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 who have 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. The occurrence of PKU varies among ethnic groups and geographic regions worldwide.
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. Those who suffer from PKU must be supplemented with tyrosine to account for PAH deficiency in converting phenylalanine to tyrosine sufficiently. Dihydrobiopterin reductase activity is to replenish quinonoid-dihydrobiopterin back into its tetrahydrobiopterin form, which is an important cofactor in many metabolic reactions in amino acid metabolism.
Those with this deficiency may produce sufficient levels of PAH, but since tetrahydrobiopterin is a cofactor for PAH activity, deficient dihydrobiopterin reductase renders any PAH enzyme non-functional. Tetrahydrobiopterin is also a cofactor in the production of L-DOPA from tyrosine and 5-hydroxy-l-tryptophan from tryptophan, which must also be supplemented as treatment in addition to the supplements for classical PKU.
Levels of dopamine can be used to distinguish between these two types. Low levels of dopamine lead to high levels of prolactin. By contrast, in classic PKU, prolactin levels would be relatively normal. Tetrahydrobiopterin deficiency can be caused by defects in four different genes. The mean incidence of PKU varies widely in different human populations.
Caucasians are affected at a rate of 1 in 10, Turkey has the highest documented rate in the world, with 1 in 2, births, while countries such as Finland and Japan have extremely low rates with fewer than one case of PKU in , births.
Treatment The mainstream treatment for classic PKU patients is a strict PHE-restricted diet supplemented by a medical formula containing amino acids and other nutrients. There were 20 missense mutations, 6 splice mutations, 4 nonsense mutations, and 2 deletions, and 1 mutation disrupted the start codon. The 8 most common mutations represented Nineteen mutations were encountered only once.
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. J Inherit Metab Dis ; 20 : - Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene. Identification and characterization of large deletions in the phenylalanine hydroxylase PAH gene by MLPA: evidence for both homologous and non-homologous mechanisms of rearrangement.
Mol Genet Metab ; 89 : - The molecular basis of phenylketonuria in Koreans. J Hum Genet ; 49 : - Heterozygosities of microsatellite markers, background linkage disequilibrium in the Korean population. Exp Mol Med ; 38 : - Molecular characterization of phenylketonuria in Japanese patients. Hum Genet ; : - Molecular characterization of phenylketonuric mutations in Japanese by analysis of phenylalanine hydroxylase mRNA from lymphoblasts.
Hum Mol Genet ; 3 : -. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res ; 30 : e57 -. Phenylketonuria mutations in Northern China. Mol Genet Metab ; 86 : S - S Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland. Am J Hum Genet ; 44 : - Large heterozygous deletion masquerading as homozygous missense mutation: a pitfall in diagnostic mutation analysis.
J Inherit Metab Dis ; 22 : - Zschocke J. Phenylketonuria mutations in Europe. Download references. You can also search for this author in PubMed Google Scholar. Correspondence to Chang-Seok Ki. Reprints and Permissions. Lee, YW. Mutation analysis of PAH gene and characterization of a recurrent deletion mutation in Korean patients with phenylketonuria.
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