AARSKOG SYNDROME, AUTOSOMAL DOMINANT
-AARSKOG SYNDROME, AUTOSOMAL DOMINANT
Amino acid or protein metabolism disease with epilepsy
-Rare neurologic disease
Disorder of phenylalanine metabolism
-Rare genetic disease
Neurometabolic disease
-Rare genetic disease
-Rare neurologic disease
Comment:
PKU is an autosomal recessive disorder caused by a defect in the hepatic enzyme phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine into tyrosine. Defective PAH results in the accumulation of phenylalanine in the brain leading to severe mental retardation as well as low tyrosine concentrations. Rare cases of PKU may also occur due to defects in tetrahydrobiopterin (BH4) biosynthesis, since PAH requires BH4 as a cofactor. (PMID:23622399)
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 ... 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.
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 ... 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.'
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 ... 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. - 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, wide 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.
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 ... 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. For more detailed information on the molecular genetics of PKU and non-PKU hyperphenylalaninemia, see 612349.
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). ... 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) analyzed polymorphic DNA haplotypes at the PAH locus in European and Asian families. Much less haplotypic variation was found in Asians than in Caucasians. In particular, in Chinese and Japanese, 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 1 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 Orientals are present in both Caucasians and Orientals, 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.