{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:33:48Z","timestamp":1791977628050,"version":"4.4.0"},"reference-count":31,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2008,10,30]],"date-time":"2008-10-30T00:00:00Z","timestamp":1225324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The value of genotyping to identify tetrahydrobiopterin\u2010responsive (BH<jats:sub>4<\/jats:sub>\u2010responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH<jats:sub>4<\/jats:sub> load and genetic mutations. Partial and full BH<jats:sub>4<\/jats:sub> responses were defined as a 10\u201329% decrease and a \u226530% decrease from baseline in blood phenylalanine levels, respectively. BH<jats:sub>4<\/jats:sub>\u2010responsive alleles were identified from BH<jats:sub>4<\/jats:sub>\u2010responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Most inconsistencies between observed genotype and BH<jats:sub>4<\/jats:sub> response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20\/62 alleles (32.2%) were non\u2010responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8\/125 alleles (6.4%) were non\u2010responsive. Seven patients had a genotype with two BH<jats:sub>4<\/jats:sub>\u2010responsive alleles resulting in no response or only a partial response to BH<jats:sub>4<\/jats:sub>. Ten patients had identical genotypes but inconsistent responses in BH<jats:sub>4<\/jats:sub> load.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results show that BH<jats:sub>4<\/jats:sub> non\u2010responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non\u2010responsiveness may be related to negative inter\u2010allelic complementation. In patients with the same genotype and inconsistent results for BH<jats:sub>4<\/jats:sub> load, external factors such as intestinal absorption of BH<jats:sub>4<\/jats:sub>, catabolic conditions or other genetic factors may be responsible. Further <jats:italic>in vitro<\/jats:italic> studies are necessary to clarify the genotype\u2013phenotype correlation in patients with BH<jats:sub>4<\/jats:sub>\u2010responsive PKU.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s10545-008-0940-8","type":"journal-article","created":{"date-parts":[[2008,10,27]],"date-time":"2008-10-27T19:46:53Z","timestamp":1225136813000},"page":"22-26","source":"Crossref","is-referenced-by-count":55,"title":["Significance of genotype in tetrahydrobiopterin\u2010responsive phenylketonuria"],"prefix":"10.1002","volume":"32","author":[{"given":"F. K.","family":"Trefz","sequence":"first","affiliation":[{"name":"Klinik f\u00fcr Kinder und Jugendmedizin Kreiskliniken Reutlingen GmbH Steinenbergstrasse 31 Reutlingen 72764 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Scheible","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Kinder und Jugendmedizin Kreiskliniken Reutlingen GmbH Steinenbergstrasse 31 Reutlingen 72764 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"G\u00f6tz","sequence":"additional","affiliation":[{"name":"Software Service GmbH Schwabach Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Frauendienst\u2010Egger","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr Kinder und Jugendmedizin Kreiskliniken Reutlingen GmbH Steinenbergstrasse 31 Reutlingen 72764 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2008,10,30]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-002-1034-5"},{"key":"e_1_2_5_3_1","first-page":"146","article-title":"Tetrahydrobiopterin therapy for hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. When and how?","volume":"64","author":"Baldellou\u2010V\u00e1zquez A","year":"2006","journal-title":"An Pediatr (Barc)"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1096-7192(02)00166-X"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2004.06.007"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3052"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407256101"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2003.09.014"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.09.014"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.05.013"},{"key":"e_1_2_5_11_1","first-page":"1","article-title":"Phenylketonuria: biochemical mechanisms","volume":"2","author":"Kaufman S","year":"1976","journal-title":"Adv Neurochem"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(99)70138-1"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015194002487"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2006.02.001"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10038-004-0197-5"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0096-3"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)61234-3"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.09.017"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9117"},{"key":"e_1_2_5_20_1","volume-title":"International Conference on tetrahydrobiopterin, PKU and NOS","author":"Martinez MA","year":"2008"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.06.024"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)41370-7"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa021654"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2004.09.005"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10198"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20097"},{"key":"e_1_2_5_27_1","first-page":"1667","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Scriver CR","year":"2001"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000111283.91564.7E"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.06.018"},{"issue":"3","key":"e_1_2_5_30_1","first-page":"407","article-title":"Supporting genotype\u2013phenotype correlation with the rare metabolic diseases database Ramedis","volume":"2","author":"T\u00f6pel T","year":"2002","journal-title":"Silico Biol"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.06.026"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20637"}],"container-title":["Journal of Inherited Metabolic Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-008-0940-8","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1007\/s10545-008-0940-8","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1007\/s10545-008-0940-8","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T18:26:06Z","timestamp":1694802366000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1007\/s10545-008-0940-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,10,30]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,2]]}},"alternative-id":["10.1007\/s10545-008-0940-8"],"URL":"https:\/\/doi.org\/10.1007\/s10545-008-0940-8","archive":["Portico"],"relation":{},"ISSN":["0141-8955","1573-2665"],"issn-type":[{"value":"0141-8955","type":"print"},{"value":"1573-2665","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,10,30]]}}}