Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 7573000; ICD10CM: E70.0; ORPHA: 2209, 716, 79253, 79254, 79651; DO: 9281;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q23.2 | [Hyperphenylalaninemia, non-PKU mild] | 261600 | Autosomal recessive | 3 | PAH | 612349 |
| 12q23.2 | Phenylketonuria | 261600 | Autosomal recessive | 3 | PAH | 612349 |
A number sign (#) is used with this entry because phenylketonuria (PKU) and non-PKU mild hyperphenylalaninemia (HPA) are caused by homozygous or compound heterozygous mutations in the PAH gene (612349) on chromosome 12q23.
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism resulting from a deficiency of phenylalanine hydroxylase (PAH; 612349), an enzyme that catalyzes the hydroxylation of phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (Zurfluh et al., 2008).
See Scriver (2007) and Blau et al. (2010) for detailed reviews of PKU.
Early diagnosis of phenylketonuria, a cause of mental retardation, is important because it is treatable by dietary means. Features other than mental retardation in untreated patients include a 'mousy' odor; light pigmentation; peculiarities of gait, stance, and sitting posture; eczema; and epilepsy (Paine, 1957). Kawashima et al. (1988) suggested that cataracts and brain calcification may be frequently overlooked manifestations of classic untreated PKU. Brain calcification has been reported in dihydropteridine reductase (DHPR) deficiency (261630). Pitt and O'Day (1991) found only 3 persons with cataracts among 46 adults, aged 28 to 71 years, with untreated PKU. They concluded that PKU is not a cause of cataracts. Levy et al. (1970) screened the serum of 280,919 'normal' teenagers and adults whose blood had been submitted for syphilis testing. Only 3 adults with the biochemical findings of PKU were found. Each was mentally subnormal. Normal mentality is very rare among patients with phenylketonuria who have not received dietary therapy.
Evidence of heterogeneity in phenylketonuria was presented by Auerbach et al. (1967) and by Woolf et al. (1968).
Coskun et al. (1990) observed scleroderma in 2 infants with PKU. Improvement in the skin lesions after commencement of a low phenylalanine diet supported the possibility of a causal relationship.
Widespread screening of neonates for phenylketonuria brought to light a class of patients with a disorder of phenylalanine metabolism milder than that in PKU. These patients show serum phenylalanine concentrations well below those in PKU, but still several times the normal. PKU and hyperphenylalaninemia breed true in families (Kaufman et al., 1975), each behaving as an autosomal recessive. Kaufman et al. (1975) studied liver biopsies from patients with HPA and their parents. The patients with HPA had levels of phenylalanine hydroxylase about 5% of normal.
Burgard et al. (1996) found that all patients but one who had predicted in vitro residual enzyme activity greater than 20% had mild PKU, while those with predicted in vitro residual enzyme activity less than 20% were identified as having classical PKU. The authors stated that 'the difficulties of some patients to adjust their blood Phe level according to their target value although they comply with the dietary recommendations might be caused by low residual enzyme activity.' In addition, when considering the R261Q (612349.0006) mutation (a mutation with a considerable amount of residual enzyme activity, which produced higher Phe levels than expected), they hypothesized a negative intraallelic complementation effect as an explanation for higher than expected diagnostic Phe values.
Mildly depressed IQ is common in treated PKU. Griffiths et al. (2000) analyzed IQ scores collected from 57 British children with early-treated classic PKU using variants of the Wechsler intelligence scale for children (WISC) in relation to indicators of dietary control such as serum phenylalanine levels and socioeconomic factors. The authors found that, after correcting for socioeconomic status, phenylalanine control at age 2 was predictive of overall IQ, although early and continuous treatment did not necessarily lead to normalization of overall IQ. Subscale analysis revealed normalized verbal IQ in those children with phenylalanine levels of less than 360 micromol/l during infancy (the recommended UK upper limit), but performance IQ remained depressed.
Weglage et al. (2000) compared 42 PKU patients, aged 10 to 18 years, with 42 diabetic patients matched for sex, age, and socioeconomic status. Patients' groups were compared with a control sample of healthy controls (2,900 individuals) from an epidemiologic study. The Child Behavior Check List, IQ tests, and monitoring of blood phenylalanine concentrations and HBA1 concentrations were used. Weglage et al. (2000) found that internalizing problems such as depressive mood, anxiety, physical complaints, or social isolation were significantly elevated in both PKU and diabetic patients, whereas externalizing problems were not. The 2 patient groups did not differ significantly either in the degree or in the pattern of their psychologic profile.
In a retrospective study from birth in 13 patients with classic PKU, Barat et al. (2002) found greater variation of phenylalanine levels and a higher mean of cumulative variations in the 8 osteopenic patients than in 5 nonosteopenic patients. Barat et al. (2002) suggested that serum phenylalanine variations may contribute to osteopenia in patients with classic PKU.
Crujeiras et al. (2015) conducted a cross-sectional observational multicenter study that included 156 patients with hyperphenylalaninemia. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing an adequate adherence to diet in nearly all patients (96.3%). Selenium was diminished in 25% of patients (95% with PKU phenotype), and 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and B12 levels were diminished only in patients with low adherence to diet.
Maternal Phenylketonuria
The occurrence of mental retardation in the offspring of homozygous mothers is an example of a genetic disease based on the genotype of the mother. Kerr et al. (1968) demonstrated 'fetal PKU' by administering large amounts of phenylalanine to mother monkeys. The offspring had reduced learning ability. They pointed out that the damage is aggravated by the normal placental process which functions to maintain higher levels of amino acids in the fetus than in the mother. Huntley and Stevenson (1969) and Hanley et al. (1987) reviewed the subject of PKU embryofetopathy, also known as the maternal PKU syndrome.
Huntley and Stevenson (1969) described 2 sisters with PKU who had a total of 28 pregnancies. Sixteen ended in spontaneous first-trimester abortion. The fetus in each of the 12 pregnancies carried to term had intrauterine growth retardation and microcephaly and 9 of the 12 term infants had cardiac malformations as well.
Superti-Furga et al. (1991) reported the maternal PKU syndrome in cousins, caused by mild unrecognized PKU in their mothers, who were homozygous for the arg261-to-gln mutation (612349.0006).
Usha et al. (1992) found 3 children with PKU embryofetopathy among the offspring of a Bedouin woman who was not recognized to have PKU until the birth of the third affected child. She had an apparently normal phenotype except for pigment dilution of the hair, which was more lightly colored than expected for the family and ethnic norms. She was not mentally retarded. One of the affected offspring had died of congenital heart disease at the age of 4 months.
Fisch et al. (1993) suggested that surrogate motherhood should be recommended as alternative management of PKU in women who wish to have children, i.e., in vitro fertilization using the parental gametes, followed by implantation of the pre-embryo in a surrogate mother.
Levy et al. (1996) compared MRI results of 5 children (age range: 8 months to 17 years) whose mothers had classic PKU and were not under metabolic control (plasma phenylalanine = 1,260 micromoles per liter) during at least the first 2 trimesters of pregnancy to MRI results of 2 sibs aged 9 and 11 years whose mother had classic PKU but whose plasma phenylalanine levels were generally below 360 micromoles per liter during both pregnancies. The MRI results showed a tendency for corpus callosum hypoplasia in those children whose mothers were not in metabolic control during their pregnancies. All children studied (even those with mothers in metabolic control) displayed some residual developmental/behavioral effects such as hyperactivity.
Rouse et al. (1997) reported a collaborative study of maternal PKU offspring. The cohort of offspring were examined for malformations, including congenital heart disease, craniofacial abnormalities, microcephaly, intrauterine and postnatal growth retardation, other major and minor defects, and early abnormal urologic signs. The mothers were grouped according to their mean phenylalanine levels during critical gestational weeks and average for phenylalanine exposure throughout the pregnancy. The frequency of congenital abnormalities increased with increasing maternal phenylalanine levels. Significant relationships included average phenylalanine levels at weeks 0 to 8 with congenital heart disease (P = 0.001); average phenylalanine at weeks 8 to 12 with brain, fetal, and postnatal growth retardation, broad nasal bridge, and anteverted nares; and average phenylalanine exposure during the entire pregnancy with neurologic signs. Although 14% of infants had congenital heart disease, none of the congenital heart disease occurred at the lower range of the maternal phenylalanine levels. At the lowest levels of phenylalanine, there were 3 infants (6%) with microcephaly, 2 (4%) with postnatal growth, and none with intrauterine growth retardation, in contrast to 85%, 51%, and 26%, respectively, with phenylalanine levels in the highest range. These data supported the concept that women with PKU should begin a low phenylalanine diet to achieve phenylalanine levels of less than 360 micromole/liter prior to conception and maintain this throughout the pregnancy.
Waisbren et al. (2000) studied 149 children of women with PKU and 33 children of women with mild hyperphenylalaninemia at 4 years of age. Children were stratified by the timing of maternal metabolic control at 0 to 10 weeks', 10 to 20 weeks', or after 20 weeks' gestation. Scores of a General Cognitive Index decreased as weeks to maternal metabolic control increased. Offspring of women who had metabolic control prior to pregnancy had a mean score of 99. Forty-seven percent of offspring whose mothers did not have metabolic control by 20 weeks' gestation had a General Cognitive Index score 2 standard deviations below the norm. Overall, 30% of children born to mothers with PKU had social and behavioral problems.
Rouse et al. (2000) studied a cohort of 354 women with PKU, followed up weekly with diet records, blood phenylalanine levels, and sonograms obtained at 18 to 20 and 32 weeks' gestation. At birth, 413 offspring were examined; they were followed up at 3 months, 6 months, and then annually. Bayley Mental Developmental Index and Psychomotor Developmental Index tests were given at 1 and 2 years. Congenital heart defects were found in 31 offspring; of these, 17 also had microcephaly. Mean phenylalanine levels at 4 to 8 weeks' gestation predicted congenital heart defects (P less than 0.0001). An infant with a congenital heart defect had a 3-fold risk of having microcephaly when the mother had higher phenylalanine levels. No direct relationship to the specific PAH mutation was found. None of the women whose offspring had congenital heart defects had blood phenylalanine levels in control during the first 8 weeks of gestation. Rouse et al. (2000) concluded that women with PKU need to be well controlled on a low phenylalanine diet before conception and throughout pregnancy.
Levy et al. (2001) reported on 416 offspring from 412 maternal PKU pregnancies that produced live births and compared them to 100 offspring from 99 control pregnancies. Thirty-four of the 235 offspring (14%; 95% confidence interval, 10.2 to 19.6%) from pregnancies in maternal PKU patients with a basal phenylalanine level of greater than 900 micromolar and not in metabolic control (defined as phenylalanine level less than or equal to 600 micromolar) by the eighth gestational week had congenital heart disease compared with 1 control offspring with congenital heart disease. One of the children among 50 from mothers with non-PKU mild hyperphenylalaninemia also had congenital heart disease. Coarctation of the aorta and hypoplastic left heart syndrome were overrepresented.
Brumm et al. (2010) reviewed studies of psychiatric symptoms and disorders in patients with PKU. Those with untreated PKU tended to have severe behavioral disturbances, including psychotic disorders, autistic features, hyperactivity, and aggression, as well as self-mutilation. Among early-treated children and adolescents, discontinuation of treatment was associated with attention-deficit disorder and decreased social competence. Children who continued treatment had fewer behavioral problems. However, most tended to be less happy and confident. Even adults who had early treatment had higher rates of depression, anxiety-related disorders, and social introversion compared to the normal population. In general, the severity of problems correlated with the timing and degree of exposure to increased blood levels of phenylalanine. Brumm et al. (2010) stated that mechanisms of psychiatric disorders in PKU most likely result from a combination of neurotransmitter imbalance, myelination defects, and the stress of living with a chronic illness.
Gentile et al. (2010) reviewed studies of psychosocial aspects of PKU and concluded that even treated individuals have hidden disabilities resulting from poor executive function, decreased mental processing speed, and psychosocial problems. These included difficulties in forming interpersonal relationships, achieving autonomy, attending educational goals, and having healthy emotional development. The most important way to reduce these problems is strict metabolic control throughout life, with particular importance on the first year of life.
Pilotto et al. (2021) performed neurologic and neuropsychologic testing and brain MRIs in a cohort of 19 adults, aged 30 to 45 years, with early-treated PKU. The median phenylalanine level in this cohort was 873 micromol/l with a range of 57 to 2,100 micromol/l; 14 of the patients reported consuming a phenylalanine-restricted diet and 1 patient was also treated with sapropterin dihydrochloride. The patients had a higher prevalence of neurologic symptoms (hyperreflexia, kinetic tremor, and slowed horizontal saccades) and cognitive and behavioral abnormalities (global cognition and depressive and behavioral symptoms) compared to controls. The patients also had increased atrophy of the putamen and right thalamus on MRI compared to controls. CSF metabolites, which were tested in 10 of the patients, had increased beta-amyloid, total tau, and phosphorylated tau compared to controls. Plasma phenylalanine level in the patients correlated to total number of pathologic cognitive tests, motor-evoked potential latency, and parietal lobe atrophy on brain MRI. Pilotto et al. (2021) concluded that these results support continuous metabolic control of phenylalanine levels in adults with PKU.
Normal blood phenylalanine levels are 58 +/- 15 micromoles/liter in adults, 60 +/- 13 micromoles/liter in teenagers, and 62 +/- 18 micromoles/liter (mean +/- SD) in childhood. In the newborn, the upper limit of normal is 120 micromoles/liter (2 mg/dl) (Scriver et al., 1985; Gregory et al., 1986). In untreated classical PKU, blood levels as high as 2.4 mM/liter can be found.
Bowden and McArthur (1972) found that phenylpyruvic acid inhibits pyruvate decarboxylase in brain but not in liver. They suggested that this accounts for the defect in formation of myelin and mental retardation in this disease.
In the liver of a fetus aborted after prenatal DNA diagnosis of PKU, Ledley et al. (1988) found no detectable phenylalanine hydroxylase enzymatic activity or immunoreactive protein, although both were found in control specimens of similar gestational age. Both the size and the amount of phenylalanine hydroxylase mRNA were normal. The findings confirmed the genetic diagnosis of PKU in the fetus and indicated that the mutations affected translation or stability of the protein.
Tolerance to dietary phenylalanine and therefore the clinical severity of PKU have been presumed to be the consequence of the rate of conversion of phenylalanine into tyrosine. However, in a study of 7 classic PKU patients, van Spronsen et al. (1998) found that although the in vivo hydroxylation of phenylalanine into tyrosine was decreased, there was no significant correlation between the in vivo hydroxylation rates and the tolerances.
Kaufman (1999) described the derivation of a quantitative model of phenylalanine metabolism in humans. The model was based on the kinetic properties of pure recombinant human PAH and on estimates of the in vivo rates of phenylalanine transamination and protein degradation. Calculated values for the steady-state concentration of blood phenylalanine, rate of clearance of phenylalanine from the blood after an oral load of the amino acid, and dietary tolerance of phenylalanine all agreed with data from normal as well as from phenylketonuric patients and obligate heterozygotes. Kaufman (1999) suggested that these calculated values may help in the decision about the degree of restriction of phenylalanine intake that is necessary to achieve a satisfactory clinical outcome in patients with classic PKU and in those with milder forms of the disease.
It has been postulated that the significant incidence of learning disabilities in treated patients with PKU may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. In a study of hypotyrosinemia in a PKU population, Hanley et al. (2000) found that the mean nonfasting plasma tyrosine was 41.1 micromol/L in 99 classic PKU patients, 53.3 micromol/L in 26 mild (atypical) PKU patients, and 66.6 micromol/L in 35 non-PKU mild hyperphenylalaninemia patients. This compared to nonfasting plasma tyrosine levels of 64.0 micromol/L in 102 non-PKU subjects in their hospital biochemistry database, 69.1 micromol/L in 58 volunteers in private office practice, and 64 to 78.8 micromol/L in infants, children, and adolescents in a literature review. The data supported previous findings that plasma tyrosine levels are low in PKU.
Leuzzi et al. (2000) assessed brain Phe concentration by in vivo proton magnetic resonance spectroscopy in 10 off-diet PKU patients, aged 15.5 to 30.5 years. An abnormal concentration of brain Phe was detected in all patients, but there was wide interindividual variability of concurrent plasma Phe. In late-detected subjects, brain Phe concentration correlated with clinical phenotype better than did plasma Phe. White-matter alterations were found in all patients.
Koch et al. (2000) referred to preliminary reports suggesting that the occasional untreated person with PKU with normal intellect has elevated blood phenylalanine but low brain phenylalanine levels, They measured blood phenylalanine levels and used MRI/MRS to measure brain phenylalanine content in 29 individuals with PKU, 4 carriers of phenylalanine hydroxylase mutations, and 5 controls. For each individual with PKU, the authors also noted IQ, mutations, whether or not a restricted diet was followed, and age at diagnosis. Koch et al. (2000) concluded that MRI/MRS measurements of brain phenylalanine content may be of value in recommending appropriate blood phenylalanine concentrations for treatment of adults.
Weglage et al. (2002) investigated 4 pairs of sibs with classical PKU using in vivo NMR spectroscopy in the course of an oral phenylalanine load (100 mg/kg body weight). Patients' brain phenylalanine concentrations were different in spite of similar blood levels. Interindividual variations of the apparent transport Michaelis constant ranged from 0.10 to 0.84 mmol/L. Sibs with lower values for the apparent transport constant, higher values for the ratio of the maximal transport velocity over the intracerebral consumption rate, and higher concurrent brain phenylalanine levels showed a lower IQ and a higher degree of cerebral white matter abnormalities. Weglage et al. (2002) concluded that blood-brain barrier transport characteristics and the resultant brain phenylalanine levels are causative factors for the individual clinical outcome in PKU.
To determine whether impairments of cerebral metabolism may play a role in acute phenylalanine neurotoxicity, Pietz et al. (2003) studied 11 adult early-treated PKU patients and 10 healthy controls for changes in concentrations of cerebral metabolites using noninvasive quantitative phosphorus-31 MRS. In adult patients, derived ADP concentration and phosphorylation potential were increased by 11% and 22%, respectively; peak areas of inorganic phosphate and phospholipids were decreased by 22% and 8%, respectively. ADP correlated with concurrent plasma (r = 0.65) and brain (r = 0.55) phenylalanine levels. PKU patients showed slowing of EEG background activity, a sign of impaired brain function, 24 hours after oral phenylalanine challenge. Pietz et al. (2003) concluded that there were subtle abnormalities of cerebral energy metabolism and encouraged more clinical studies on the relationship of imbalances of high energy phosphates and cerebral energy metabolism to acute phenylalanine neurotoxicity.
Classical PKU is inherited in a strictly autosomal recessive manner and is the result of mutations in the PAH gene. Most variation in classical PKU is due to heterogeneity in the mutant alleles with many patients being compound heterozygotes rather than homozygotes for one particular mutant allele. Bartholome et al. (1984) concluded that examples of parent (usually mother)-to-child transmission of hyperphenylalaninemia are likely to be due to compound heterozygosity for PKU and HPA in either the parent or the child or both.
Using a cDNA probe for human phenylalanine hydroxylase to analyze human-mouse hybrid cells by Southern hybridization, Lidsky et al. (1984) showed that the PAH locus is on chromosome 12 and presumably on the distal part of 12q because in hybrids containing translocated chromosome 12, it segregated with PEPB (12q21) and not with TPI (12p13). Since in family studies concordance of segregation between a mutant PAH gene and PKU was found (Woo et al., 1983), one can state that the 'PKU locus' is on chromosome 12. By in situ hybridization, the assignment of the PAH locus was narrowed to chromosome 12q22-q24.1 (Woo et al., 1984).
For information on early mapping studies, see HISTORY.
The first PKU mutation identified in the PAH gene was a single base change (GT-to-AT) in the canonical 5-prime splice donor site of intron 12 (612349.0001). Gene transfer and expression experiments demonstrated that the splice donor site mutation resulted in abnormal PAH mRNA processing and loss of PAH activity (DiLella et al., 1986).
Eisensmith and Woo (1992) reviewed mutations and polymorphisms in the human PAH gene. About 50 of the mutations were single-base substitutions, including 6 nonsense mutations and 8 splicing mutations, with the remainder being missense mutations. Of the missense mutations, 12 apparently resulted from the methylation and subsequent deamination of highly mutagenic CpG dinucleotides. Recurrent mutations had been observed at several sites, producing associations with different haplotypes in different populations. Studies of in vitro expression showed significant correlations between residual PAH activity and severity of the disease phenotype.
Martinez-Pizarro et al. (2018) investigated the mechanism of pathogenicity of 2 intron 11 mutations in the PAH gene, c.1199+17G-A and c.1199+20G-C. Minigene assays with each mutation showed increased exon 11 skipping compared to wildtype.
By whole-genome sequencing in 10 patients with PKU from Northwest China in whom only 1 heterozygous PAH mutation had been identified, Jin et al. (2022) identified 3 heterozygous deep intronic mutations, c.706+368T-C, c.1065+241C-A, and c.1199+502A-T. The c.1199+502A-T mutation was identified in 6 of the patients, and may therefore be a recurrent mutation in Northwest China.
For more detailed information on the molecular genetics of PKU and non-PKU hyperphenylalaninemia, see 612349.
For information on genotype/phenotype correlations in PKU and non-PKU hyperphenylalaninemia, see 612349.
Waters et al. (2000) characterized 4 PKU-associated PAH mutations that change an amino acid distant from the enzyme active site. Using 3 complementary in vitro protein expression systems and 3D structural localization, Waters et al. (2000) demonstrated a common mechanism, i.e., PAH protein folding is affected, causing altered oligomerization and accelerated proteolytic degradation, leading to reduced cellular levels of this cytosolic protein. Enzyme-specific activity and kinetic properties are not adversely affected, implying that the only way these mutations reduce enzyme activity within cells in vivo is by producing structural changes which provoke the cell to destroy the aberrant protein. The mutations were chosen because of their associations with a spectrum of in vivo hyperphenylalaninemia among patients. Waters et al. (2000) concluded that their in vitro data suggests that interindividual differences in cellular handling of the mutant but active PAH proteins contributes to the observed variability of phenotypic severity.
Most PAH missense mutations impair enzyme activity by causing increased protein instability and aggregation. Gjetting et al. (2001) described an alternative mechanism by which some PAH mutations may render phenylalanine hydroxylase defective. They used database searches to identify regions in the N-terminal domain of PAH with homology to the regulatory domain of prephenate dehydratase (PDH), the rate-limiting enzyme in the bacterial phenylalanine biosynthesis pathway. Naturally occurring N-terminal PAH mutations are distributed in a nonrandom pattern and cluster within residues 46-48 (amino acids GAL) and 65-69 (amino acids IESRP), 2 motifs highly conserved in PDH. To examine whether N-terminal PAH mutations affect the ability of PAH to bind phenylalanine at the regulatory domain, wildtype and 5 mutant forms (including G46S, 612349.0055; A47V, 612349.0056; and I65T, 612349.0063) of the N-terminal domain (residues 2-120) of human PAH were expressed as fusion proteins in E. coli. Binding studies showed that the wildtype form of this domain specifically binds phenylalanine, whereas all mutations abolished or significantly reduced this phenylalanine-binding capacity. The data suggested that impairment of phenylalanine-mediated activation of PAH may be an important disease-causing mechanism of some N-terminal PAH mutations.
Most missense mutations found in PKU result in misfolding of the phenylalanine hydroxylase protein, increased protein turnover, and loss of enzymatic function. Pey et al. (2007) studied the prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, using the protein-design algorithm FoldX. For the 80 mutations for which expression analyses had been performed in eukaryotes, in most cases they found substantial overall correlation between the mutational energetic impact and both in vitro residual activities and patient metabolic phenotype. This finding confirmed that the decrease in protein stability is the main molecular pathogenic mechanism in PKU and the determinant for phenotypic outcome. Metabolic phenotypes had been shown to be better predicted than in vitro residual activities, probably because of greater stringency in the phenotyping process. All the remaining 238 PKU missense mutations compiled in the PAH locus knowledgebase (PAHdb) were analyzed, and their phenotypic outcomes were predicted on the basis of the energetic impact provided by FoldX. Residues in exons 7-9 and in interdomain regions within the subunit appeared to play an important structural role and constitute hotspots for destabilization.
Using recombinant proteins expressed in E. coli, Gersting et al. (2008) characterized 10 BH4-responsive PAH mutations, including arg408 to trp (R408W; 612349.0002) and tyr414 to cys (Y414C; 612349.0017). Residual activity was generally high, but allostery was disturbed in almost all variants, suggesting altered protein conformation. This hypothesis was confirmed by reduced proteolytic stability, impaired tetramer assembly or aggregation, increased hydrophobicity, and accelerated thermal unfolding, which primarily affected the regulatory domain, in most variants. Three-dimensional modeling revealed that the misfolding was communicated throughout the protein. Gersting et al. (2008) concluded that global conformational changes in PAH hinder the molecular motions essential for enzyme function.
Matalon et al. (1977) reported high levels of phenylalanine hydroxylase in placenta and suggested use of placental biopsy in prenatal diagnosis.
Woo (1983) identified a DNA restriction polymorphism detected by a phenylalanine hydroxylase cDNA probe and tentatively demonstrated the feasibility of carrier detection and prenatal diagnosis, using the haplotypes defined by the DNA polymorphism.
By the use of RFLPs related to the phenylalanine hydroxylase gene, Lidsky et al. (1985) achieved prenatal diagnosis of a PKU homozygote and a PKU heterozygote. Riess et al. (1987) described experience with prenatal diagnosis of PKU by RFLP analysis. They pointed out that in those cases in which the affected child had died but a phenotypically normal brother or sister is available for investigation, full genetic predictability could be obtained only if this child proved to be homozygously healthy in the phenylalanine-loading heterozygote test.
DiLella et al. (1988) showed that the 2 mutant alleles of PAH common among Caucasians of northern European ancestry can be detected by direct analysis of genomic DNA after specific amplification of a DNA fragment by PCR. The results suggested that it is technically feasible to develop a program for carrier detection of the genetic trait in a population of individuals without a family history of PKU.
Ramus et al. (1992) used PCR amplification of the low levels of mRNA resulting from illegitimate transcription of the PAH gene in fibroblasts and Epstein-Barr virus-transformed lymphocytes to detect mutations in patients with PKU.
Taking advantage of the 'illegitimate' transcription of the PAH gene in circulating lymphocytes, Abadie et al. (1993) succeeded in making the DNA diagnosis of phenylketonuria. Furthermore, they identified 3 novel mutations in 2 patients.
Kalaydjieva et al. (1991) identified 3 silent mutations in the PAH gene, in codons 232, 245, and 385, linked to specific RFLP haplotypes in several Caucasian populations. All 3 mutations created a new restriction site and were easily detected on PCR-amplified DNA. The combined analysis of these markers and 1 or 2 PKU mutations formed a simple panel of diagnostic tests with full informativeness in a large proportion of PKU families.
Forrest et al. (1991) used a modification of the chemical cleavage of mismatch (CCM) method to identify mutations in PAH in PKU. They stated that 'judicious choice of probes gives the CCM method the potential to detect close to 100% of single-base mutations.'
Dietary Treatment
Phenylketonuria is treatable by a low phenylalanine diet. In treated patients, severe white matter abnormalities are predominantly associated with blood phenylalanine levels above 15 mg per deciliter (Thompson et al., 1993). Ullrich et al. (1994) performed MRI on 15 adolescents with good dietary control (phenylalanine levels below 10 mg per deciliter). Ten of these patients had a normal cranial MRI whereas 4 showed mild changes of the signal intensity of the white matter on T2-weighted images confined to the parietooccipital region. The affected and unaffected patients could not be distinguished by age, sex, or mean blood phenylalanine concentrations.
From studies in 4 women, Rohr et al. (1987) concluded that fetal damage from maternal PKU can be largely and perhaps entirely prevented by dietary therapy, but that therapy must begin before conception for the best chance of a normal infant. Drogari et al. (1987) presented evidence suggesting that only a diet restricting phenylalanine intake started before conception is likely to prevent fetal damage.
In a report of preliminary results from the North American Maternal PKU Study, Hanley et al. (1996) suggested that early and adequate dietary treatment during pregnancy may provide some protection to the fetus for later intellectual development. The German Maternal PKU Study had followed 43 pregnancies (Cipcic-Schmidt et al., 1996). For minimizing risks of ill effects, preconceptional dietary control was strongly recommended.
Brenton and Lilburn (1996) reported that by November 1994, 39 pregnancies had been completed in PKU mothers. Dietary control was post-conception in 6; 2 of these offspring died of congenital heart disease and another needed surgery for coarctation. There were no heart defects in the 34 offspring of the 33 pregnancies following preconception diet controlled by Guthrie assays of maternal Phe 3 times weekly. Excessively high and low values occurred intermittently in many pregnancies, both of which may adversely affect the fetus.
A multicenter follow-up study (Holtzman et al., 1986) presented evidence that treatment of PKU should be continued beyond age 8 years.
Weglage et al. (1999) reported results of testing of IQ, fine motor abilities, and sustained and selective attention in 10 boys and 10 girls with early-treated phenylketonuria and 20 healthy controls matched for age, sex, and IQ; the individuals were tested twice, at mean ages of 11 and 14 years. At the first test, examination showed significant blood phenylalanine-correlated neuropsychologic deficits in PKU patients. In spite of raised blood phenylalanine concentrations during the following 3 years, the repeated measurements revealed a significant decrease in patients' deficits compared to controls. Clinical-neurologic status of patients and controls was normal at both test times. The results indicated decreased vulnerability of PKU patients with respect to their neuropsychologic functioning against elevated phenylalanine levels on aging.
Greeves et al. (2000) examined the effect of diet relaxation after the age of 8 years in 125 children from Northern Ireland with PKU or non-PKU hyperphenylalaninemia, correlating verbal, performance, and overall IQ at ages 8, 14, and 18 with the predicted residual enzyme activity conferred by their genotype. Multiple regression analysis demonstrated a significant reduction in verbal and overall IQ between the ages of 8 and 14 or 18, with a greater reduction in those with a lower predicted residual enzyme activity. This study also showed that patients with residual enzyme activities of 25% or more were more likely to maintain or gain IQ points after dietary relaxation than those patients with lower enzyme activities. These data suggested that continued dietary control in this latter group, as defined by genotype, may prove beneficial.
Recognizing that a low phenylalanine diet is also low in the long-chain polyunsaturated fatty acids (LCPUFA) necessary for cell membrane formation and normal brain and visual development, Agostoni et al. (2000) examined the effects of a 12-month supplementation of LCPUFA on fatty acid composition of erythrocyte lipids and visual evoked potentials in children with well-controlled PKU. The children who received supplementation showed a significant increase in docosahexaenoic acid (DHA) levels of erythrocyte lipids and improved visual function, as measured by a decreased P100 wave latency.
Huijbregts et al. (2002) sought to answer whether there is an effect of dietary interventions that induce relatively small changes in phenylalanine concentration on neuropsychologic outcome of early and continuously treated PKU patients and whether there are differences in effect for PKU children versus adolescents. Huijbregts et al. (2002) sought short-term dietary intervention of 1 to 2 weeks and compared this for patients whose phenylalanine concentrations increased versus those whose phenylalanine concentrations decreased. Huijbregts et al. (2002) found that relatively small fluctuations in phenylalanine concentration influenced neuropsychologic task performance of PKU patients. Patients whose phenylalanine concentrations had decreased by the second assessment showed generally more improvement than controls. Patients whose phenylalanine concentrations had increased showed minimal improvement or deterioration of task performance. The strongest effects were observed when sustained attention and manipulation of working memory content were required.
Koch et al. (2002) reported the follow-up studies of 125 children who were a part of the original cohort for short-term versus long-term treatment of PKU with diet. Seventy of the 125 children were located and evaluated in adulthood. Mental problems, including phobias and depression, were reported in 41% of those off diet and 22% of continuers. The 'on diet' group had only 2 reported episodes of transient depression not requiring psychiatric care. The neurologic signs related primarily to increased or decreased muscle tone and deep tendon reflex changes. The group who remained on a phenylalanine-restricted diet had fewer problems overall than the discontinued group (P = 0.02).
Singh et al. (2014) reported updated recommendations for the nutritional management of phenylalanine hydroxylase deficiency. Their paper was accompanied by an American College of Medical Genetics practice guideline authored by Vockley et al. (2014), which updated phenylalanine hydroxylase deficiency diagnosis and management, including the use of sapropterin dihydrochloride to achieve improved metabolic control and/or increased protein tolerance in patients who respond.
Van Vliet et al. (2022) examined the effects of large neutral amino acid (LNAA) supplementation with and without various levels of dietary phenylalanine (Phe)-restriction on plasma phenylalanine, brain amino acid, and brain monoamine levels in a mouse model of phenylketonuria (BTBR Pah-emu2). LNAA supplementation resulted in higher brain Phe levels compared to mice on a severe Phe-restricted diet but in lower brain Phe levels compared to mice on a semi-Phe-restricted diet. LNAA supplementation resulted in similar brain levels of monoamide compared to mice on a severe Phe-restricted diet but in lower brain levels of monoamide compared to mice on a semi-Phe-restricted diet. Van Vliet et al. (2022) suggested that LNAA treatment could be employed in PKU for treatment of low brain monoamide levels without the addition of a Phe-restricted diet.
Sapropterin (Tetrahydrobiopterin)-Responsive PKU
At least half of patients with phenylketonuria have a mild clinical phenotype. Muntau et al. (2002) explored the therapeutic efficacy of tetrahydrobiopterin for the treatment of mild phenylketonuria. Tetrahydrobiopterin significantly lowered blood phenylalanine levels in 27 of 31 patients with mild hyperphenylalaninemia (10 patients) or mild phenylketonuria (21 patients). Phenylalanine oxidation was significantly enhanced in 23 of these 31 patients. Conversely, none of the 7 patients with classic phenylketonuria had a response to tetrahydrobiopterin. Long-term treatment with tetrahydrobiopterin in 5 children increased daily phenylalanine tolerance, allowing them to discontinue their restricted diets. Mutations connected to tetrahydrobiopterin responsiveness were predominantly in the catalytic domain of the PAH protein and were not directly involved in cofactor binding. Muntau et al. (2002) concluded that responsiveness could not consistently be predicted on the basis of genotype, particularly in compound heterozygotes.
Lassker et al. (2002) reported 2 new patients with tetrahydrobiopterin-responsive PKU who carried missense mutations in the PAH gene. Both patients showed no effect of tetrahydrobiopterin at 7.5 mg/kg/day on plasma phenylalanine levels in the newborn period, and the authors suggested that a normal neonatal tetrahydrobiopterin test does not necessarily exclude tetrahydrobiopterin responsiveness in all such patients.
Matalon et al. (2004) found that 21 of 36 (58.3%) PKU patients responded favorably to oral tetrahydrobiopterin (BH4) supplementation. A single dose of 10 mg/kg resulted in a mean decrease of greater than 30% in blood phenylalanine levels. Patients who responded were found to have mutations in the PAH gene within the catalytic, regulatory, oligomerization, and BH4-binding domains.
Steinfeld et al. (2004) reported 2 unrelated infants with PKU who responded favorably to daily BH4 supplementation. They no longer needed dietary restriction and showed normal development after 2 years. One of the patients was homozygous for a mild PAH mutation (Y414C; 612349.0017). No side effects were observed.
Keil et al. (2013) reported the follow-up of 147 patients treated with sapropterin dihydrochloride for up to 12 years: 41.9% had mild hyperphenylalaninemia, 50.7% mild PKU, and 7.4% classic PKU. Median phenylalanine (Phe) tolerance increased 3.9 times with BH4/sapropterin therapy, compared with dietary treatment, and median Phe blood concentrations were within the therapeutic range in all patients. Compared with diet alone, improvement in quality of life was reported in 49.6% of patients, improvement in adherence to diet in 47% of patients, and improvement in adherence to treatment in 63.3% of patients. No severe adverse events were reported. Keil et al. (2013) concluded that their data documented a long-term beneficial effect of orally administered BH4/sapropterin in responsive PKU patients by improving metabolic control, increasing daily tolerance for dietary Phe intake, and for some, by improving dietary adherence and quality of life.
Waisbren et al. (2021) reported the long-term effects of sapropterin treatment on intellectual functioning and other outcomes in 62 children who started sapropterin before 6 years of age. Intellectual functioning (as measured by the full-scale intelligent quotient (FSIQ)) and growth rates were maintained over a follow-up period of 7 years and stayed in the normal range. Approximately 60% of patients maintained their blood phenylalanine levels in the therapeutic range of 120-360 micromol/L throughout the study. All of the patients had at least one adverse event during the study period; the most common adverse events were upper respiratory tract infections, abdominal pain and vomiting, and diarrhea.
For more detailed information on genotype/phenotype correlations in tetrahydrobiopterin-responsive PKU, see 612349.
Treatment with Phenylalanine Ammonia Lyase (PAL)
Hoskins et al. (1980) showed that the plant enzyme phenylalanine ammonia lyase (PAL; EC 4.3.1.5) will survive in the gut long enough to deplete the phenylalanine derived from food protein and so reduce the rise in blood phenylalanine that otherwise occurs after a protein meal. Preliminary studies suggested that it may have a place in the treatment of PKU.
Sarkissian et al. (1999) described experiments on a mouse model using a different modality for treatment of PKU compatible with better compliance using ancillary PAL to degrade phenylalanine, the harmful nutrient of PKU; in this treatment, PAL acts as a substitute for the enzyme phenylalanine monooxygenase, which is deficient in PKU. PAL, a robust enzyme without need for a cofactor, converts phenylalanine to trans-cinnamic acid, a harmless metabolite. Sarkissian et al. (1999) described (i) an efficient recombinant approach to produce large quantities of PAL enzyme using a construct of the PAL gene from Rhodosporidium toruloides and expressing it in a strain of E. coli; (ii) testing of PAL in orthologous mouse with hyperphenylalaninemia induced by N-ethyl-N-nitrosourea (ENU) mutation; and (iii) proofs of principle (PAL reduces hyperphenylalaninemia), both pharmacologic (with a clear dose-response effect) and physiologic (protected enteral PAL is significantly effective against hyperphenylalaninemia). They concluded that the appropriate dosage of orally administered PAL, perhaps in combination with a controlled and modestly low protein diet, should effectively control the phenylalanine pool size through its effect on the gastrointestinal tract. These findings opened a new avenue to the treatment of this classic genetic disorder.
Zori et al. (2019) found that after 1 and 2 years of treatment with subcutaneous pegvaliase (a pegylated PAL derivative) in adults with PKU whose baseline Phe was greater than or equal to 600 micromoles per liter, Phe levels were significantly improved compared to a matched historical cohort treated with sapropterin plus diet and diet alone. Pegvaliase-treated individuals also had diets with significantly higher protein intake.
Hollander et al. (2022) evaluated subcutaneous pegvaliase dosing in 15 patients with PKU who participated in a pegvaliase clinical trial and 24 PKU patients who were started on pegvaliase after the drug was on the market (post-marketing cohort). The patients in the clinical trial cohort had an average of 4.8 years longer treatment compared to the post-marketing cohort. The patients who were in the clinical trial cohort had a lower average pegvaliase dose compared to the post-marketing cohort and the post-marketing cohort had an inverse correlation with dose change and number of weeks from a response. Hollander et al. (2022) found that the patients tolerated a reduction in pegvaliase dosing over time while still retaining therapeutic efficacy, suggesting that pegvaliase dose required for efficacy may decrease over time in patients with PKU.
Other Treatments
Stegink et al. (1989) tested the effect of aspartame (N-L-alpha-aspartyl-L-phenylalanine methyl ester--a widely used dipeptide sweetener) on phenylalanine concentrations in persons heterozygous for PKU. They found moderate elevations in phenylalanine levels above baseline for heterozygotes for PKU (2.3-4.7 micromoles, 30-45 minutes after ingestion of a 12-ounce beverage).
Liver transplantation is not a usual therapy for PKU because of the usually good results achieved with early dietary restriction and because liver disease is not part of the clinical picture of PKU. Vajro et al. (1993) reported that orthotopic liver transplantation in a 10-year-old boy with PKU and concomitant, unrelated end-stage liver disease cured the PKU.
Eisensmith and Woo (1996) reviewed the current state of gene therapy for phenylketonuria. Of the 3 basic steps required, 2 have been accomplished: a cDNA clone expressing human phenylalanine hydroxylase and a phenylalanine hydroxylase-deficient animal model have been developed, while vectors for efficient gene transfer in vivo have yet to be developed. Retroviral vectors, while effective in vitro, have a low transduction efficiency in vivo. Similarly, DNA/protein complexes have not been efficiently transduced in vivo. Recombinant adenoviral vectors, although completely successful in the short term, did not persist beyond a few weeks due to an immune response against the adenoviral vector.
PKU occurs in about 1 in 10,000 births (Steinfeld et al., 2004).
Peculiarities in the distribution of phenylketonuria have been noted. The disorder is rare in Ashkenazi Jews (Cohen et al., 1961; Centerwall and Neff, 1961). Carter and Woolf (1961) noted that of the cases seen in London and presently living in southeast England, a disproportionately large number had parents and grandparents born in Ireland or West Scotland. The frequency at birth in northern Europeans may be about 1 per 10,000 (Guthrie and Susi, 1963).
In Kuwait, Teebi et al. (1987) found 7 cases of PKU among 451 institutionalized mentally retarded persons (1.9%).
Saugstad (1975) determined the frequency and distribution of PKU in Norway and concluded that the PKU gene was probably of Celtic origin, i.e., was brought from Ireland and Scotland (which have the highest frequency of PKU) with wives and slaves of the Vikings. Rh, Kell, and PGM-1 types support the suggestion. PKU was first discovered in Norway by Folling (1934).
From the increase in frequency of parental consanguinity, Romeo et al. (1983) estimated that the frequency of PKU in Italy is between 1 in 15,595 and 1 in 17,815 (according to 2 different formulas), values not greatly different from that derived from screening programs (about 1 in 12,000). Flatz et al. (1984) concluded that the PKU gene was 1.37 times more frequent in prewar northeastern Germany than northwestern Germany.
DiLella et al. (1986) cited an incidence of 1 per 4,500 in Ireland and 1 per 16,000 in Switzerland with an average incidence of about 1 per 8,000 in U.S. Caucasians. The PKU gene has been considered to be Celtic in origin. Perhaps surprisingly, DiLella et al. (1986) found the splice donor site mutation of intron 12 (612349.0001) in Denmark, England, Ireland, Scotland, Switzerland, and Italy. Furthermore, the association with RFLP haplotype 3 was preserved in these populations. This is a difficult finding to explain in population genetics terms that are compatible with demographic history.
Guttler and Woo (1986) identified 12 different haplotypes in Danish PKU families; however, of 132 chromosomes analyzed from 66 obligate heterozygotes, 59 of 66 PKU genes were associated with only 4 haplotypes. Mutant PAH alleles related to 2 of the 4 RFLP haplotypes seemed to be associated with a more severe clinical phenotype.
In Denmark, Guttler et al. (1987) found that 89% of families were accounted for by 4 RFLP haplotypes. Patients who were either homozygous or heterozygous for the mutant alleles of haplotypes 2 or 3 had a severe clinical course, whereas patients who had a mutant allele of haplotypes 1 or 4 usually had a less severe clinical phenotype.
Woo (1988) provided a collation of the 43 RFLP haplotypes at the PAH locus identified to date. Ninety percent of all mutant alleles in Danes are associated with only 4 haplotypes, of which 2 had been fully characterized at the molecular level. The haplotypes are based on the combined pattern of presence or absence of sites of cutting by 7 restriction enzymes (BglIII, PvuII, EcoRI, MspI, XmnI, HindIII, and EcoRV), of which one, PvuII, has 2 cut sites. The GT-to-AT transition at the canonical splice donor site of intron 12, causing skipping of the preceding exon during RNA splicing, is associated with a mutant haplotype 3. The missense mutation involving an arginine-to-tryptophan substitution at residue 408 (612349.0002) of the enzyme is associated with mutant haplotype 2. Both mutant alleles are in linkage disequilibrium with the corresponding RFLP haplotypes throughout Europe, suggesting that 2 mutational events occurred on background chromosomes of the 2 haplotypes, followed by spread and expansion in the Caucasian population.
In 37 French kindreds, Rey et al. (1988) found that two-thirds of all mutant alleles were confined within 4 haplotypes, whereas the remaining third were accounted for by 12 haplotypes, including 8 absent from Caucasian pedigrees reported up to that time. Several mutant haplotypes were present in typical PKU only, others were present in variants only, and some were present in both. Because of the relatively large number of different alleles and the expected consequences of compound heterozygosity, one can account for the broad spectrum of individual phenotypes observed in France.
Hertzberg et al. (1989) used 8 RFLPs to construct haplotypes for the PAH locus in 5 ethnic groups from Polynesia; 630 distinct haplotypes were observed. Three common haplotypes constituted more than 95% of alleles. The finding of the same major haplotypes in a control group of individuals from Southeast Asia, as well as the finding of these haplotypes in the Caucasian population, suggested that the origin of these alleles predates the divergence of the races. The absence of severe PKU in Polynesians and Southeast Asians is consistent with the absence of the PAH haplotypes in which the most severe PKU mutants have been found among Caucasians.
Chen et al. (1989) found no DNA rearrangement or deletion of the PAH locus among 7 Chinese classical PKU families. Five different haplotypes were found in the 7 families: haplotypes 4 and 11, and 3 previously unreported haplotypes.
In the highly consanguineous Welsh Gypsy population, Tyfield et al. (1989) demonstrated that PKU is associated with haplotype 4, which is identical to that found in the northern European population.
Among 17 Turkish PKU families, Stuhrmann et al. (1989) identified 27 mutated PAH alleles representing 19 different haplotypes, of which 5 had not previously been described. The haplotype distribution differed significantly from that of northern European populations, suggesting that mutant PAH alleles had multiple origins and spread through different populations probably because of a selective advantage to the heterozygote. No deletions were discovered.
In 2 reports, Daiger et al. (1989) and Daiger et al. (1989) analyzed polymorphic DNA haplotypes at the PAH locus in European and Asian (Chinese and Japanese) families. Much less haplotypic variation was found in Asians than in Caucasians. In particular, in Asians, haplotype 4 accounted for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. The next most common Asian haplotype was 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations, several of the most common haplotypes are equally frequent. Within European populations, a parent carrying a PKU mutation has an average probability of greater than 86% of being heterozygous--and hence informative for linkage--at one or more PAH RFLP sites. In Asian families about 36% of carriers are expected to be heterozygous at one or more RFLP sites.
In a study of 29 patients in Bulgaria, Kalaydjieva et al. (1990) found that the arg408-to-trp mutation (R408W; 612349.0002) was the most frequent, representing 34% of PKU alleles on the haplotype 2 background. The splicing defect in intron 12, which was found to account for nearly 40% of PKU alleles in Denmark, was absent in Bulgaria as was also the haplotype 3 associated with it. The arg158-to-gln mutation (612349.0010), which had been found in about 40% of mutant haplotype 4 alleles in western Europeans, was detected in only 1 out of 58 PKU chromosomes in Bulgaria.
Judging from the distribution of haplotypes and a limited investigation of the molecular defects, Dianzani et al. (1990) concluded that the 2 mutations most frequent in northern Europe, the splicing mutation (612349.0001) and the missense mutation (612349.0002), are uncommon in Italy, where haplotypes 1 and 6 account for about 57% of the PKU chromosomes and haplotypes 2 and 3 are found in less than 9%.
Konecki and Lichter-Konecki (1991) reviewed the haplotypes associated with specific PAH mutations in PKU patients. Haplotypes 2 and 3 are associated with mutant alleles among European populations north of the Alps; the same haplotypes are of little significance in European populations south of the Alps. A different haplotype 2 mutation (met1-to-val) was observed among French-Canadian PKU patients (John et al., 1990).
On the basis of 10 years of Maryland newborn-screening data, Hofman et al. (1991) concluded that the frequency of PKU in U.S. blacks is about 1 in 50,000, or one-third that in whites. They performed haplotype analysis of the PAH gene of 36 U.S. blacks, of whom 16 had classic PKU and 20 were controls. In the control blacks, 20% of wildtype PAH alleles had a common Caucasian haplotype, namely, haplotype 1, whereas 80% had a variety of haplotypes, all rare in Caucasians and Asians. One of these, haplotype 15, accounted for 30%. Among black mutant PAH alleles, 20% had a haplotype, either 1 or 4, common in Caucasians; 40% had a haplotype rare in Caucasians and Asians, and 40% had 1 of 2 previously undescribed haplotypes. Both of the latter could be derived from known haplotypes by a single event.
Eisensmith and Woo (1992) gave an updated listing of haplotypes at the PAH locus. Most if not all PAH mutations appear to have occurred after the divergence of the races (Eisensmith et al., 1992). Eisensmith et al. (1992) studied the haplotype associations, relative frequencies, and distributions of 5 prevalent PAH mutations in European populations: IVS12nt1 (612349.0001), arg408-to-trp (612349.0002), arg261-to-gln (612349.0006), arg158-to-gln (612349.0010), and IVS10nt546 (612349.0033). Each of these 5 mutations was strongly associated with only 1 of the more than 70 chromosomal haplotypes defined by 8 RFLPs in or near the PAH gene. These findings suggested that each of these mutations arose through a single founding event that occurred within time periods ranging from several hundred to several thousand years ago. From the significant differences observed in the relative frequencies and distributions of these 5 alleles throughout Europe, 4 of the putative founding events could be localized to specific ethnic subgroups: the IVS12nt1 mutation appears to have occurred on a normal haplotype 3 chromosome in a Danish founding population. The arg408-to-trp mutation probably originated on a haplotype 2 chromosome in a Czechoslovakian population, although the absence of haplotype and frequency data from the more eastern regions of the Russian and other republics of the former Soviet Union precluded precise localization of a putative founding population. The absence of this mutation from haplotype 2 chromosomes in Chinese and Japanese populations suggested that the founding event was unique to Caucasoid peoples. Furthermore, the strong association still present between this mutation and haplotype 2 suggested that the founding event occurred within the past few millennia. The IVS10nt546 mutation was thought to be of Turkish origin but further study of its distribution within the Italian population showed that the allele was present primarily in regions that had been settled by Italian peoples prior to 1000 B.C., not in regions settled by Turks or other Middle Eastern groups. The arg261-to-gln mutation was relatively frequent in both Switzerland and Turkey where it occurred on haplotype 1. A putative founding population could not be identified for the arg158-to-gln mutation. Since only 2 of the 20 or so PAH mutations that account for more than 70% of all mutant alleles in Asians are present in both Caucasians and Asians, and since the 2 exceptions occur on different haplotype backgrounds suggesting that they result from recurrent mutation, most if not all PAH mutations appear to have occurred after the divergence of the races.
PKU has a very low incidence in Finland (Palo, 1967). Guldberg et al. (1995) studied all 4 known patients in Finland. The R408W mutation (612349.0002) was found on 4 mutant chromosomes (all haplotype 2), and IVS7nt1 (612349.0025), R261Q (612349.0006), and IVS2nt1 were each found on a single chromosome. No mutation was found on the remaining chromosome. The authors stated that the findings supported a pronounced negative founder effect as the cause of the low incidence of PKU in Finland. Eisensmith et al. (1992) demonstrated that the R408W mutation clusters in 2 regions: in northwest Europe, with the highest frequency reported in Ireland, and eastern Europe, with the highest frequency reported in Lithuania. In these 2 sites, the mutation is associated with haplotype 1 and haplotype 2, respectively, leading to the suggestion that R408W had 2 independent origins in Europe: 1 Celtic, and 1 Slavic. It is the Slavic mutation that has found its way to Finland in a small number of cases.
In an analysis of 236 Norwegian PKU alleles, Eiken et al. (1996) identified 33 different mutations constituting 99.6% of all mutant alleles; only 1 allele remained unidentified. Twenty-three of these mutations had been identified also in other European countries. 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 83.5% of the PKU alleles, with single allele frequencies ranging from 5.9% to 15.7%. Nineteen mutations were encountered only once. Most of the PKU mutations were found in the same RFLP/VNTR haplotype backgrounds in Norway as in other European populations, suggesting that only a few of the mutations may represent recurrent mutations (less than 3.4%). Among 10 mutations reported only in Norway, Eiken et al. (1996) detected 2 de novo mutations. 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. (1997) examined the PAH gene in the PKU populations of 4 geographic areas of the British Isles: the west of Scotland, southern Wales, and southwestern and southeastern England. 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. Allele frequencies of the more common mutations exhibited significant nonrandom distribution in a north/south differentiation.
In Quebec, Carter et al. (1998) analyzed 135 of 141 chromosomes from PKU probands and 8 additional chromosomes from a small number of probands with non-PKU hyperphenylalaninemia. The full set of chromosomes harbored 45 different PAH mutations: 7 polymorphisms, 4 mutations causing non-PKU HPA, and 34 mutations causing PKU. Only 6 mutations occurred in the whole province at relative frequencies greater than 5%; most of the mutations were rare and probably identical by descent. 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. (1996) screened for tyrosinemia in the West Midlands region of the U.K., which includes the city of Birmingham, and demonstrated an increased frequency of tyrosinemia I in infants of 'non-oriental Asian ethnicity,' presumably mostly Pakistani. The incidence in this group was estimated to be 3.7 per million as compared with 0.04 per million in the rest of the population. Of the 12 patients with tyrosinemia I in the West Midlands, 10 were of 'non-oriental Asian' origin.
Zschocke et al. (1997) suggested that analysis of PKU mutations in Northern Ireland shows that most major episodes of immigration have left a record in the modern gene pool. The mutation ile65 to thr (612349.0063) could be traced to the Paleolithic people of western Europe who, in the Mesolithic period, first colonized Ireland. In contrast, arg408 to trp (612349.0002) on haplotype 1, the most common Irish PKU mutation, may have been prevalent in the Neolithic families who settled in Ireland after 4500 B.C. 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. This indicated that PKU was not brought to Norway from the British Isles, as had been previously argued. The rarity in Northern Ireland of the IVS12nt1 mutation (612349.0001), the most common mutation in Denmark and England, indicated that the English colonization of Ireland did not alter the local gene pool in a direction that could be described as Anglo-Saxon.
Iceland was settled during the late ninth and early tenth centuries A.D. by Vikings who arrived from Norway and the British Isles. 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. Guldberg et al. (1997) investigated the molecular basis of PKU in 17 Icelandic patients and found 9 different mutations in the PAH gene. One novel mutation accounted for 40% of the mutant chromosomes: deletion of 1 of 2 successive thymidine residues in codons 376 and 377 in exon 11, resulting in a frameshift and the introduction of a termination codon at residue 399 (612349.0061). 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. (2003) discussed population screening in the age of genomic medicine using PKU as a classic example and extending the discussion to population screening for genetic susceptibility to common disorders such as hereditary hemochromatosis (235200) and factor V Leiden (see 612309.0001). 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.
Among 34 unrelated patients with PKU from Serbia and Montenegro. Stojiljkovic et al. (2006) found that the 2 most common mutations were L48S and R408W, accounting for 21% and 18% of mutant alleles, respectively. Overall, 5 mutations accounted for 60% of all mutant alleles. The results suggested that PKU in this population is heterogeneous and reflects numerous migrations over the Balkan peninsula.
Wang et al. (2007) reported unexpected PAH allelic heterogeneity between 2 groups of Old Order Amish: the Lancaster County, Pennsylvania settlement, and the Geauga County, Ohio settlement. Individuals with PKU from the Geauga County settlement were homozygous for a splice site mutation (612349.0033), and the incidence of PKU in this group was estimated to be 1 in 1,000, much higher than in other populations. In contrast, those with PKU from Lancaster County were compound heterozygous for 2 PAH mutations: R261Q (612349.0006) and a 3-bp deletion (612349.0030). The incidence of PKU in the Lancaster County Amish was 1 in 10,000, similar to that in other populations. Wang et al. (2007) commented that the findings highlighted important points in population genetics: rare genetic diseases in isolated populations are not uniformly caused by a single mutation and genetic drift is random, thus sampling effects are as likely to decrease as they are to increase mutation frequency within a given population.
Among 140 unrelated Iranian patients with classic PKU, 84 of whom were born to consanguineous families, Esfahani and Vallian (2019) identified 34 different mutations, the most prevalent being IVS10nt546 (612349.0033) and P281L (612349.0012), with frequencies of 26.07% and 19.3%, respectively.
Woolf (1986) 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. (1990) isolated mutant mice exhibiting hereditary hyperphenylalaninemia after ethylnitrosourea mutagenesis of the germ line. 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 (1997) identified a mutation within the protein coding sequence of the Pah gene in each of 2 genetic mouse models for human phenylketonuria. A genotype/phenotype relationship that was strikingly similar to the human disease emerged, underscoring the similarity of PKU in mouse and man. 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. (2010) reviewed the findings from animal studies on the mechanism of phenylalanine action in the PKU brain, including defects in myelin and protein synthesis, blood-brain barrier transport, direct neurotoxic effects of phenylalanine, neurotransmitter imbalances, activity of glutamate receptors, and animal behavior.
Gersting et al. (2010) found that loss of function in Pah-enu1 mice was a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. 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 (1934) in Norway first described PKU under the designation oligophrenica phenylpyruvica. Jervis (1947) localized the metabolic error as an inability to oxidize phenylalanine to tyrosine, and Jervis (1953) demonstrated deficiency of phenylalanine hydroxylase in the liver of a patient.
Guthrie (1996) 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 1961 and was reported by Guthrie and Susi (1963). In the first 2 years, 400,000 infants were tested in 29 states and 39 cases of PKU were found--an incidence of about 1 per 10,000. None was missed by screening. Guthrie (1996) 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 1967.
Bickel (1996) described his first introduction to the disease PKU in 1949 at the University Children's Hospital Zurich where Professor G. 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., 1953) speculated that there might be a causal relation between the Phe excess in the biologic fluids and the girl's brain damage and that it might be possible to improve her condition by reducing Phe intake. The use of a Phe-restricted casein hydrolysate as the main protein source of the diet was considered. Early results were dramatic.
Early Mapping Studies
Berg and Saugstad (1974) found low positive lod scores for linkage between PKU and PGM-1, Rh, Hp, and Kell. A previous suggestion of linkage between PKU and ABO could not be confirmed.
Kamaryt et al. (1978) studied linkage of the chromosome 1 amylase loci with PKU. Combined data for linkage with the two amylase loci yielded a lod score of 4.214 at a recombination fraction of 0.00. Paul et al. (1979) were unable to confirm linkage of PKU to chromosome 1 markers. Linkage with theta less than 0.10 was excluded for AMY2. They expressed reservations about the data of Kamaryt et al. (1978) because of the questionable accuracy of scoring AMY1 in urine and because data were used twice from a family with a parent heterozygous at both amylase loci. In this study done in Indiana, no evidence of linkage heterogeneity between Amish and non-Amish families was found.
Rao et al. (1979) derived a maximum likelihood map of chromosome 1, using data on 13 loci. They concluded that assignment of the PKU locus to chromosome 1 could be confirmed, but left as uncertain its location in the PGM1-AMY segment. Cabalska (1980) was unable, however, to confirm the linkage of chromosome 1 markers. Knapp et al. (1982) excluded close linkage between the amylase and PKU loci. They considered loose linkage unlikely. Genetic heterogeneity was considered a possible but unlikely explanation.
Abadie, V., Jaruzelska, J., Lyonnet, S., Millasseau, P., Berthelon, M., Rey, F., Munnich, A., Rey, J. Illegitimate transcription of the phenylalanine hydroxylase gene in lymphocytes for identification of mutations in phenylketonuria. Hum. Molec. Genet. 2: 31-34, 1993. [PubMed: 8098245] [Full Text: https://doi.org/10.1093/hmg/2.1.31]
Abadie, V., Lyonnet, S., Maurin, N., Berthelon, M., Caillaud, C., Giraud, F., Mattei, J.-F., Rey, J., Rey, F., Munnich, A. CpG dinucleotides are mutation hot spots in phenylketonuria. Genomics 5: 936-939, 1989. [PubMed: 2574153] [Full Text: https://doi.org/10.1016/0888-7543(89)90137-7]
Agostoni, C., Massetto, N., Biasucci, G., Rottoli, A., Bonvissuto, M., Bruzzese, M., Giovannini, M., Riva, E. Effects of long-chain polyunsaturated fatty acid supplementation on fatty acid status and visual function in treated children with hyperphenylalaninemia. J. Pediat. 137: 504-509, 2000. [PubMed: 11035829] [Full Text: https://doi.org/10.1067/mpd.2000.108398]
Aoki, K., Siegel, F. L. Hyperphenylalaninemia: disaggregation of brain polyribosomes in young rats. Science 168: 129-130, 1970. [PubMed: 5461364] [Full Text: https://doi.org/10.1126/science.168.3927.129]
Arthur, L. J. H., Hulme, J. D. Intelligent, small for dates baby born to oligophrenic phenylketonuric mother after low phenylalanine diet during pregnancy. Pediatrics 46: 235-239, 1970. [PubMed: 5432154]
Auerbach, V. H., DiGeorge, A. M., Carpenter, G. G. Phenylalaninemia: a study of the diversity of disorders which produce elevation of blood concentrations of phenylalanine. In: Nyhan, W. L.: Amino Acid Metabolism and Genetic Variation. New York: McGraw-Hill (pub.) 1967. Pp. 11-68.
Barat, P., Barthe, N., Redonnet-Vernhet, I., Parrot, F. The impact of the control of serum phenylalanine levels on osteopenia in patients with phenylketonuria. Europ. J. Pediat. 161: 687-688, 2002. [PubMed: 12536994] [Full Text: https://doi.org/10.1007/s00431-002-1091-9]
Bartholome, K., Olek, K., Trefz, F. Compound heterozygotes in hyperphenylalaninaemia. Hum. Genet. 65: 405-406, 1984. [PubMed: 6693130] [Full Text: https://doi.org/10.1007/BF00291569]
Berg, K., Saugstad, L. F. A linkage study of phenylketonuria. Clin. Genet. 6: 147-152, 1974. [PubMed: 4214640] [Full Text: https://doi.org/10.1111/j.1399-0004.1974.tb00644.x]
Bickel, H., Gerrard, J., Hickmans, E. M. Influence of phenylalanine intake on phenylketonuria. Lancet 265: 812-813, 1953. Note: Originally Volume II. [PubMed: 13098090] [Full Text: https://doi.org/10.1016/s0140-6736(53)90473-5]
Bickel, H., Gerrard, J., Hickmans, E. M. The influence of phenylalanine intake on the chemistry and behaviour of a phenylketonuric child. Acta Paediat. (Stockh.) 43: 64-77, 1954. [PubMed: 13138177] [Full Text: https://doi.org/10.1111/j.1651-2227.1954.tb04000.x]
Bickel, H. The first treatment of phenylketonuria. Europ. J. Pediat. 155 (suppl. 1): S2-S3, 1996. [PubMed: 8828598] [Full Text: https://doi.org/10.1007/BF03036506]
Blau, N., van Spronsen, F. J., Levy, H. L. Phenylketonuria. Lancet 376: 1417-1427, 2010. [PubMed: 20971365] [Full Text: https://doi.org/10.1016/S0140-6736(10)60961-0]
Bowden, J. A., McArthur, C. L., III. Possible biochemical model for phenylketonuria. Nature 235: 230, 1972. [PubMed: 4551128] [Full Text: https://doi.org/10.1038/235230a0]
Brenton, D. P., Lilburn, M. Maternal phenylketonuria: a study from the United Kingdom. Europ. J. Pediat. 155 (suppl. 1): S177-S180, 1996. [PubMed: 8828640] [Full Text: https://doi.org/10.1007/pl00014242]
Brumm, V. L., Bilder, D., Waisbren, S. E. Psychiatric symptoms and disorders in phenylketonuria. Molec. Genet. Metab. 99: S59-S63, 2010. [PubMed: 20123472] [Full Text: https://doi.org/10.1016/j.ymgme.2009.10.182]
Burgard, P., Rupp, A., Konecki, D. S., Trefz, F. K., Schmidt, H., Lichter-Konecki, U. Phenylalanine hydroxylase genotypes, predicted residual enzyme activity and phenotypic parameters of diagnosis and treatment of phenylketonuria. Europ. J. Pediat. 155 (suppl.): S11-S15, 1996. [PubMed: 8828601] [Full Text: https://doi.org/10.1007/pl00014222]
Cabalska, B. Personal Communication. Warsaw, Poland 1980.
Carter, C. O., Woolf, L. I. The birthplaces of parents and grandparents of a series of patients with phenylketonuria in southeast England. Ann. Hum. Genet. 25: 57-64, 1961. [PubMed: 13691132] [Full Text: https://doi.org/10.1111/j.1469-1809.1961.tb01497.x]
Carter, K. C., Byck, S., Waters, P. J., Richards, B., Nowacki, P. M., Laframboise, R., Lambert, M., Treacy, E., Scriver, C. R. Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience. Europ. J. Hum. Genet. 6: 61-70, 1998. [PubMed: 9781015] [Full Text: https://doi.org/10.1038/sj.ejhg.5200153]
Centerwall, W. R., Neff, C. A. Phenylketonuria: a case report of children of Jewish ancestry. Arch. Pediat. 78: 379-384, 1961.
Chen, S.-H., Hsiao, K.-J., Lin, L.-H., Liu, T.-T., Tang, R.-B., Su, T.-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. Hum. Genet. 81: 226-230, 1989. [PubMed: 2563988] [Full Text: https://doi.org/10.1007/BF00278993]
Cipcic-Schmidt, S., Trefz, F. K., Funders, B., Seidlitz, G., Ullrich, K. German maternal phenylketonuria study. Europ. J. Pediat. 155 (suppl. 1): S173-S176, 1996. [PubMed: 8828639] [Full Text: https://doi.org/10.1007/pl00014241]
Cohen, B. E., Bodonyi, E., Szeinberg, A. Phenylketonuria in Jews. Lancet 277: 344-345, 1961. Note: Originally Volume I.
Coskun, T., Ozalp, I., Kale, G., Gogus, S. Scleroderma-like skin lesions in two patients with phenylketonuria. Europ. J. Pediat. 150: 109-110, 1990. [PubMed: 2279504] [Full Text: https://doi.org/10.1007/BF02072050]
Crujeiras, V., Aldamiz-Echevarria, L., Dalmau, J., Vitoria, I., Andrade, F., Roca, I., Leis, R., Fernandez-Marmiesse, A., Couce, M. L. Vitamin and mineral status in patients with hyperphenylalaninemia. Molec. Genet. Metab. 115: 145-150, 2015. [PubMed: 26123187] [Full Text: https://doi.org/10.1016/j.ymgme.2015.06.010]
Cunningham, G. C., Day, R. W., Berman, J. L., Hsia, D. Y.-Y. Phenylalanine tolerance tests in families with phenylketonuria and hyperphenylalaninemia. Am. J. Dis. Child. 117: 626-635, 1969. [PubMed: 5771502]
Daiger, S. P., Chakraborty, R., Reed, L., Fekete, G., Schuler, D., Berenssi, G., Nasz, I., Brdicka, R., Kamaryt, J., Pijackova, A., Moore, S., Sullivan, S., Woo, S. L. C. Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU). Am. J. Hum. Genet. 45: 310-318, 1989. [PubMed: 2569271]
Daiger, S. P., Lidsky, A. S., Chakraborty, R., Koch, R., Guttler, F., Woo, S. L. C. Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria. Lancet 327: 229-232, 1986. Note: Originally Volume I. [PubMed: 2868252] [Full Text: https://doi.org/10.1016/s0140-6736(86)90771-3]
Daiger, S. P., Reed, L., Huang, S.-S., Zeng, Y.-T., Wang, T., Lo, W. H. Y., Okano, Y., Hase, Y., Fukuda, Y., Oura, T., Tada, K., Woo, S. L. C. Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU). Am. J. Hum. Genet. 45: 319-324, 1989. [PubMed: 2569272]
Dianzani, I., Devoto, M., Camaschella, C., Saglio, G., Ferrero, G. B., Cerone, R., Romano, C., Romeo, G., Giovannini, M., Riva, E., Angeneydt, F., Trefz, F. K., Okano, Y., Woo, S. L. C. Haplotype distribution and molecular defects at the phenylalanine hydroxylase locus in Italy. Hum. Genet. 86: 69-72, 1990. [PubMed: 1979309] [Full Text: https://doi.org/10.1007/BF00205176]
DiLella, A. G., Huang, W.-M., Woo, S. L. C. Screening for phenylketonuria mutations by DNA amplification with the polymerase chain reaction. Lancet 331: 497-499, 1988. Note: Originally Volume I. [PubMed: 2893918] [Full Text: https://doi.org/10.1016/s0140-6736(88)91295-0]
DiLella, A. G., Kwok, S. C. M., Ledley, F. D., Marvit, J., Woo, S. L. C. Molecular structure and polymorphic map of the human phenylalanine hydroxylase gene. Biochemistry 25: 743-749, 1986. [PubMed: 3008810] [Full Text: https://doi.org/10.1021/bi00352a001]
Drogari, E., Smith, I., Beasley, M., Lloyd, J. K. Timing of strict diet in relation to fetal damage in maternal phenylketonuria: an international collaborative study by the MRC/DHSS phenylketonuria register. Lancet 330: 927-930, 1987. Note: Originally Volume II. [PubMed: 2889860] [Full Text: https://doi.org/10.1016/s0140-6736(87)91418-8]
Dworniczak, B., Aulehla-Scholz, C., Horst, J. Phenylalanine hydroxylase gene: silent mutation uncovers evolutionary origin of different alleles. Clin. Genet. 38: 270-273, 1990. [PubMed: 2268974] [Full Text: https://doi.org/10.1111/j.1399-0004.1990.tb03580.x]
Eiken, H. G., Knappskog, P. M., Boman, H., Thune, K. S., Kaada, G., Motzfeldt, K., Apold, J. Relative frequency, heterogeneity and geographic clustering of PKU mutations in Norway. Europ. J. Hum. Genet. 4: 205-213, 1996. [PubMed: 8875186] [Full Text: https://doi.org/10.1159/000472200]
Eisensmith, R. C., Okano, Y., Dasovich, M., Wang, T., Guttler, F., Lou, H., Guldberg, P., Lichter-Konecki, U., Konecki, D. S., Svensson, E., Hagenfeldt, L., Rey, F., Munnich, A., Lyonnet, S., Cockburn, F., Connor, J. M., Pembrey, M. E., Smith, I., Gitzelmann, R., Steinmann, B., Apold, J., Eiken, H. G., Giovannini, M., Riva, E., Longhi, R., Romano, C., Cerone, R., Naughten, E. R., Mullins, C., Cahalane, S., Ozalp, I., Fekete, G., Schuler, D., Berencsi, G. Y., Nasz, I., Brdicka, R., Kamaryt, J., Pijackova, A., Cabalska, B., Boszkowa, K., Schwartz, E., Kalinin, V. N., Jin, L., Chakraborty, R., Woo, S. L. C. Multiple origins for phenylketonuria in Europe. Am. J. Hum. Genet. 51: 1355-1365, 1992. [PubMed: 1361100]
Eisensmith, R. C., Woo, S. L. C. Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. Hum. Mutat. 1: 13-23, 1992. [PubMed: 1301187] [Full Text: https://doi.org/10.1002/humu.1380010104]
Eisensmith, R. C., Woo, S. L. C. Updated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus. (Letter) Am. J. Hum. Genet. 51: 1445-1448, 1992. [PubMed: 1361103]
Eisensmith, R. C., Woo, S. L. C. Gene therapy for phenylketonuria. Europ. J. Pediat. 155 (suppl. 1): S16-S19, 1996. [PubMed: 8828602] [Full Text: https://doi.org/10.1007/pl00014237]
Esfahani, M. S., Vallian, S. A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients. Europ. J. Med. Genet. 62: 103559, 2019. Note: Electronic Article. [PubMed: 30389586] [Full Text: https://doi.org/10.1016/j.ejmg.2018.10.011]
Fisch, R. O., Tagatz, G., Stassart, J. P. Gestational carrier--a reproductive haven for offspring of mothers with phenylketonuria (PKU): an alternative therapy for maternal PKU. J. Inherit. Metab. Dis. 16: 957-961, 1993. [PubMed: 8127071] [Full Text: https://doi.org/10.1007/BF00711511]
Flatz, G., Oelbe, M., Herrmann, H. Ethnic distribution of phenylketonuria in the north German population. Hum. Genet. 65: 396-399, 1984. [PubMed: 6693127] [Full Text: https://doi.org/10.1007/BF00291566]
Folling, A. Ueber Ausscheidung von Phenylbrenztraubensaeure in den Harn als Stoffwechselanomalie in Verbindung mit Imbezillitaet. Ztschr. Physiol. Chem. 227: 169-176, 1934.
Forrest, S. M., Dahl, H. H., Howells, D. W., Dianzani, I., Cotton, R. G. H. Mutation detection in phenylketonuria by using chemical cleavage of mismatch: importance of using probes from both normal and patient samples. Am. J. Hum. Genet. 49: 175-183, 1991. Note: Erratum: Am. J. Hum. Genet. 50: 659 only, 1992. [PubMed: 2063869]
Frankenburg, W. K., Duncan, B. R., Coffelt, R. W., Koch, R., Coldwell, J. G., Son, C. D. Maternal phenylketonuria: implications for growth and development. J. Pediat. 73: 560-570, 1968. [PubMed: 5677997] [Full Text: https://doi.org/10.1016/s0022-3476(68)80271-9]
Friedman, P. A., Fisher, D. B., Kang, E. S., Kaufman, S. Detection of hepatic phenylalanine 4-hydroxylase in classical phenylketonuria. Proc. Nat. Acad. Sci. 70: 552-556, 1973. [PubMed: 4405625] [Full Text: https://doi.org/10.1073/pnas.70.2.552]
Gentile, J. K., Ten Hoedt, A. E., Bosch, A. M. Psychosocial aspects of PKU: hidden disabilities - a review. Molec. Genet. Metab. 99: S64-S67, 2010. [PubMed: 20123473] [Full Text: https://doi.org/10.1016/j.ymgme.2009.10.183]
Gersting, S. W., Kemter, K. F., Staudigl, M., Messing, D. D., Danecka, M. K., Lagler, F. B., Sommerhoff, C. P., Roscher, A. A., Muntau, A. C. Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. Am. J. Hum. Genet. 83: 5-17, 2008. [PubMed: 18538294] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.013]
Gersting, S. W., Lagler, F. B., Eichinger, A., Kemter, K. F., Danecka, M. K., Messing, D. D., Staudigl, M., Domdey, K. A., Zsifkovits, C., Fingerhut, R., Glossmann, H., Roscher, A. A., Muntau, A. C. Pah-enu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Hum. Molec. Genet. 19: 2039-2049, 2010. [PubMed: 20179079] [Full Text: https://doi.org/10.1093/hmg/ddq085]
Gjetting, T., Petersen, M., Guldberg, P., Guttler, F. Missense mutations in the N-terminal domain of human phenylalanine hydroxylase interfere with binding of regulatory phenylalanine. Am. J. Hum. Genet. 68: 1353-1360, 2001. [PubMed: 11326337] [Full Text: https://doi.org/10.1086/320604]
Greeves, L. G., Patterson, C. C., Carson, D. J., Thom, R., Wolfenden, M. C., Zshocke, J., Graham, C. A., Nevin, N. C., Trimble, E. R. Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia. Arch. Dis. Child. 82: 216-221, 2000. [PubMed: 10685924] [Full Text: https://doi.org/10.1136/adc.82.3.216]
Gregory, D. M., Sovetts, D., Clow, C. L., Scriver, C. R. Plasma free amino acid values in normal children and adolescents. Metabolism 35: 967-969, 1986. [PubMed: 3762400] [Full Text: https://doi.org/10.1016/0026-0495(86)90063-6]
Griffiths, P. V., Demellweek, C., Fay, N., Robinson, P. H., Davidson, D. C. Wechsler subscale IQ and subtest profile in early treated phenylketonuria. Arch. Dis. Child. 82: 209-215, 2000. [PubMed: 10685922] [Full Text: https://doi.org/10.1136/adc.82.3.209]
Guldberg, P., Henriksen, K. F., Sipila, I., Guttler, F., de la Chapelle, A. Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland. J. Med. Genet. 32: 976-978, 1995. [PubMed: 8825928] [Full Text: https://doi.org/10.1136/jmg.32.12.976]
Guldberg, P., Zschocke, J., Dagbjartsson, A., Henriksen, K. F., Guttler, F. A molecular survey of phenylketonuria in Iceland: identification of a founding mutation and evidence of predominant Norse settlement. Europ. J. Hum. Genet. 5: 376-381, 1997. [PubMed: 9450182]
Guthrie, R., Susi, A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 32: 338-343, 1963. [PubMed: 14063511]
Guthrie, R. The introduction of newborn screening for phenylketonuria: a personal history. Europ. J. Pediat. 155 (suppl. 1): S4-S5, 1996. [PubMed: 8828599] [Full Text: https://doi.org/10.1007/pl00014247]
Guttler, F., Hansen, G. Heterozygote detection in phenylketonuria. Clin. Genet. 11: 137-146, 1977. [PubMed: 837563] [Full Text: https://doi.org/10.1111/j.1399-0004.1977.tb01291.x]
Guttler, F., Ledley, F. D., Lidsky, A. S., DiLella, A. G., Sullivan, S. E., Woo, S. L. C. Correlation between polymorphic DNA haplotypes at phenylalanine hydroxylase locus and clinical phenotypes of phenylketonuria. J. Pediat. 110: 68-71, 1987. [PubMed: 2878985] [Full Text: https://doi.org/10.1016/s0022-3476(87)80290-1]
Guttler, F., Woo, S. L. C. Molecular genetics of PKU. J. Inherit. Metab. Dis. 9 (suppl. 1): 58-68, 1986. [PubMed: 2878116] [Full Text: https://doi.org/10.1007/BF01800859]
Guttler, F. Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Acta Paediat. Scand. Suppl. 280: 1-80, 1980. [PubMed: 7006308]
Hanley, W. B., Clarke, J. T. R., Schoonheyt, W. Maternal phenylketonuria (PKU)--a review. Clin. Biochem. 20: 149-156, 1987. [PubMed: 3308176] [Full Text: https://doi.org/10.1016/s0009-9120(87)80112-1]
Hanley, W. B., Koch, R., Levy, H. L., Matalon, R., Rouse, B., Azen, C., de la Cruz, F. The North American Maternal Phenylketonuria Collaborative Study, developmental assessment of the offspring: preliminary report. Europ. J. Pediat. 155 (suppl. 1): S169-S172, 1996. [PubMed: 8828638] [Full Text: https://doi.org/10.1007/pl00014240]
Hanley, W. B., Lee, A. W., Hanley, A. J. G., Lehotay, D. C., Austin, V. J., Schoonheyt, W. E., Platt, B. A., Clarke, J. T. R. 'Hypotyrosinemia' in phenylketonuria. Molec. Genet. Metab. 69: 286-294, 2000. [PubMed: 10870846] [Full Text: https://doi.org/10.1006/mgme.2000.2985]
Hertzberg, M., Jahromi, K., Ferguson, V., Dahl, H. H. M., Mercer, J., Mickleson, K. N. P., Trent, R. J. Phenylalanine hydroxylase gene haplotypes in Polynesians: evolutionary origins and absence of alleles associated with severe phenylketonuria. Am. J. Hum. Genet. 44: 382-387, 1989. [PubMed: 2563633]
Hofman, K. J., Steel, G., Kazazian, H. H., Valle, D. Phenylketonuria in U.S. blacks: molecular analysis of the phenylalanine hydroxylase gene. Am. J. Hum. Genet. 48: 791-798, 1991. [PubMed: 2014802]
Hollander, S., Viau, K., Sacharow, S. Pegvaliase dosing in adults with PKU: requisite dose for efficacy decreases over time. Molec. Genet. Metab. 137: 104-106, 2022. [PubMed: 35964530] [Full Text: https://doi.org/10.1016/j.ymgme.2022.08.001]
Holtzman, N. A., Kronmal, R. A., van Doorninck, W., Azen, C., Koch, R. Effect of age at loss of dietary control on intellectual performance and behavior of children with phenylketonuria. New Eng. J. Med. 314: 593-598, 1986. [PubMed: 3945244] [Full Text: https://doi.org/10.1056/NEJM198603063141001]
Hoskins, J. A., Jack, G., Wade, H. E., Peiris, R. J. D., Wright, E. C., Starr, D. J. T., Stern, J. Enzymatic control of phenylalanine intake in phenylketonuria. Lancet 315: 392-394, 1980. Note: Originally Volume I. [PubMed: 6101846] [Full Text: https://doi.org/10.1016/s0140-6736(80)90944-7]
Howell, R. R., Stevenson, R. E. The offspring of phenylketonuric women. Soc. Biol. 18 (suppl.): S19-S29, 1971. [PubMed: 4945474]
Hsia, D. Y.-Y. Phenylketonuria and its variants. Prog. Med. Genet. 7: 29-68, 1970. [PubMed: 4915811]
Huijbregts, S. C. J., De Sonneville, L. M. J., Licht, R., van Spronsen, F. J., Sergeant, J. A. Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. J. Inherit. Metab. Dis. 25: 419-430, 2002. [PubMed: 12555935] [Full Text: https://doi.org/10.1023/a:1021205713674]
Huntley, C. C., Stevenson, R. E. Maternal phenylketonuria: course of two pregnancies. Obstet. Gynec. 34: 694-700, 1969. [PubMed: 5391176]
Hutchesson, A. C. J., Hall, S. K., Preece, M. A., Green, A. Screening for tyrosinaemia type I. Arch. Dis. Child. Fetal Neonatal Ed. 74: F191-F194, 1996. [PubMed: 8777683] [Full Text: https://doi.org/10.1136/fn.74.3.f191]
Jervis, G. A. Studies on phenylpyruvic oligophrenia: the position of the metabolic error. J. Biol. Chem. 169: 651-656, 1947. [PubMed: 20259098]
Jervis, G. A. Phenylpyruvic oligophrenia deficiency of phenylalanine-oxidizing system. Proc. Soc. Exp. Biol. Med. 82: 514-515, 1953. [PubMed: 13047448]
Jin, X., Yan, Y., Zhang, C., Tai, Y., An, L., Yu, X., Zhang, L., Hao, S., Cao, X., Yin, C., Ma, X. Identification of novel deep intronic PAH gene variants in patients diagnosed with phenylketonuria. Hum. Mutat. 43: 56-66, 2022. [PubMed: 34747549] [Full Text: https://doi.org/10.1002/humu.24292]
John, S. W. M., Rozen, R., Scriver, C. R., Laframboise, R., Laberge, C. Recurrent mutation, gene conversion, or recombination at the human phenylalanine hydroxylase locus: evidence in French-Canadians and a catalog of mutations. Am. J. Hum. Genet. 46: 970-974, 1990. [PubMed: 1971147]
Kalaydjieva, L., Dworniczak, B., Aulehla-Scholz, C., Devoto, M., Romeo, G., Sturhmann, M., Kucinskas, V., Yurgelyavicius, V., Horst, J. Silent mutations in the phenylalanine hydroxylase gene as an aid to the diagnosis of phenylketonuria. J. Med. Genet. 28: 686-690, 1991. [PubMed: 1682495] [Full Text: https://doi.org/10.1136/jmg.28.10.686]
Kalaydjieva, L., Dworniczak, B., Aulehla-Scholz, C., Kremensky, I., Bronzova, J., Eigel, A., Horst, J. Classical phenylketonuria in Bulgaria: RFLP haplotypes and frequency of the major mutations. J. Med. Genet. 27: 742-745, 1990. [PubMed: 1981599] [Full Text: https://doi.org/10.1136/jmg.27.12.742]
Kalaydjieva, L., Dworniczak, B., Kucinskas, V., Yurgeliavicius, V., Kunert, E., Horst, J. Geographical distribution gradients of the major PKU mutations and the linked haplotypes. Hum. Genet. 86: 411-413, 1991. [PubMed: 1671852] [Full Text: https://doi.org/10.1007/BF00201847]
Kamaryt, J., Mrskos, A., Podhradska, O., Kolcova, V., Cabalska, B., Duzynska, N., Borzymowska, J. PKU locus: genetic linkage with human amylase (AMY) loci and assignment to linkage group 1. Hum. Genet. 43: 205-210, 1978. [PubMed: 308492] [Full Text: https://doi.org/10.1007/BF00293596]
Kaufman, S., Max, E. E., Kang, E. S. Phenylalanine hydroxylase activity in liver biopsies from hyperphenylalaninemia heterozygotes: deviation from proportionality with gene dosage. Pediat. Res. 9: 632-634, 1975. [PubMed: 1153238] [Full Text: https://doi.org/10.1203/00006450-197508000-00004]
Kaufman, S. Phenylketonuria: biochemical mechanisms. Adv. Neurochem. 2: 1-132, 1976.
Kaufman, S. Differential diagnosis of variant forms of hyperphenylalaninemia. Pediatrics 65: 840-842, 1980. [PubMed: 7367098]
Kaufman, S. A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients. Proc. Nat. Acad. Sci. 96: 3160-3164, 1999. Note: Erratum: Proc. Nat. Acad. Sci. 96: 11687 only, 1999. [PubMed: 10077654] [Full Text: https://doi.org/10.1073/pnas.96.6.3160]
Kawashima, H., Kawano, M., Masaki, A., Sato, T. Three cases of untreated classical PKU: a report on cataracts and brain calcification. Am. J. Med. Genet. 29: 89-93, 1988. [PubMed: 3344778] [Full Text: https://doi.org/10.1002/ajmg.1320290111]
Keil, S., Anjema, K., van Spronsen, F. J., Lambruschini, N., Burlina, A., Belanger-Quintana, A., Couce, M. L., Feillet, F., Cerone, R., Lotz-Havla, A. S., Muntau, A. C., Bosch, A. M., Meli, C. A. P., Billette de Villemeur, T., Kern, I., Riva, E., Giovannini, M., Damaj, L., Leuzzi, V., Blau, N. Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. Pediatrics 131: e1881-e1888, 2013. Note: Electronic Article. [PubMed: 23690520] [Full Text: https://doi.org/10.1542/peds.2012-3291]
Kerr, G. R., Chamove, A. S., Harlow, H. F., Waisman, H. A. 'Fetal PKU': the effect of maternal hyperphenylalaninemia during pregnancy in the rhesus monkey (Macaca mulatta). Pediatrics 42: 27-36, 1968. [PubMed: 4968669]
Khoury, M. J., McCabe, L. L., McCabe, E. R. B. Population screening in the age of genomic medicine. New Eng. J. Med. 348: 50-58, 2003. [PubMed: 12510043] [Full Text: https://doi.org/10.1056/NEJMra013182]
Kidd, K. K. Phenylketonuria: population genetics of a disease. Nature 327: 282-283, 1987. [PubMed: 2884567] [Full Text: https://doi.org/10.1038/327282a0]
Knapp, A., Tintschewa, R., Scheibe, E., Schiebe, E., Jager, B., Biebler, K. E. The genetic linkage between the PKU locus and the loci for amylase-1, amylase-2, Fy, PGM-1, and Rh and the question of assignment of the PKU locus to chromosome no. 1. Hum. Genet. 60: 122-125, 1982. [PubMed: 6176531] [Full Text: https://doi.org/10.1007/BF00569696]
Koch, R., Burton, B., Hoganson, G., Peterson, R., Rhead, W., Rouse, B., Scott, R., Wolff, J., Stern, A. M., Guttler, F., Nelson, M., de la Cruz, F., Coldwell, J., Erbe, R., Geraghty, M. T., Shear, C., Thomas, J., Azen, C. Phenylketonuria in adulthood: a collaborative study. J. Inherit. Metab. Dis. 25: 333-346, 2002. [PubMed: 12408183] [Full Text: https://doi.org/10.1023/a:1020158631102]
Koch, R., Moats, R., Guttler, F., Guldberg, P., Nelson, M., Jr. Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics 106: 1093-1096, 2000. [PubMed: 11061780] [Full Text: https://doi.org/10.1542/peds.106.5.1093]
Komrower, G. M., Sardharwalla, I. B., Coutts, J. M. J., Ingham, D. Management of maternal phenylketonuria: an emerging clinical problem. Brit. Med. J. 1: 1383-1387, 1979. [PubMed: 445095] [Full Text: https://doi.org/10.1136/bmj.1.6175.1383]
Konecki, D. S., Lichter-Konecki, U. The phenylketonuria locus: current knowledge about alleles and mutations of the phenylalanine hydroxylase gene in various populations. Hum. Genet. 87: 377-388, 1991. [PubMed: 1679029] [Full Text: https://doi.org/10.1007/BF00197152]
Lasala, J. M., Coscia, C. J. Accumulation of a tetrahydroisoquinoline in phenylketonuria. Science 203: 283-284, 1979. [PubMed: 153583] [Full Text: https://doi.org/10.1126/science.153583]
Lassker, U., Zschocke, J., Blau, N., Santer, R. Tetrahydrobiopterin responsiveness in phenylketonuria: two new cases and a review of molecular genetic findings. J. Inherit. Metab. Dis. 25: 65-70, 2002. [PubMed: 11999982] [Full Text: https://doi.org/10.1023/a:1015194002487]
Ledley, F. D., DiLella, A. G., Woo, S. L. C. Molecular biology of phenylalanine hydroxylase and phenylketonuria. Trends Genet. 1: 309-313, 1985.
Ledley, F. D., Grenett, H. E., DiLella, A. G., Kwok, S. C. M., Woo, S. L. C. Gene transfer and expression of human phenylalanine hydroxylase. Science 228: 77-79, 1985. [PubMed: 3856322] [Full Text: https://doi.org/10.1126/science.3856322]
Ledley, F. D., Koch, R., Jew, K., Beaudet, A., O'Brien, W. E., Bartos, D. P., Woo, S. L. C. Phenylalanine hydroxylase expression in liver of a fetus with phenylketonuria. J. Pediat. 113: 463-468, 1988. [PubMed: 2900886] [Full Text: https://doi.org/10.1016/s0022-3476(88)80629-2]
Ledley, F. D., Levy, H. L., Woo, S. L. C. Molecular analysis of the inheritance of phenylketonuria and mild hyperphenylalaninemia in families with both disorders. New Eng. J. Med. 314: 1276-1280, 1986. [PubMed: 3702929] [Full Text: https://doi.org/10.1056/NEJM198605153142002]
Lenke, R. R., Levy, H. L. Maternal phenylketonuria and hyperphenylalaninemia: an international survey of the outcome of untreated and treated pregnancies. New Eng. J. Med. 303: 1202-1208, 1980. [PubMed: 7421947] [Full Text: https://doi.org/10.1056/NEJM198011203032104]
Leuzzi, V., Bianchi, M. C., Tosetti, M., Carducci, C., Carducci, C., Antonozzi, I. Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria. J. Inherit. Metab. Dis. 23: 563-570, 2000. [PubMed: 11032331] [Full Text: https://doi.org/10.1023/a:1005621727560]
Levy, H. L., Guldberg, P., Guttler, F., Hanley, W. B., Matalon, R., Rouse, B. M., Trefz, F., Azen, C., Allred, E. N., de la Cruz, F., Koch, R. Congenital heart disease in maternal phenylketonuria: report from the Maternal PKU Collaborative Study. Pediat. Res. 49: 636-642, 2001. [PubMed: 11328945] [Full Text: https://doi.org/10.1203/00006450-200105000-00005]
Levy, H. L., Karolkewicz, V., Houghton, S. A., MacCready, R. A. Screening the 'normal' population in Massachusetts for phenylketonuria. New Eng. J. Med. 282: 1455-1458, 1970. [PubMed: 5419295] [Full Text: https://doi.org/10.1056/NEJM197006252822604]
Levy, H. L., Lobbregt, D., Barnes, P. D., Poussaint, T. Y. Maternal phenylketonuria: magnetic resonance imaging of the brain in offspring. J. Pediat. 128: 770-775, 1996. [PubMed: 8648535] [Full Text: https://doi.org/10.1016/s0022-3476(96)70328-1]
Levy, H. L., Waisbren, S. E. Effects of untreated maternal phenylketonuria and hyperphenylalaninemia on the fetus. New Eng. J. Med. 309: 1269-1274, 1983. [PubMed: 6633585] [Full Text: https://doi.org/10.1056/NEJM198311243092101]
Lidsky, A. S., Guttler, F., Woo, S. L. C. Prenatal diagnosis of classic phenylketonuria by DNA analysis. Lancet 325: 549-551, 1985. Note: Originally Volume I. [PubMed: 2857902] [Full Text: https://doi.org/10.1016/s0140-6736(85)91208-5]
Lidsky, A. S., Ledley, F. D., DiLella, A. G., Kwok, S. C. M., Daiger, S. P., Robson, K. J. H., Woo, S. L. C. Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria. Am. J. Hum. Genet. 37: 619-634, 1985. [PubMed: 9556654]
Lidsky, A. S., Robson, K. J. H., Thirumalachary, C., Barker, P. E., Ruddle, F. H., Woo, S. L. C. The PKU locus in man is on chromosome 12. Am. J. Hum. Genet. 36: 527-533, 1984. [PubMed: 6547271]
Martinez-Pizarro, A., Dembic, M., Perez, B., Andresen, B. S., Desviat, L. R. Intronic PAH gene mutations cause a splicing defect by a novel mechanism involving U1snRNP binding downstream of the 5-prime splice site. PLoS Genet. 14: e1007360, 2018. [PubMed: 29684050] [Full Text: https://doi.org/10.1371/journal.pgen.1007360]
Martynyuk, A. E., van Spronsen, F. J., Van der Zee, E. A. Animal models of brain dysfunction in phenylketonuria. Molec. Genet. Metab. 99: S100-S105, 2010. [PubMed: 20123463] [Full Text: https://doi.org/10.1016/j.ymgme.2009.10.181]
Matalon, R., Justice, P., Deanching, M. N. Phenylalanine hydroxylase in human placenta: novel system for study of phenylketonuria. (Letter) Lancet 309: 853-854, 1977. Note: Originally Volume I. [PubMed: 67354] [Full Text: https://doi.org/10.1016/s0140-6736(77)92797-0]
Matalon, R., Koch, R., Michals-Matalon, K., Moseley, K., Surendran, S., Tyring, S., Erlandsen, H., Gamez, A., Stevens, R. C., Romstad, A., Moller, L. B., Guttler, F. Biopterin responsive phenylalanine hydroxylase deficiency. Genet. Med. 6: 27-32, 2004. [PubMed: 14726806] [Full Text: https://doi.org/10.1097/01.gim.0000108840.17922.a7]
McDonald, J. D., Bode, V. C., Dove, W. F., Shedlovsky, A. Pah(hph-5): a mouse mutant deficient in phenylalanine hydroxylase. Proc. Nat. Acad. Sci. 87: 1965-1967, 1990. [PubMed: 2308957] [Full Text: https://doi.org/10.1073/pnas.87.5.1965]
McDonald, J. D., Charlton, C. K. Characterization of mutations at the mouse phenylalanine hydroxylase locus. Genomics 39: 402-405, 1997. [PubMed: 9119379] [Full Text: https://doi.org/10.1006/geno.1996.4508]
Menkes, J. H., Aeberhard, E. Maternal phenylketonuria. J. Pediat. 74: 924-931, 1969. [PubMed: 5771752] [Full Text: https://doi.org/10.1016/s0022-3476(69)80227-1]
Muntau, A. C., Roschinger, W., Habich, M., Demmelmair, H., Hoffmann, B., Sommerhoff, C. P., Roscher, A. A. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. New Eng. J. Med. 347: 2122-2132, 2002. [PubMed: 12501224] [Full Text: https://doi.org/10.1056/NEJMoa021654]
Murphey, R. M. Phenylketonuria (PKU) and the single gene: an old story retold. Behav. Genet. 13: 141-157, 1983. [PubMed: 6860251] [Full Text: https://doi.org/10.1007/BF01065663]
Nyhan, W. L. Fifty years ago: Asbjorn Folling and phenylketonuria. Trends Biochem. Sci. 9: 71-72, 1984.
O'Flynn, M. E., Tillman, P., Hsia, D. Y.-Y. Hyperphenylalaninemia without phenylketonuria. Am. J. Dis. Child. 113: 22-30, 1967. [PubMed: 6015901] [Full Text: https://doi.org/10.1001/archpedi.1967.02090160072005]
Paine, R. S. The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 20: 290-302, 1957. [PubMed: 13452670]
Palo, J. Prevalence of phenylketonuria and some other metabolic disorders among mentally retarded patients in Finland. Acta Neurol. Scand. 43: 573-579, 1967. [PubMed: 6083364] [Full Text: https://doi.org/10.1111/j.1600-0404.1967.tb05552.x]
Paul, T. D., Brandt, I. K., Elsas, L. J., Jackson, C. E., Mamunes, P., Nance, C. S., Nance, W. E. Phenylketonuria heterozygote detection in families with affected children. Am. J. Hum. Genet. 30: 293-301, 1978. [PubMed: 677126]
Paul, T. D., Brandt, I. K., Elsas, L. J., Jackson, C. E., Nance, C. S., Nance, W. E. Linkage analysis using heterozygote detection in phenylketonuria. Clin. Genet. 16: 217-232, 1979. [PubMed: 519892] [Full Text: https://doi.org/10.1111/j.1399-0004.1979.tb00994.x]
Perry, T. L., Hansen, S., Tischler, B., Bunting, R., Diamond, S. Glutamine depletion in phenylketonuria: possible cause of the mental defect. New Eng. J. Med. 282: 761-766, 1970. [PubMed: 5416968] [Full Text: https://doi.org/10.1056/NEJM197004022821401]
Pey, A. L., Stricher, F., Serrano, L., Martinez, A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am. J. Hum. Genet. 81: 1006-1024, 2007. [PubMed: 17924342] [Full Text: https://doi.org/10.1086/521879]
Pietz, J., Rupp, A., Ebinger, F., Rating, D., Mayatepek, E., Boesch, C., Kreis, R. Cerebral energy metabolism in phenylketonuria: findings by quantitative in vivo (31)P MR spectroscopy. Pediat. Res. 53: 654-662, 2003. [PubMed: 12612190] [Full Text: https://doi.org/10.1203/01.PDR.0000055867.83310.9E]
Pilotto, A., Zipser, C. M., Leks, E., Haas, D., Gramer, G., Freisinger, P., Schaeffer, E., Liepelt-Scarfone, I., Brockmann, K., Maetzler, W., Schulte, C., Deuschle, C., Hauser, A. K., Hoffmann, G. F., Scheffler, K., van Spronsen, F. J., Padovani, A., Trefz, F., Berg, D. Phenylalanine effects on brain function in adult phenylketonuria. Neurology 96: e399-e411, 2021. [PubMed: 33093221] [Full Text: https://doi.org/10.1212/WNL.0000000000011088]
Pitt, D. B., O'Day, J. Phenylketonuria does not cause cataracts. Europ. J. Pediat. 150: 661-664, 1991. [PubMed: 1915521] [Full Text: https://doi.org/10.1007/BF02072629]
Ramus, S. J., Forrest, S. M., Cotton, R. G. H. Illegitimate transcription of phenylalanine hydroxylase for detection of mutations in patients with phenylketonuria. Hum. Mutat. 1: 154-158, 1992. [PubMed: 1301202] [Full Text: https://doi.org/10.1002/humu.1380010211]
Ramus, S. J., Forrest, S. M., Saleeba, J. A., Cotton, R. G. H. CpG hotspot causes second mutation in codon 408 of the phenylalanine hydroxylase gene. Hum. Genet. 90: 147-148, 1992. [PubMed: 1358783] [Full Text: https://doi.org/10.1007/BF00210760]
Rao, D. C., Keats, B. J., Lalouel, J. M., Morton, N. E., Yee, S. A maximum likelihood map of chromosome 1. Am. J. Hum. Genet. 31: 680-696, 1979. [PubMed: 293128]
Rey, F., Berthelon, M., Caillaud, C., Lyonnet, S., Abadie, V., Blandin-Savoja, F., Feingold, J., Saudubray, J.-M., Frezal, J., Munnich, A., Rey, J. Clinical and molecular heterogeneity of phenylalanine hydroxylase deficiencies in France. Am. J. Hum. Genet. 43: 914-921, 1988. [PubMed: 2904221]
Riess, O., Michel, A., Speer, A., Cobet, G., Coutelle, C. Introduction of genomic diagnosis of classical phenylketonuria to the health care system of the German Democratic Republic. Clin. Genet. 32: 209-215, 1987. [PubMed: 2890455] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03303.x]
Rohr, F. J., Doherty, L. B., Waisbren, S. E., Bailey, I. V., Ampola, M. G., Benacerraf, B., Levy, H. L. New England maternal PKU project: prospective study of untreated and treated pregnancies and their outcomes. J. Pediat. 110: 391-398, 1987. [PubMed: 3819940] [Full Text: https://doi.org/10.1016/s0022-3476(87)80500-0]
Romeo, G., Menozzi, P., Ferlini, A., Prosperi, L., Cerone, R., Scalisi, S., Romano, C., Antonozzi, I., Riva, E., Piceni Sereni, L., Zammarchi, E., Lenzi, G., Sartorio, R., Andria, G., Cioni, M., Fois, A., Burroni, M., Burlina, A. B., Carnevale, F. Incidence of classic PKU in Italy estimated from consanguineous marriages and from neonatal screening. Clin. Genet. 24: 339-345, 1983. [PubMed: 6652943]
Rosenblatt, D. S., Scriver, C. R. Heterogeneity in genetic control of phenylalanine metabolism in man. Nature 218: 677-678, 1968. [PubMed: 5655958] [Full Text: https://doi.org/10.1038/218677a0]
Rouse, B., Azen, C., Koch, R., Matalon, R., Hanley, W., de la Cruz, F., Trefz, F., Friedman, E., Shifrin, H. Maternal phenylketonuria collaborative study (MPKUCS) offspring: facial anomalies, malformations, and early neurological sequelae. Am. J. Med. Genet. 69: 89-95, 1997. [PubMed: 9066890] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970303)69:1<89::aid-ajmg17>3.0.co;2-k]
Rouse, B., Matalon, R., Koch, R., Azen, C., Levy, H., Hanley, W., Trefz, F., de la Cruz, F. Maternal phenylketonuria syndrome: congenital heart defects, microcephaly, and developmental outcomes. J. Pediat. 136: 57-61, 2000. [PubMed: 10636975] [Full Text: https://doi.org/10.1016/s0022-3476(00)90050-7]
Sarkissian, C. N., Shao, Z., Blain, F., Peevers, R., Su, H., Heft, R., Chang, T. M. S., Scriver, C. R. A different approach to treatment of phenylketonuria: phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc. Nat. Acad. Sci. 96: 2339-2344, 1999. [PubMed: 10051643] [Full Text: https://doi.org/10.1073/pnas.96.5.2339]
Saugstad, L. F. Anthropological significance of phenylketonuria. Clin. Genet. 7: 52-61, 1975. [PubMed: 803884]
Saugstad, L. F. Frequency of phenylketonuria in Norway. Clin. Genet. 7: 40-51, 1975. [PubMed: 1116309] [Full Text: https://doi.org/10.1111/j.1399-0004.1975.tb00361.x]
Scott, T. M., Fyfe, W. M., Hart, D. M. Maternal phenylketonuria: abnormal baby despite low phenylalanine diet during pregnancy. Arch. Dis. Child. 55: 634-649, 1980. [PubMed: 7436520] [Full Text: https://doi.org/10.1136/adc.55.8.634]
Scriver, C. R., Clow, C. L. Phenylketonuria and other phenylalanine hydroxylation mutants in man. Annu. Rev. Genet. 14: 179-202, 1980. [PubMed: 7011173] [Full Text: https://doi.org/10.1146/annurev.ge.14.120180.001143]
Scriver, C. R., Clow, C. L. Phenylketonuria: epitome of human biochemical genetics. New Eng. J. Med. 303: 1336-1342 and 1394-1400, 1980. [PubMed: 7001231] [Full Text: https://doi.org/10.1056/NEJM198012043032305]
Scriver, C. R., Eisensmith, R. C., Woo, S. L. C., Kaufman, S. The hyperphenylalaninemias of man and mouse. Annu. Rev. Genet. 28: 141-165, 1994. [PubMed: 7893121] [Full Text: https://doi.org/10.1146/annurev.ge.28.120194.001041]
Scriver, C. R., Gregory, D. M., Sovetts, D., Clow, C. L., Tissenbaum, G. Normal plasma free amino acid values in adults: the influence of some common physiological variables. Metabolism 34: 868-873, 1985. [PubMed: 4033427] [Full Text: https://doi.org/10.1016/0026-0495(85)90112-x]
Scriver, C. R. The PAH gene, phenylketonuria, and a paradigm shift. Hum. Mutat. 28: 831-845, 2007. [PubMed: 17443661] [Full Text: https://doi.org/10.1002/humu.20526]
Singh, R. H., Rohr, F., Frazier, D., Cunningham, A., Mofidi, S., Ogata, B., Splett, P. L., Moseley, K., Huntington, K., Acosta, P. B., Vockley, J., Van Calcar, S. C. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. Genet. Med. 16: 121-131, 2014. [PubMed: 24385075] [Full Text: https://doi.org/10.1038/gim.2013.179]
Smith, I., Macartney, F. J., Erdohazi, M., Pincott, J. R., Wolff, O. H., Brenton, D. P., Biddle, S. A., Fairweather, D. V. I., Dobbing, J. Fetal damage despite low-phenylalanine diet after conception in a phenylketonuric woman. Lancet 313: 17-19, 1979. Note: Originally Volume I. [PubMed: 83464] [Full Text: https://doi.org/10.1016/s0140-6736(79)90456-2]
Steffens, C. No difference in dermatoglyphics of fingers and palms between phenylketonuria patients and controls. (Letter) Hum. Genet. 69: 195 only, 1985. [PubMed: 3972420] [Full Text: https://doi.org/10.1007/BF00293300]
Stegink, L. D., Filer, L. J., Jr., Baker, G. L., Bell, E. F., Ziegler, E. E., Brummel, M. C., Krause, W. L. Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria. Metabolism 38: 78-84, 1989. [PubMed: 2909831] [Full Text: https://doi.org/10.1016/0026-0495(89)90184-4]
Steinfeld, R., Kohlschutter, A., Ullrich, K., Lukacs, Z. Efficiency of long-term tetrahydrobiopterin monotherapy in phenylketonuria. J. Inherit. Metab. Dis. 27: 449-453, 2004. [PubMed: 15303001] [Full Text: https://doi.org/10.1023/B:BOLI.0000037351.10132.99]
Stojiljkovic, M., Jovanovic, J., Djordjevic, M., Grkovic, S., Cvorkov Drazic, M., Petrucev, B., Tosic, N., Karan Djurasevic, T., Stojanov, L., Pavlovic, S. Molecular and phenotypic characteristics of patients with phenylketonuria in Serbia and Montenegro. Clin. Genet. 70: 151-155, 2006. [PubMed: 16879198] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00650.x]
Stuhrmann, M., Riess, O., Monch, E., Kurdoglu, G. Haplotype analysis of the phenylalanine hydroxylase gene in Turkish phenylketonuria families. Clin. Genet. 36: 117-121, 1989. [PubMed: 2569949] [Full Text: https://doi.org/10.1111/j.1399-0004.1989.tb03173.x]
Superti-Furga, A., Steinmann, B., Duc, G., Gitzelmann, R. Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase arg261-to-gln mutation. Europ. J. Pediat. 150: 493-497, 1991. [PubMed: 1915502] [Full Text: https://doi.org/10.1007/BF01958431]
Teebi, A. S., Al-Awadi, S. A., Farag, T. I., Naguib, K. K., El-Khalifa, M. Y. Phenylketonuria in Kuwait and Arab countries. Europ. J. Pediat. 146: 59-60, 1987. [PubMed: 3582406] [Full Text: https://doi.org/10.1007/BF00647286]
Thompson, A. J., Tillotson, S., Smith, I., Kendall, B., Moore, S. G., Brenton, D. P. Brain MRI changes in phenylketonuria: associations with dietary status. Brain 116: 811-821, 1993. [PubMed: 8353710] [Full Text: https://doi.org/10.1093/brain/116.4.811]
Tourian, A. Y., Sidbury, J. B., Jr. Phenylketonuria. In: Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S. (eds.): Metabolic Basis of Inherited Disease. (4th ed.) New York: McGraw-Hill (pub.) 1978. Pp. 240-255.
Tyfield, L. A., Meredith, A. L., Osborn, M. J., Harper, P. S. Identification of the haplotype pattern associated with the mutant PKU allele in the Gypsy population of Wales. J. Med. Genet. 26: 499-503, 1989. [PubMed: 2570158] [Full Text: https://doi.org/10.1136/jmg.26.8.499]
Tyfield, L. A., Stephenson, A., Cockburn, F., Harvie, A., Bidwell, J. L., Wood, N. A. P., Pilz, D. T., Harper, P., Smith, I. Sequence variation at the phenylalanine hydroxylase gene in the British Isles. Am. J. Hum. Genet. 60: 388-396, 1997. [PubMed: 9012412]
Ullrich, K., Weglage, J., Schuierer, G., Funders, B., Pietsch, M., Koch, H. G., Hahn-Ullrich, H. Cranial MRI in PKU: evaluation of a critical threshold for blood phenylalanine. (Letter) Neuropediatrics 25: 278-279, 1994. [PubMed: 7885543] [Full Text: https://doi.org/10.1055/s-2008-1073039]
Usha, R., Uma, R., Farag, T. I., Girish, Y., Al-Ghanim, M. M. A., Al-Najdi, K., Al-Awadi, S. A., El-Badramany, M. H. Late diagnosis of phenylketonuria in a Bedouin mother. Am. J. Med. Genet. 44: 713-715, 1992. [PubMed: 1481837] [Full Text: https://doi.org/10.1002/ajmg.1320440603]
Vajro, P., Strisciuglio, P., Houssin, D., Huault, G., Laurent, J., Alvarez, F., Bernard, O. Correction of phenylketonuria after liver transplantation in a child with cirrhosis. (Letter) New Eng. J. Med. 329: 363 only, 1993. [PubMed: 8321274] [Full Text: https://doi.org/10.1056/NEJM199307293290517]
van Spronsen, F. J., Reijngoud, D.-J., Smit, G. P. A., Nagel, G. T., Stellaard, F., Berger, R., Heymans, H. S. A. Phenylketonuria: the in vivo hydroxylation rate of phenylalanine into tyrosine is decreased. J. Clin. Invest. 101: 2875-2880, 1998. [PubMed: 9637722] [Full Text: https://doi.org/10.1172/JCI737]
van Vliet, D., van der Goot, E., van Ginkel, W. G., van Faassen, H. J. R., de Blaauw, P., Kema, I. P., Heiner-Fokkema, M. R., van der Zee, E. A., van Spronsen, F. J. The increasing importance of LNAA supplementation in phenylketonuria at higher plasma phenylalanine concentrations. Molec. Genet. Metab. 135: 27-34, 2022. [PubMed: 34974973] [Full Text: https://doi.org/10.1016/j.ymgme.2021.11.003]
Vockley, J., Andersson, H. C., Antshel, K. M., Braverman, N. E., Burton, B. K., Frazier, D. M., Mitchell, J., Smith, W. E., Thompson, B. H., Berry, S. A. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet. Med. 16: 188-200, 2014. Note: Erratum: Genet. Med. 16: 356 only, 2014. [PubMed: 24385074] [Full Text: https://doi.org/10.1038/gim.2013.157]
Waisbren, S., Burton, B. K., Feigenbaum, A., Konczal, L. L., Lilienstein, J., McCandless, S. E., Rowell, R., Sanchez-Valle, A., Whitehall, K. B., Longo, N. Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: a seven-year analysis. Molec. Genet. Metab. 132: 119-127, 2021. [PubMed: 33485801] [Full Text: https://doi.org/10.1016/j.ymgme.2021.01.001]
Waisbren, S. E., Hanley, W., Levy, H. L., Shifrin, H., Allred, E., Azen, C., Chang, P.-N., Cipcic-Schmidt, S., de la Cruz, F., Hall, R., Matalon, R., Nanson, J., Rouse, B., Trefz, F., Koch, R. Outcome at age 4 years in offspring of women with maternal phenylketonuria: the maternal PKU collaborative study. JAMA 283: 756-762, 2000. [PubMed: 10683054] [Full Text: https://doi.org/10.1001/jama.283.6.756]
Wang, H., Nye, L., Puffenberger, E., Morton, H. Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large Old Order Amish settlements. Am. J. Med. Genet. 143A: 1938-1940, 2007. [PubMed: 17630668] [Full Text: https://doi.org/10.1002/ajmg.a.31852]
Waters, P. J., Parniak, M. A., Akerman, B. R., Scriver, C. R. Characterization of phenylketonuria missense substitutions, distant from the phenylalanine hydroxylase active site, illustrates a paradigm for mechanism and potential modulation of phenotype. Molec. Genet. Metab. 69: 101-110, 2000. Note: Erratum: Molec. Genet. Metab. 72: 89 only, 2001. [PubMed: 10720436] [Full Text: https://doi.org/10.1006/mgme.2000.2965]
Weglage, J., Grenzebach, M., Pietsch, M., Feldmann, R., Linnenbank, R., Denecke, J., Koch, H. G. Behavioural and emotional problems in early-treated adolescents with phenylketonuria in comparison with diabetic patients and healthy controls. J. Inherit. Metab. Dis. 23: 487-496, 2000. [PubMed: 10947203] [Full Text: https://doi.org/10.1023/a:1005664231017]
Weglage, J., Pietsch, M., Denecke, J., Sprinz, A., Feldmann, R., Grenzebach, M., Ullrich, K. Regression of neuropsychological deficits in early-treated phenylketonurics during adolescence. J. Inherit. Metab. Dis. 22: 693-705, 1999. [PubMed: 10472530] [Full Text: https://doi.org/10.1023/a:1005587915468]
Weglage, J., Wiedermann, D., Denecke, J., Feldmann, R., Koch, H.-G., Ullrich, K., Moller, H. E. Individual blood-brain barrier phenylalanine transport in siblings with classical phenylketonuria. J. Inherit. Metab. Dis. 25: 431-436, 2002. [PubMed: 12555936] [Full Text: https://doi.org/10.1023/a:1021234730512]
Woo, S. L. C., Lidsky, A., Law, M., Kao, F. T. Regional mapping of the human phenylalanine hydroxylase gene and PKU locus to 12q21-qter. (Abstract) Am. J. Hum. Genet. 36: 210S only, 1984.
Woo, S. L. C., Lidsky, A. S., Guttler, F., Chandra, T., Robson, K. J. H. Cloned human phenylalanine hydroxylase gene permits prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 306: 151-155, 1983. [PubMed: 6316140] [Full Text: https://doi.org/10.1038/306151a0]
Woo, S. L. C., Lidsky, A. S., Guttler, F., Thirumalachary, C., Robson, K. J. H. Prenatal diagnosis of classical phenylketonuria by gene mapping. JAMA 251: 1998-2002, 1984. [PubMed: 6700105]
Woo, S. L. C. Personal Communication. Houston, Tex. 1/11/1983.
Woo, S. L. C. Collation of RFLP haplotypes at the human phenylalanine hydroxylase (PAH) locus. (Letter) Am. J. Hum. Genet. 43: 781-783, 1988. [PubMed: 2903669]
Woolf, L. I., Cranston, W. I., Goodwin, B. L. Genetics of phenylketonuria. I. Heterozygosity for phenylketonuria. II. Third allele at the phenylalanine hydroxylase locus in man. Nature 213: 882-885, 1967. [PubMed: 6030045] [Full Text: https://doi.org/10.1038/213882a0]
Woolf, L. I., Goodwin, B. L., Cranston, W. I., Wade, D. N., Woolf, F., Hudson, F. P., McBean, M. S. A third allele at the phenylalanine-hydroxylase locus in mild phenylketonuria (hyperphenylalaninaemia). Lancet 291: 114-117, 1968. Note: Originally Volume I. [PubMed: 4169602] [Full Text: https://doi.org/10.1016/s0140-6736(68)92722-0]
Woolf, L. I., McBean, M. S., Woolf, F. M., Cahalane, S. F. Phenylketonuria as a balanced polymorphism: the nature of the heterozygote advantage. Ann. Hum. Genet. 38: 461-469, 1975. [PubMed: 1190737] [Full Text: https://doi.org/10.1111/j.1469-1809.1975.tb00635.x]
Woolf, L. I. The heterozygote advantage in phenylketonuria. (Letter) Am. J. Hum. Genet. 38: 773-775, 1986. [PubMed: 3717163]
Yu, J. S., O'Halloran, M. T. Atypical phenylketonuria in a family with a phenylketonuric mother. Pediatrics 46: 707-711, 1970. [PubMed: 5481071]
Zori, R., Ahring, K., Burton, B., Pastores, G. M., Rutsch, F., Jha, A., Jurecki, E., Rowell, R., Harding, C. Long-term comparative effectiveness of pegvaliase versus standard of care comparators in adults with phenylketonuria. Molec. Genet. Metab. 128: 92-101, 2019. [PubMed: 31439512] [Full Text: https://doi.org/10.1016/j.ymgme.2019.07.018]
Zschocke, J., Mallory, J. P., Eiken, H. G., Nevin, N. C. Phenylketonuria and the peoples of Northern Ireland. Hum. Genet. 100: 189-194, 1997. [PubMed: 9254847] [Full Text: https://doi.org/10.1007/s004390050488]
Zurfluh, M. R., Zschocke, J., Lindner, M., Feillet, F., Chery, C., Burlina, A., Stevens, R. C., Thony, B., Blau, N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum. Mutat. 29: 167-175, 2008. Note: Erratum: Hum. Mutat. 29: 1079 only, 2008. [PubMed: 17935162] [Full Text: https://doi.org/10.1002/humu.20637]
Zygulska, M., Eigel, A., Dworniczak, B., Sutkowska, A., Pietrzyk, J. J., Horst, J. Phenylketonuria in Poland: 66% of PKU alleles are caused by three mutations. Hum. Genet. 88: 91-94, 1991. [PubMed: 1683647] [Full Text: https://doi.org/10.1007/BF00204935]