Blau, Nenad

Kern, Ilse

Kierat, Lucja

Opladen, Thomas

Thöny, Beat

Zurflüh, Marcel

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SHORT REPORTThomas Opladen Æ Marcel Zurﬂu¨h Æ Ilse KernLucja Kierat Æ Beat Tho¨ny Æ Nenad BlauSevere mucitis after sublingual administration of tetrahydrobiopterinin a patient with tetrahydrobiopterin-responsive phenylketonuriaReceived: 2 November 2004 / Accepted: 12 January 2005 / Published online: 22 February 2005 Springer-Verlag 2005Tetrahydrobiopterin (BH4) is the cofactor for phenyl-alanine hydroxylase (PAH) and is essential to treatdiﬀerent forms of hyperphenylalaninaemia, i.e. patientswith defects in the biosynthesis of BH4, but also in thePAH gene [1, 4,5]. Responsiveness of mutant PAH toBH4 administration relies on a chemical chaperon eﬀectof BH4 preventing PAH from protein misfolding andinactivation [6], but several other mechanisms may alsobe involved [2]. Recently, we reported that sublingualadministration of BH4 tablets in a single control personresulted in 58%–67% higher plasma BH4 concentra-tions than the usual oral route [3]. Drawbacks includedrapid decomposition of tablets, acidic taste, and in-creased salivation. Since sublingual application couldreduce therapy costs, orange ﬂavoured artiﬁciallysweetened BH4 pastilles were tested on four healthyvolunteers and a child with mild phenylketonuria(PKU).BH4 (Schircks, Switzerland) was administered tofour healthy male volunteers (age 28–57 years) on 2subsequent days either as tablets (50 mg) or pastilles(100 mg, containing 5 mg aspartame and orange ar-oma) with a 1 week wash-out between the two trials.Blood was collected before, and 1, 2, 3, and 4 h afteradministration. An 8-year-old patient with mild PKU(genotype P281L/R261Q) who was already on regularBH4 therapy was treated with BH4 pastilles (sublin-gually, 12 mg/kg/day; bid) in addition to P-AM 2formula for 2 weeks. Written consensus was obtainedfrom the family.In the four healthy male volunteers, total biopterinvalues before and up to 4 h after oral and sublingualadministration were compared (Fig. 1A). No statisti-cally signiﬁcant diﬀerence between oral and sublingualadministration was observed. Pterin concentrations in-creased after both oral and sublingual administration,reﬂecting instability of BH4 in blood. The ratio ofpterin to cumulated biopterin and pterin ranged be-tween 22.8% and 33.5%. Summing biopterin andpterin instead of total biopterin did not alter the ratiobetween oral and sublingual administration (data notshown).Changing from standard therapy to sublingualadministration in a child with mild PKU resulted inalmost unchanged plasma phenylalanine concentrations(Fig. 1B). After 2 weeks of twice daily sublingual BH4administration, the patient complained of a painfulprickling sensation at the tip of the tongue. He never-theless continued the treatment for a further 10 days,moving the tablets in his mouth from one side to theother, which resulted in severe mucitis. His conditionnormalised rapidly upon discontinuation of the sub-lingual form. No mucitis appeared in healthy volun-teers.A clinical trial with sublingual BH4 in a patient withmild PKU failed despite pharmacological eﬀectivenesson blood phenylalanine levels because of an adversepastille-related side-eﬀect. Formulation of buﬀered tab-lets approaching neutral pH and further investigationson BH4 metabolism and pharmacokinetics are needed.Acknowledgements The authors thank the patient and his family fortheir exemplary participation. This work was supported by theSwiss National Science Foundation grant no. 3100-066953.01.Thomas Opladen received a research grant from the AachenMedical Faculty and support from the ‘‘Sanita¨tsrat-Dr.-Emil-Alexander-Huebner-und Gemahlin-Stiftung’’.The ﬁrst two authors contributed equally to this work.T. Opladen Æ M. Zurﬂu¨h Æ L. Kierat Æ B. Tho¨ny Æ N. Blau (&)Division of Clinical Chemistry and Biochemistry,University Children’s Hospital, Steinwiesstrasse 75,8032 Zurich, SwitzerlandE-mail: nenad.blau@kispi.unizh.chTel.: +41-1-2667544Fax: +41-1-2667169T. OpladenDivision of Paediatric Neurology,Department of Paediatrics, University Hospital,Aachen, GermanyI. KernDivision of Metabolism, Department of Paediatrics,University Hospital, Geneva, SwitzerlandEur J Pediatr (2005) 164: 395–396DOI 10.1007/s00431-005-1638-7References1. Bernegger C, Blau N (2002) High frequency of tetrahydrobiop-terin-responsiveness among hyperphenylalaninemias: a study of1919 patients observed from 1988 to 2002. Mol Genet Metab 77:304–3132. Blau N, Erlandsen H (2004) The metabolic and molecular basesof tetrahydrobiopterin-responsive phenylalanine hydroxylasedeﬁciency. Mol Genet Metab 82: 101–1113. Fiege B, Ballhausen D, Kierat L, Leimbacher W, Goriouniv D,Schircks B, Tho¨ny B, Blau N (2004) Plasma tetrahydrobiopterinand its pharmacokinetics following oral administration. MolGenet Metab 81: 45–514. Kure S, Hou DC, Ohura T, Iwamoto H, Suzuki S, Sugiyama N,Sakamoto O, Fujii K, Matsubara Y, Narisawa K (1999) Tet-rahydrobiopterin-responsive phenylalanine hydroxylase deﬁ-ciency. J Pediatr 135: 375–3785. Muntau AC, Roschinger W, Habich M, Demmelmair H, Hoﬀ-mann B, Sommerhoﬀ CP, Roscher AA (2002) Tetrahydrobiop-terin as an alternative treatment for mild phenylketonuria.N Engl J Med 347: 2122–21326. Tho¨ny B, Ding Z, Martinez A (2004) Tetrahydrobiopterin pro-tects phenylalanine hydroxylase activity in vivo: implications fortetrahydrobiopterin-responsive hyperphenylalaninemia. FEBSLett 577: 507–511Fig. 1 A Comparison of totalplasma biopterin levels (median± SD) after oral or sublingualadministration of BH4 (2 mg/kg) in four healthy volunteers atdiﬀerent time points. B Driedblood spot phenylalanine ( solidsquares) and biopterin ( opensquares) measured 3 h after oral(15 mg/kg) or sublingual(12 mg/kg) administration ofBH4 in a patient with mild PKU( s.l.sublingual)396

Severe mucitis after sublingual administration of tetrahydrobiopterin in a patient with tetrahydrobiopterin-responsive phenylketonuria

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Severe mucitis after sublingual administration of tetrahydrobiopterin in a patient with tetrahydrobiopterin-responsive phenylketonuria

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