Laura Vilarinho*, Ana Queirós*, Paula Leandro†, Isabel Tavares de Almeida†, Isabel Rivera†
*Laboratório Nacional de Rastreios, Instituto de Genética Médica, Porto; † Unidade de Biologia Molecular e Biopatologia Experimental, Centro de Patogénese Molecular, Faculdade de Farmácia de Lisboa
Resumo
A fenilcetonúria é a aminoacidopatia mais comum da população caucasiana e tornou-se o paradigma de uma doença que pode ser facilmente identificada através de um rastreio sistemático e que, tratada atempadamente, evita a deterioração neurológica grave com atraso mental profundo. Em Portugal, até ao final de 2005, foram rastreados 2.481.988 recém-nascidos e detectados 226 doentes através do Programa Nacional para o Diagnóstico Precoce, sendo a prevalência desta doença no nosso país de 1/11.031 recémnascidos. A fenilcetonúria constitui uma patologia com grande heterogeneidade molecular conforme é demonstrado pelas 29 mutações diferentes identificadas nos 103 doentes caracterizados de 98 famílias, correspondendo a 196 alelos independentes, sendo a IVS10nt-11G→A a mutação mais frequente (17,3%).
Palavras-chave: PKU; fenilcetonúria; rastreio neonatal; programa nacional de diagnóstico precoce.
Phenylketonuria Revisited
]]> AbstractPKU, the most common amino acid disorder in the Caucasian population, became the paradigma of an easily diagnosed disease by neonatal screening. Early treatment prevents neurological damage and severe mental retardation. In Portugal, until the end of 2005, 2,481,988 newborns were screened for by the National Neonatal Screening Program and 226 PKU patients identified, displaying a prevalence of 1/11,031. One-hundred and three patients, corresponding to 196 independent alleles, were fully genotyped. Among the 29 different mutations identified, IVS10nt-11G→A revealed to be the most frequent one (17.3%). These results demonstrate that, as expected, PKU is a highly heterogeneous disease at the molecular level.
Key-words: PKU; phenylketonuria; neonatal screening; newborn screening program.
Texto completo disponível apenas em PDF.
Full text only available in PDF format.
REFERÊNCIAS
]]>1 -Scriver CR, Kaufman S, Eisensmith RC, Woo SLC. The hyperphenylalaninemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The metabolic and molecular bases of inherited disease. 8th Ed McGraw Hill, New York 2001; pp 16671724.
[ Links ]2 -Campistol J, Lambruschini N, Vilaseca MA et al. Hiperfenilalaninemia. In: Sanjurjo P, Baldellou A (eds). Diagnóstico e tratamiento de las Enfermedades Metabólicas Hereditárias. Madrid, Ed Ergon 2001, pp 195-206.
3 -Güttler F, Lou H. Phenylketonuria and hyperphenylalaninemia. In : Fernandes J, Saudubray JM, Tada K, (eds). Inborn metabolic diseases : diagnosis and treatment. Springer-Verlag, 1990, pp161-174.
4 -Weglage J, Pietshy M, Funders B, et al. Deficits selective and sustained attention processes in early treated children with phenylketonuria-result of impaired lobe functions. Eur J Pediatr 1996;155:200-204.
5 -Guthrie R, Susi A. A simple plenylalanine methods for detec-ting phenylketonuria in large populations of newborn infants. Pediatrics 1963,32:338-343.
6 -Woo SL, Lidsky AS, Guttler F, Chandra T, Robson KJ. Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria. Nature 1983;306(5939):151-5.
7 -Kaufman S, Fisher DB. Pterin-requiring aromatic amino acid hydroxylases. In: Hayaishi O (ed). Molecular mechanisms of oxygen activation. Academy of New York, 1974:285-327.
8 -Blau N. Inborn errors of pterin metabolism. Annu Rev Nutr 1988;8:185-209. Review
9 -Zschocke J. Phenylketonuria mutations in Europe. Hum Mut 2003;21:345-356.
10 -Scriver CR, Hurtubise M, Konecki D, et al. PAHdb 2003: what a locus-specific knowledgebase can do. Hum Mutat 2003;21(4):333-44.
]]> 11 -Mallolas J, Vilaseca MA, Campistol J et al. Mutational spectrum of phenylalanine hydroxylase deficiency in the population residente in Catalonia: genotype-phenotype correlation. Hum Genet 1999;105:468-73.12 -Vaz Osório R, Vilarinho L, Pires Soares M, Almeida MF, Carmona C, Martins E. Programa Nacional para o Diagnóstico Precoce - 20 anos de rastreio neonatal. Arq Med 1999;13(3):163-8.
13 -Vilarinho L, Marques J, Osório R. Fenilcetonúria em Portugal. Arq Med 1994;86:401-404.
14 -Vilarinho L, Rocha H, Marcão A, Sousa C, Fonseca H, Bo-gas M, Vaz Osório R. Diagnóstico Precoce: resultados preliminares do rastreio metabólico alargado. Act Ped Port 2006;37(5):186-91.
15 -Blau N, Dhondt JL. Tetrahydrobiopterin deficiency and an internacional database of patients. Adv Exp Med Biol 1993; 338:255-61.
16 -Kure S, Hou DC, Ohura T, et al. Tetrahydrobiopterin-res-ponsive phenylalanine hydroxylase deficiency. J Pediatr 1999;135(3):375-8.
17 -Spaapen IJ, Bakker JA, Velter C, et al. Tetrahydrobiopterinresponsive phenylalanine hydroxilase deficiency in Dutch neonates. J Inherit Metab Dis 2001;24(3):352-8.
18 -Pey AL, Perez B, Desviat LR, et al. Mechanisms underlying responsiveness to tetrahydrobiop-terin in mild phenylketonuria mutations. Hum Mut 2004;24(5):388-99.
19 -Hanley WB, Lee AW, Hanley AJ et al. Hypotyrosinemia in PKU. Mol Genet Metab 1999;69:286-94.
20 -Rivera I, Cabral A, Almeida M, et al. The correlation of Genotype and Phenotype in Portuguese Hyperphenylalaninemic Patients. Mol Genet Metab 2000;69:195-203.
]]> 21 -Rivera I, Leandro P, Lichter-Konecki U, Tavares De Almeida I, Lechner MC. Population genetics of hyperphenylalaninaemia resulting from phenylalanine hydroxylase deficiency in Portugal. J Med Genet 1998;35(4):301-4.22 -Rivera, P Leandro, U Lichter-Konecki, I Tavares de Almeida e MC Lechner. Relative frequency of IVS10nt546 mutation in a Portuguese phenylketonuric population. Hum Mut 1997;9:272-273.
23 -Eisensmith RC, Okano Y, Dasovich M et al. Multiple origins for phenylketonuria in Europe. Am J Hum Genet 1992;51: 1355-65.
24 -Leandro P, Rivera I, Ribeiro V, de Almeida IT, da Silveira C, Lechner MC. Mutation analysis of phenylketonuria in south and central of Portugal: prevalence of V388M mutation. Hum Mutat 1995;6(2):192-4.
25 -Leandro P, Rivera I, Lechner MC, Konecki DS, Tavares de Almeida I. Prokaryotic expression analysis of I269L and R270K mutations of the phenylalanine hydroxylase (PAH) gene. Gene Funct Dis, 2001;1:46-50.
26 -Leandro P, Rivera I, Lechner MC, de Almeida IT, Konecki D. The V388M mutation results in a kinetic variant form of phenylalanine hydroxylase. Mol Genet Metab 2000;69(3): 204-12.
27 -Takahashi K, Kure S, Matsubara Y, Narisawa K. Novel phe-nylketonuria mutation detected by analysis of ectopically transcribed phenylalanine hydroxylase mRNA from lympho-blast. Lancet 1992;340:1473.
28 -Scriver CR, Waters PJ. Monogenic traits are not simple: lessons from phenylketonuria. TIG 1999;15:267-72.
29 -Erlandsen H, Stevens RC. The strutural basis of Phenylketonuria. Mol Genet Metab 1999;68:103-25.
30 -Hennermann JB, Vetter B, Wolf C, et al. Phenylketonuria and hyperphenylalninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. Hum Mutat 2000;15(3):254-60.
]]>Correspondência:
Dr.ª Laura Vilarinho
Laboratório Nacional de Rastreios
Instituto de Genética Médica Praça Pedro Nunes, 88
4099-028 Porto
e-mail: laura.vilarinho@igm.min-saude.pt
]]>