PKU : an alternative therapy for maternal PKU. Flatz, G. Ethnic distribution of phenylketonuria in the north German population.
Folling, A. Forrest, S. Mutation detection in phenylketonuria by using chemical cleavage of mismatch: importance of using probes from both normal and patient samples. Note: Erratum: Am. Frankenburg, W. Maternal phenylketonuria: implications for growth and development. Friedman, P. Detection of hepatic phenylalanine 4-hydroxylase in classical phenylketonuria. Gentile, J. Psychosocial aspects of PKU: hidden disabilities - a review.
Gersting, S. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Pah-enu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo.
Gjetting, T. Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Greeves, L. Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia.
Gregory, D. Plasma free amino acid values in normal children and adolescents. Metabolism , Griffiths, P. Wechsler subscale IQ and subtest profile in early treated phenylketonuria.
Guldberg, P. Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland. A molecular survey of phenylketonuria in Iceland: identification of a founding mutation and evidence of predominant Norse settlement. Guthrie, R. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. The introduction of newborn screening for phenylketonuria: a personal history.
Guttler, F. Heterozygote detection in phenylketonuria. Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria. Molecular genetics of PKU. Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Hanley, W. Maternal phenylketonuria PKU --a review. The North American Maternal Phenylketonuria Collaborative Study, developmental assessment of the offspring: preliminary report.
Hertzberg, M. Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria.
Hofman, K. Phenylketonuria in U. Holtzman, N. Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. New Eng. Hoskins, J. Enzymatic control of phenylalanine intake in phenylketonuria. Howell, R. The offspring of phenylketonuric women. Hsia, D. Phenylketonuria and its variants. Huijbregts, S.
Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. Huntley, C. Maternal phenylketonuria: course of two pregnancies. Hutchesson, A. Screening for tyrosinaemia type I. Fetal Neonatal Ed. Jervis, G. Studies on phenylpyruvic oligophrenia: the position of the metabolic error. Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system.
John, S. Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations. Kalaydjieva, L. Silent mutations in the phenylalanine hydroxylase gene as an aid to the diagnosis of phenylketonuria.
Geographical distribution gradients of the major PKU mutations and the linked haplotypes. Kamaryt, J. Kaufman, S. Phenylalanine hydroxylase activity in liver biopsies from hyperphenylalaninemia heterozygotes: deviation from proportionality with gene dosage. Phenylketonuria: biochemical mechanisms.
Differential diagnosis of variant forms of hyperphenylalaninemia. A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients. Note: Erratum: Proc. Kawashima, H. Three cases of untreated classical PKU: a report on cataracts and brain calcification. Keil, S. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study.
Pediatrics ee, Kerr, G. Khoury, M. Population screening in the age of genomic medicine. Kidd, K. Phenylketonuria: population genetics of a disease. Knapp, A. Koch, R.
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