RESUMO
We aimed to assess if the same cognitive batteries can be used cross-nationally to monitor the effect of Phenylketonuria (PKU). We assessed whether a battery, previously used with English adults with PKU (AwPKU), was also sensitive to impairments in Italian AwPKU. From our original battery, we selected a number of tasks that comprehensively assessed visual attention, visuo-motor coordination, executive functions (particularly, reasoning, planning, and monitoring), sustained attention, and verbal and visual memory and learning. When verbal stimuli/or responses were involved, stimuli were closely matched between the two languages for psycholinguistic variables. We administered the tasks to 19 Italian AwPKU and 19 Italian matched controls and compared results from with 19 English AwPKU and 19 English matched controls selected from a previously tested cohort. Participant election was blind to cognitive performance and metabolic control, but participants were closely matched for age and education. The Italian AwPKU group had slightly worse metabolic control but showed levels of performance and patterns of impairment similar to the English AwPKU group. The Italian results also showed extensive correlations between adult cognitive measures and metabolic measures across the life span, both in terms of Phenylalanine (Phe) levels and Phe fluctuations, replicating previous results in English. These results suggest that batteries with the same and/or matched tasks can be used to assess cognitive outcomes across countries allowing results to be compared and accrued. Future studies should explore potential differences in metabolic control across countries to understand what variables make metabolic control easier to achieve.
Assuntos
Disfunção Cognitiva/diagnóstico , Testes Neuropsicológicos/estatística & dados numéricos , Fenilcetonúrias/etnologia , Fenilcetonúrias/psicologia , População Branca/psicologia , Adolescente , Adulto , Cognição , Disfunção Cognitiva/etnologia , Disfunção Cognitiva/etiologia , Comparação Transcultural , Feminino , Humanos , Itália/etnologia , Idioma , Masculino , Fenilalanina/sangue , Fenilcetonúrias/sangue , Reprodutibilidade dos Testes , Reino Unido/etnologia , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) and several other inherited metabolic diseases (IMD) require a lifelong low-protein diet (LPD), otherwise they lead to many health complications. LPDs, however, carry a significant economic burden for patients and their families. The objective of this study was to explore the costs of low-protein foods (LPFs) necessary for LPD as well as dietary patterns and compliance towards an LPD. SUBJECTS/METHODS: A detailed questionnaire was created in cooperation with National Association of PKU and other IMD (NSPKU), and consequently sent to all NSPKU members treated with an LPD (n=303). A total of 184 respondents from the Czech Republic were included in the study (174 had PKU, 10 had other IMD). RESULTS: The average daily consumption of LPF was equal to 411.7 g (PKU) and 345.6 g (other IMD), which corresponds to energy value of 5558 kJ and 4438 kJ, respectively, per patient per day. Patients mostly consumed low-protein flour (≈30% of energy intake), pasta (≈18%), basic pastry (≈15%) and sweets (≈10%). The average monthly costs of LPDs were equal to [euro ]130 (PKU) and [euro ]129 (other IMD) per patient per month. The compliance with LPD was decreasing with increasing age (P<0.0001). CONCLUSIONS: This is the largest study examining costs and dietary patterns of LPDs in patients with PKU and the first study of this kind in other IMD patients requiring an LPD. The study clearly showed that an LPD carries a very high economic burden for families, which may lead to less LPD compliance and potential severe health consequences.
Assuntos
Fenômenos Fisiológicos da Nutrição do Adolescente , Fenômenos Fisiológicos da Nutrição Infantil , Efeitos Psicossociais da Doença , Dieta com Restrição de Proteínas , Erros Inatos do Metabolismo/dietoterapia , Cooperação do Paciente , Fenilcetonúrias/dietoterapia , Adolescente , Fenômenos Fisiológicos da Nutrição do Adolescente/etnologia , Adulto , Cuidadores , Criança , Fenômenos Fisiológicos da Nutrição Infantil/etnologia , Pré-Escolar , Custos e Análise de Custo , República Tcheca , Dieta com Restrição de Proteínas/economia , Dieta com Restrição de Proteínas/etnologia , Feminino , Abastecimento de Alimentos/economia , Humanos , Deficiência Intelectual/economia , Deficiência Intelectual/etnologia , Deficiência Intelectual/etiologia , Deficiência Intelectual/prevenção & controle , Masculino , Erros Inatos do Metabolismo/economia , Erros Inatos do Metabolismo/etnologia , Erros Inatos do Metabolismo/fisiopatologia , Cooperação do Paciente/etnologia , Fenilcetonúrias/economia , Fenilcetonúrias/etnologia , Fenilcetonúrias/fisiopatologia , Doenças Raras/dietoterapia , Doenças Raras/economia , Doenças Raras/etnologia , Doenças Raras/fisiopatologia , Autorrelato , Adulto JovemRESUMO
OBJECTIVE: To analyze the types and distribution of large deletion of phenylalanine hydroxylase (PAH) gene in Chinese patients with phenylketonuria (PKU). METHODS: On the basis of 953 PKU patients from Peking Union Medical College and Gansu Province Medical Genetics Center, which were detected by directed sequencing of PAH gene between 2006 and 2014. Multiplex ligation-dependent probe amplification (MLPA) of PAH gene was performed in 43 patients with one or two unknown genotypes. And the deletion breakpoints were characterized by Gap PCR-sequencing. RESULTS: Twenty-four large deletion/duplication alleles were found in 22 patients, accounting for 51.1%(24/47)of the 47 unknown mutations of the 43 patients.There were 6 different large deletions, including Ex1del3758 (n=10), Ex4_5del (n=4), Ex4_7del (n=3), Ex1del5329ins56 (n=3), Ex3del6599ins8 (n=2), and Ex4del (n=1); and 1 duplication was found (Ex12dup, n=1). The most common large deletions in Chinese patients were Ex1del3758 (21.3%), Ex4_5del (8.5%), and Ex4_7del (6.4%). CONCLUSIONS: Large deletion mutations of PAH gene are present in Chinese PKU patients. It's important to detect the large del/dup mutation, and there are different hotspot mutation genotypes in Chinese patients.
Assuntos
Povo Asiático/genética , Éxons , Fenilalanina Hidroxilase , Deleção de Sequência , Alelos , Genótipo , Humanos , Reação em Cadeia da Polimerase Multiplex , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/etnologia , Fenilcetonúrias/genéticaRESUMO
BACKGROUND: A growing body of research has suggested that tetrahydrobiopterin (BH4) responsive phenotype can be predicted by the phenylalanine hydroxylase (PAH) genotype in patients with phenylketonuria (PKU), but data concerning the association between genotype and BH4 responsiveness are scarce in China. METHODS: A total of 165 PKU patients from China who had undergone a 24-h loading test with BH4 administration were recruited. Genotyping was performed by the next-generation sequencing (NGS) technique. Using the predicted residual PAH activity, we analyzed the association between genotype and BH4-responsiveness. RESULTS: Among the 165 patients, 40 patients (24.24%) responded to BH4. A total of 74 distinct mutations were observed, including 13 novel mutations. The mutation p.R241C was most frequently associated with response. Two known mutations (p.A322T and p.Q419R) and two novel mutations (p.L98V and IVS3-2A>T) were first reported as responsive to BH4. Residual PAH activity of at least 12.5% was needed for responsive genotypes. CONCLUSION: Genotype-based predictions of BH4-responsiveness are only for selecting potential responders. Accordingly, it is necessary to test potential responders with a long-term BH4 challenge.
Assuntos
Biopterinas/análogos & derivados , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Povo Asiático/genética , Biopterinas/administração & dosagem , China , Análise Mutacional de DNA , Frequência do Gene , Predisposição Genética para Doença , Humanos , Fenótipo , Fenilalanina Hidroxilase/metabolismo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/enzimologia , Fenilcetonúrias/etnologia , Valor Preditivo dos TestesRESUMO
Phenylketonuria (PKU) is an autosomal recessive disorder characterized by a mutation in the phenylalanine hydroxylase (PAH) gene. Untreated PKU can lead to mental retardation, seizures, and other serious medical problems. This study was designed to investigate the status of molecular defects in the PAH gene and their association with polymorphisms in Kurdish patients with PKU in the Kermanshah province, western Iran. The study was conducted on 27 unrelated patients with PKU over a 2-year period (from 2010 to 2012). All 13 exons plus exon-intron boundaries of the PAH gene were analyzed and we identified 15 different mutations, including two novel mutations, in 51 of the 54 mutant alleles (diagnostic efficiency of 94.4 %). IVS4 + 1G > C (c.441 + 1G > C) and IVS7 - 5 T > C (c.843 - 5 T > C) are novel mutations that have not been reported in the academic literature or the PAH locus database ( http://www.pahdb.mcgill.ca ); therefore, they may be specific to the Kurdish population. IVS2 + 5G > C and IVS9 + 5G > A were the two most prevalent mutations in our sample, with frequencies of 26 % and 17 %, respectively. The second most common mutations were p.R261X, IVS10 - 11G > A, p.K363 > Nfs and IVS7 - 5 T > C, with each showing a relative frequency of 7.4 %. All other detected mutations, including p.F55 > Lfs, p.R176X, p.R243Q, p.V230I, p.R243X, p.R261Q, IVS8 - 7A > G and p.E390G had frequencies of less than 4 %. The present study showed that there is a distinct difference in the characteristics of PAH mutations between the Kermanshah province and other parts of Iran, suggesting that Kermanshah may have a unique population distribution of PAH gene mutations. Iran lies on the route of major ancient movements of the Caucasian people toward the Mediterranean basin, and Kermanshah has previously been called the gateway to Asia. Most of the mutations identified in this study are common in the Mediterranean region. Therefore, our findings are consistent with the historical and geographical links between the Iranian population and the populations of Mediterranean region.
Assuntos
Etnicidade/genética , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Polimorfismo Genético , Adolescente , Alelos , Criança , Pré-Escolar , Códon sem Sentido , Consanguinidade , Análise Mutacional de DNA , Éxons/genética , Feminino , Frequência do Gene , Migração Humana , Humanos , Íntrons/genética , Irã (Geográfico)/epidemiologia , Masculino , Região do Mediterrâneo , Mutação de Sentido Incorreto , Fenilcetonúrias/etnologia , Análise de Sequência de DNA , Deleção de Sequência , População Branca/genética , Adulto JovemRESUMO
Phenylketonuria (PKU) associated mutations in phenylalanine hydroxylase (PAH) gene were identified by direct DNA sequencing in 46 PKU patients and members of their families from Kemerovskaya Region and Saha Republic. Mutations found included both widespread known mutations (R158Q, R252W, R261Q, P281L, IVS10-11G>A, R408W, IVS12+1G>A) and several rare mutations (IVS2+5G>A, R155H, Y168H, W187R, E221_D222>Efs, A342T, Y386C, IVS11+1G>C). We observed the increase in diversity of PKU-associated alleles in the populations studied, probably due to their complex mixed ethnic structure.
Assuntos
Povo Asiático , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , População Branca , Alelos , Análise Mutacional de DNA , Éxons , Humanos , Íntrons , Fenilcetonúrias/etnologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Federação Russa/epidemiologiaRESUMO
The absence of a comprehensive analysis for phenylketonuria (PKU) mutations in the Chinese Han population has resulted in continued studies during the past 18 y to elucidate the mutational spectrum in patients from virtually all Chinese regions. Our study systematically investigated 13 exons and their surrounding introns of the phenylalanine hydroxylase (PAH) gene in 212 unrelated patients using PCR and direct sequencing. A total of 79 different mutations were identified in 405 of 424 mutant PAH alleles including 15 novel ones. Eight mutations, R243Q, Ex6-96A>G, IVS4 - 1G>A, R413P, Y356X, R111X, R241C, and V399V, with a relative frequency of 3% or more, accounted for two thirds of the identified ones. The data presented in this study indicates that the total pool of mutant PAH alleles in China consisted of a small number of common mutations and a very high number of rare mutations. Moreover, by merging the findings of previous studies to generate a more composite data set for the Chinese mainland, it is shown that there are no significant differences of the common mutations between southern and northern except for R413P statistically, raising questions about the previous hypothesis that great variations on mutation frequencies exist between above regions.
Assuntos
Povo Asiático/genética , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/etnologia , Fenilcetonúrias/genética , Distribuição de Qui-Quadrado , Pré-Escolar , China/epidemiologia , Análise Mutacional de DNA , Éxons , Frequência do Gene , Genótipo , Humanos , Lactente , Recém-Nascido , Íntrons , Fenótipo , Fenilcetonúrias/enzimologia , Características de ResidênciaRESUMO
Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify approximately 14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.
Assuntos
Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Deleção de Sequência , Povo Asiático/genética , Sítios de Ligação/genética , Análise Mutacional de DNA , Éxons/genética , Humanos , Coreia (Geográfico) , Modelos Moleculares , Fenilalanina Hidroxilase/química , Fenilcetonúrias/etnologia , Estrutura Terciária de ProteínaRESUMO
Phenylketonuria (PKU; MIM 261600) is an autosomal recessive metabolic disorder caused by a deficiency of phenylalanine hydroxylase (PAH; EC 1.14.16.1). Point mutations in the PAH gene are known to cause PKU in various ethnic groups, and large deletions or duplications account for up to 3% of the PAH mutations in some ethnic groups. However, a previous study could not identify ~14% of the mutant alleles by sequence analysis in Korean patients with PKU, which suggests that large deletions or duplication might be frequent causes of PKU in Koreans. To test this hypothesis, we performed multiplex ligation-dependent probe amplification (MLPA) for the identification of uncharacterized mutant alleles after PAH sequence analysis of 33 unrelated Korean patients with PKU. Bi-directional sequencing of the PAH exons and flanking intronic regions revealed 27 different mutations, including four novel mutations (two missense and two deletion mutations), comprising 57/66 (86%) mutant alleles. MLPA identified a large deletion that encompassed exons 5 and 6 in four patients, another large deletion that extended from exon 4 to exon 7 in one patient, and a duplication of exon 4 in one patient. Chromosomal walking characterized the deletion breakpoint of the most common large deletion that involved exons 5 and 6 (c.456_706+138del). The present study shows that the allelic frequency of exon deletion or duplication is 9% (6/66) in Korean PKU patients, which suggests that these mutations may be frequent causes of PKU in Korean subjects.
Assuntos
Humanos , Povo Asiático/genética , Sítios de Ligação/genética , Análise Mutacional de DNA , Éxons/genética , Coreia (Geográfico) , Modelos Moleculares , Fenilalanina Hidroxilase/química , Fenilcetonúrias/etnologia , Estrutura Terciária de Proteína , Deleção de SequênciaRESUMO
Phenylketonuria (PKU) is an autosomal recessive disorder due to phenylalanine hydroxylase (PAH) deficiency. The PAH gene, located at 12q22-q24.1, includes about 90kb and contains 13 exons. To date, more than 420 different alterations have been identified in the PAH gene. To determine the nature and frequency of PAH mutations in PKU patients from South Brazil, mutation analysis was performed on genomic DNA from 23 unrelated PKU patients. The 13 exons and flanking regions of the PAH gene were amplified by PCR and the amplicons were analyzed by single strand conformation polymorphism (SSCP). Amplicons that showed abnormal migration patterns were analyzed by restriction endonuclease digestion and/or sequencing. Twenty-two previously reported mutations were identified including R261X, R408W, IVS2nt5g-->c, R261Q, and V388M. Polymorphisms were observed in 48.8% of the PKU patients, the most frequent being IVS2nt19t-->c, V245V, and IVS12nt-35c-->t. In addition, two novel sequence variants were identified: 1378g-->t in the 3(')-untranslated region in exon 13 which may be disease-causing and an intron 12 polymorphism, IVS12nt-15t-->c. The mutation spectrum in the patients from Southern Brazil differed from that observed in patients from other Latin American countries and further defined the molecular heterogeneity of this disease.
Assuntos
Mutação , Fenilcetonúrias/genética , Polimorfismo Genético , Brasil/epidemiologia , Análise Mutacional de DNA , Genótipo , Haplótipos , Humanos , Fenótipo , Fenilalanina Hidroxilase/deficiência , Fenilcetonúrias/enzimologia , Fenilcetonúrias/etnologia , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita Simples , Mapeamento por RestriçãoRESUMO
Phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene (12q22-q24) resulting in a primary deficiency of the PAH enzyme activity, intolerance to the dietary intake of phenylalanine (Phe) and production of the phenylketonuria (PKU) disease. To date there have been no reports on the molecular analysis of PKU in Iranian population. In this study, the states of the PKU disease in terms of prevalence and mutation spectrum among patients reside in the institutions for mentally retarded in Isfahan was investigated. In the first step, 611 out of 1541 patients with PKU phenotype or severe mental retardation were screened for the PKU disease using the Guthrie bacterial inhibition assay (GBIA) followed by HPLC. Among the patients screened 34 (5.56%) were found positive with abnormal serum Phe of above 7mg/dl. In the next step, the presence of 18 common mutations of the PAH gene in 26 of the patients with classical PKU (serum Phe above 20mg/dl) was investigated, using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Of the 52 independent mutant alleles that were analyzed, 34 (65.38%) were genotyped showing 8 mutations as follows: R252W (15.38%), Q232Q (13.46%), R261Q (7.69%), delL364 (7.69%), IVS10-11g>a (5.77%), L333F (5.77%), V245V (5.77%) and S67P (3.85%). The results from this study may serve as a reference to analyze the PKU mutations in other part of Iran, and to establish diagnostic tests for carrier detection and prenatal diagnosis of the PKU disease in Iranian population.
Assuntos
Deficiência Intelectual , Mutação/genética , Fenilcetonúrias/etnologia , Fenilcetonúrias/genética , Cromatografia Líquida de Alta Pressão , Frequência do Gene , Humanos , Institucionalização , Irã (Geográfico)/epidemiologia , Leucócitos/metabolismo , Programas de Rastreamento , Testes de Sensibilidade Microbiana , Fenilalanina/sangue , Fenilalanina Hidroxilase/sangue , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/enzimologia , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Mapeamento por RestriçãoRESUMO
The Texas Department of Health's Newborn Screening Program screens for five inherited disorders: phenylketonuria (PKU), congenital adrenal hyperplasia (CAH), congenital hypothyroidism (CH), galactosemia (GAL), and sickle cell disease (SCD). The objective of this study was to determine the prevalence of these disorders and to describe ethnic and gender patterns in their distribution. Cases were identified from blood specimens collected at birth from live births in Texas from 1992 through 1998. During this time, the overall prevalence of these disorders per 10,000 live births was 0.70 for PKU, 0.21 for GAL, 4.18 for CH, 1.03 for CAH, and 3.92 for SCD. Ethnic and gender disparities were observed among PKU, CH, CAH, and SCD prevalence. Results suggest that unidentified mutations and environmental factors may exist that contribute to these patterns. This warrants further investigation to determine possible modifiable risk factors for populations with higher prevalence.
Assuntos
Doenças Genéticas Inatas/epidemiologia , Hiperplasia Suprarrenal Congênita/epidemiologia , Hiperplasia Suprarrenal Congênita/etnologia , Anemia Falciforme/epidemiologia , Anemia Falciforme/etnologia , Hipotireoidismo Congênito , Feminino , Galactosemias/epidemiologia , Galactosemias/etnologia , Doenças Genéticas Inatas/etnologia , Humanos , Hipotireoidismo/epidemiologia , Hipotireoidismo/etnologia , Recém-Nascido , Masculino , Fenilcetonúrias/epidemiologia , Fenilcetonúrias/etnologia , Prevalência , Distribuição por Sexo , Texas/epidemiologiaRESUMO
The spectrum and frequency of mutations of exon 7 of the gene for phenylalanine hydroxylase (PAH) were studied in 34 phenylketonuria (PKU) patients living in Novosibirsk oblast. The five most prevalent mutations constituted 17.64% of defective alleles: R243Q (1.47%), R252W (1.47%), R261Q (5.88%), E280K (1.47%), and P281L (7.35%). A neutral polymorphic locus V245V was found within exon 7.
Assuntos
Éxons , Mutação , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/genética , Humanos , Fenilcetonúrias/enzimologia , Fenilcetonúrias/etnologia , Polimorfismo Genético , SibériaRESUMO
A genealogical study was performed in Lithuanian phenylketonuria (PKU) families with the aim of tracing the origins of the R408W/haplotype 2/VNTR3 allele. The relative frequency of six phenylalanine hydroxylase (PAH) mutations (R408W, R158Q, R261Q, G272X, IVS10nt-11g --> a, and IVS12nt1g --> a) common in Eastern European populations and their association with variable number of tandem repeat (VNTR) and short tandem repeat (STR) sites in the PAH gene were examined in 130 PKU Lithuanian chromosomes, including 95 of Baltic, 28 of Slavonic and 7 of unknown origin. R408W was found to be the most frequent (70%) mutation in both Balts or Slavonians with a uniform frequency distribution. No statistically significant differences in the frequency distribution of the other mutations analysed were found. In Balts and Slavonians, the R408W mutation is strongly associated with the three-copy VNTR and the 240-bp STR allele. The frequency of this association is 68% in both ethnic groups. The genealogical data provided in this paper indicate that the most common R408W/VNTR3/STR240 allele arose in ancient times possibly among pre-Indo-Europeans and suggest that the high frequency of the R408W mutation and associated minihaplotype in Balts of Lithuania is due to a founder effect.
Assuntos
Haplótipos , Mutação/genética , Fenilcetonúrias/genética , Evolução Molecular , Efeito Fundador , Humanos , Lituânia , Repetições Minissatélites/genética , Fenilalanina Hidroxilase/genética , Fenilcetonúrias/etnologia , Sequências Repetitivas de Ácido Nucleico/genéticaAssuntos
Haplótipos , Mutação , Fenilcetonúrias/genética , Heterozigoto , Homozigoto , Humanos , Fenilcetonúrias/etnologia , Roma (Grupo Étnico) , EspanhaRESUMO
Phenylalanine hydroxylase (PAH) is the enzyme which converts phenylalanine into tyrosine. In case of its deficiency, hyperphenylalaninemia is observed, which leads to phenylketonuria (PKU), a disease causing mental retardation, unless treated with a low-phenylalanine diet since early childhood. In Estonia, PKU is among the most common inherited metabolic diseases. The data from retrospective study and newborn screening show an approximate incidence of 1 in 6,000 newborns. Molecular analysis of 34 Estonian patients has revealed high genotypic homogeneity in this group, as 84% of the mutant alleles carry the R408W mutation. The high rate of this mutation in the Estonian population rises the speculation of Finno-Ugric contribution to the East European pool of mutant PAH alleles. Five more mutations-IVS12nt1, R261Q, R252W, R158Q, S349P-have been detected. The mutation detection rate was 92% among the studied patients.