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Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment
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Molecular Genetics and Metabolism 92 (2007) 287–291 www.elsevier.com/locate/ymgme
Commentary
Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment Harvey Levy
a,*,1
, Barbara Burton
b,1
, Stephen Cederbaum
c,1
, Charles Scriver
d,1
a Children’s Hospital Boston and Harvard Medical School, Boston, MA, United States Children’s Memorial Hospital and Feinberg School of Medicine, Northwestern University, Chicago, IL, United States Division of Human Genetics and Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States d Department of Human Genetics and Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada b
c
Received 18 September 2007; accepted 18 September 2007
Abstract Some individuals with phenylketonuria (PKU) respond to pharmacologic treatment with tetrahydrobiopterin (BH4) by a reduction in the blood phenylalanine concentration. This can result in increased dietary tolerance for phenylalanine or, in rare instances, replacement of the phenylalanine-restricted diet. BH4 is now available as sapropterin dihydrochloride under the name KUVAN, a formulation of natural BH4. This commentary contains recommendations for determining responsiveness to sapropterin dihydrochloride. The recommendations include challenging with an initial daily dose of 20 mg/kg and blood phenylalanine determinations pre-challenge and on days 1, 7, and 14 with the option of an additional continuation to day 28 if required to clarify whether a response has occurred. An algorithm depicting this recommendation for the challenge is included. The most widely accepted standard of response is P30% reduction in the blood phenylalanine concentration, but a lower degree of response might also be considered clinically meaningful in some individual circumstances. Issues include the potential treatment of those with mild hyperphenylalaninemia who are not on diet, challenging neonates who have hyperphenylalaninemia identified by newborn screening, and the use of sapropterin dihydrochloride in treatment of maternal PKU pregnancies. These recommendations are intended to provide a basis for the use of sapropterin dihydrochloride in the treatment of PKU but may be altered after close observation of treated patients and carefully performed research. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Phenylketonuria; PKU; KUVAN; Tetrahydrobiopterin; BH4; Responsiveness; Sapropterin dihydrochloride
Background Phenylketonuria (PKU) is an inherited disorder in the activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine to tyrosine. In PKU this enzyme is defective, leading to a neurologically toxic accumulation of phenylalanine when a normal amount of protein is ingested. Almost 30 years ago Scriver and Clow characterized PKU as the epitome of human biochemical genetics [1]. Among the several reasons for this characterization, the ability to prevent the phenotype by early die*
1
Corresponding author. Fax: +1 617 730 0907. E-mail address: [email protected] (H. Levy). Writing for the National PKU Advisory Board.
1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.09.017
tary treatment was key. Even today, PKU remains one of the few inborn errors of metabolism for which there is effective therapy [2,3]. In order to be effective, however, the therapy imposes a substantial burden on the individual with PKU and the family. Most of the foods that are staples must be excluded because they contain too much phenylalanine. Moreover, the phenylalanine-free medical product (‘‘formula’’) that must be ingested three times a day to supply the required amount of protein as well as minerals and vitamins has an unpleasant taste and odor. Although the organoleptic properties of the diet products available today for the treatment of PKU, including ‘‘formulas’’ and low-protein foods, have improved, thereby increasing dietary compliance, adherence to the treatment protocol is still poor in some cases, resulting in suboptimal
288
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
metabolic control and the risk of complications, especially among adolescents and adults [4]. Consequently, the possibility that PKU may be treated without diet or with substantial modification of the diet has great appeal. Enter tetrahydrobiopterin (BH4), a catalytic cofactor for PAH [5]. In 1975, Milstien and Kaufman suggested that BH4 might be effective in treating PKU by stimulating PAH activity in patients with residual activity [6]. Eight years ago, Kure et al. reported that indeed this is so. In four of five patients with mild PKU, BH4 loading produced reductions of 40–70% in the blood phenylalanine concentration while they were on a normal diet [7]. Since then, numerous studies have confirmed this finding [8–11]. From these studies it is clear that the most frequent responders have mild PKU. Nevertheless, even those with classic PKU occasionally respond [8,10]. Beyond response to loading doses of BH4, continued treatment with BH4 in responding patients has been shown to allow substantial easing of dietary restrictions or even replacement of the diet [12–14]. Until now, BH4 has only been available for research, thus severely limiting its use for the treatment of PKU. With the availability of sapropterin dihydrochloride, a formulation of natural BH4 known as KUVANä,2 it is now possible to use BH4 in the treatment of some individuals with PKU. Recommendations Patient selection for sapropterin dihydrochloride responsiveness All patients known to have PKU should be offered a challenge with sapropterin dihydrochloride to determine responsiveness. Large clinics, however, may not be able to initially schedule all patients who are interested. Therefore, a triage system may be required. For this, we suggest the following in order of preference: (a) Younger patients on diet but not in optimal phenylalanine control (b) Patients considered to have mild PKU, based on dietary phenylalanine tolerance and initial confirmatory blood phenylalanine concentration, as these are the most likely to respond [8] (the PAH genotype may be a further clue to identifying these patients) (c) All other patients with PKU, beginning with younger patients on diet, then older patients struggling with diet or not on diet (but experiencing psychological difficulties), and finally, all patients not yet tested.
2 KUVANä is the trade name for sapropterin dihydrochloride manufactured by BioMarin Pharmaceutical Inc., Novato, CA 90907.
Regimen for sapropterin dihydrochloride responsiveness Fig. 1 is a suggested algorithm for determining responsiveness to BH4. The initial test dose should be 20 mg/kg ingested daily (a lower test dose may be used if the patient experiences side effects at the 20 mg/kg/day level). The medication should be taken with food or formula to enhance absorption and minimize the possibility of gastrointestinal side effects. Before the first dose, a blood specimen for phenylalanine determination must be collected. There should be no change in diet. Subsequent specimens for phenylalanine determination should be collected on days 1, 7, 14, and 28 (the last, if needed, to clarify whether a response has occurred). The blood should be collected at the same time of day for each patient. For instance, this could be at 10 a.m. or noon or 2 p.m. but should be consistent for the patient. Sapropterin dihydrochloride has demonstrated a correlation between dose and level of response with the greatest response occurring with the 20 mg/kg/day dose. The dose of sapropterin dihydrochloride may be titrated between 5 and 20 mg/kg/day to achieve the desired results. Determination of responsiveness What constitutes a clinically meaningful blood phenylalanine response to sapropterin dihydrochloride will likely vary depending on individual circumstances. The most widely accepted standard of response to BH4 is a P30% reduction in the blood phenylalanine concentration [10,11]. In the clinical trials of sapropterin dihydrochloride leading to approval of the drug, this was also the standard for responsiveness [15,16]. However, we recognize that a lower degree of responsiveness, e.g. 20%, might also be considered sufficient in some individual circumstances. Dietary phenylalanine tolerance Studies for Europe and Japan have shown that treatment of BH4-responsive patients can result in an increased dietary tolerance for phenylalanine. Lambruschini et al. reported that in 11 of 14 Spanish patients this increase was sufficient to allow for discontinuation of formula [12]. Shintaku et al. found that in Japan long-term therapy with BH4 could replace or modify the phenylalaninerestricted diet in a considerable number of patients with mild PKU [14]. Hennermann et al. reported a two-to-sevenfold increase in dietary phenylalanine tolerance among patients in Germany and Switzerland [13]. Thus, it is clear that in some patients the restrictive low phenylalanine diet can be modified. The degree of permissible dietary modification requires a detailed dietary assessment. Briefly, dietary phenylalanine can be gradually increased by addition of dry milk or egg powder to the diet with frequent monitoring of blood phenylalanine. When the limit of phenylalanine tolerance is achieved, as determined by the maximum amount of
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
289
Fig. 1.
dietary phenylalanine that maintains the blood phenylalanine concentration within the accepted metabolic control range, the amount of formula can be adjusted accordingly and the dry milk or egg powder supplement can be replaced by increased protein intake. Clinical follow-up Continuing careful medical and psychological assessment of sapropterin dihydrochloride-treated patients is important. The standard of follow-up in each clinic should be adhered to, perhaps with more frequent assessments to evaluate the early and still limited experience with sapropterin dihydrochloride therapy. Issues (1) Mild hyperphenylalaninemia Challenging and treating patients with sapropterin dihydrochloride might be considered in those who have mild hyperphenylalaninemia as determined by a blood phenylalanine concentration of 180–
360 lmol/L (2–6 mg/dL) or perhaps up to 600 lmol/L (10 mg/dL) while maintaining a normal diet. These phenylalanine concentrations are 2–5 times above normal and some clinicians might consider them potentially damaging, although there is evidence that such concentrations may be benign [17,18]. In many instances these patients may not have been treated with diet because it was believed that the possible benefit did not justify the intervention of a difficult and life-altering treatment. However, these patients are the most likely to respond to sapropterin dihydrochloride, with a response frequency approaching 90% [8,11], and some might wish to lower the blood phenylalanine concentration with a less interventive therapy than diet to avoid even the possibility of a toxic effect from the hyperphenylalaninemia. This is an area fertile for controlled studies. (2) Neonatal and early childhood treatment with sapropterin dihydrochloride An area of much interest in using sapropterin dihydrochloride cofactor therapy is in the newborn
290
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
identified with PKU by routine screening. It would be valuable to know as early as possible whether the baby responds and thus might be treated without diet or with fewer dietary restrictions. In Europe challenging the neonate with BH4 has been practiced for several years [8]. However, the clinical trials of sapropterin dihydrochloride have not included children younger than 4 years of age. Consequently, the drug has not been approved for younger children. (3) Maternal PKU Another area of interest is the possible use of sapropterin dihydrochloride in pregnant women with PKU who are responsive. Koch and coworkers reported good blood phenylalanine control, no complications of pregnancy, and normal neonatal outcome when BH4 was included in the treatment of a maternal PKU pregnancy but the dose used was only about 10% of that required for the treatment of PKU [19]. Here again, however, the clinical trials of sapropterin dihydrochloride have excluded those with a maternal PKU pregnancy and the drug has not been approved for use during pregnancy. Mechanism of response A positive response is likely to be limited to those genotypes/alleles that change amino acid composition but do not lead to absent or truncated protein products [20]. The mechanism of the response is likely to be complex and will include one or more of the following processes: (1) Overcoming unfavorable kinetics (2) Overcoming the effect of misfolding of the mutant protein [21] (3) An additional mechanism of response may include appropriate saturation of the enzyme by cofactor [22]. Regardless of the molecular mechanism, a positive therapeutic response to a pharmacological dose of BH4 clearly involves enhanced disposal of phenylalanine by conversion to tyrosine and access to the oxidative pathway [11]. Conclusion Stimulation of PAH enzyme activity by the administration of its cofactor, BH4, represents a physiologically direct approach to the treatment of PKU, in contrast to indirect dietary treatment. Until now, however, BH4 has been available for the treatment of PKU only for research. This has been changed by the approval of sapropterin dihydrochloride, a formulation of natural BH4, as a drug for PKU therapy. The use of sapropterin dihydrochloride in treating patients with PKU must be carefully considered. The recommendations provided in this commentary represent an attempt to develop a proper approach to the use of
sapropterin dihydrochloride for treating PKU. We recognize, however, that further experience may alter our understanding of its optimal use and require some changes in the recommendations. This is important and can only be properly done with close observation of cofactor-treated patients and carefully performed research. Acknowledgments The PKU Advisory Board consists of Co-Chairs Harvey L. Levy, MD, and Charles R. Scriver, MDCM, along with members Barbara Burton, MD, Stephen D. Cedarbaum, MD, Linda Marie Randolph, MD, FAAP, FACMG, and Desiree A. White, PhD. We thank Simpson Healthcare Executives, Alex Dorenbaum, MD at BioMarin Pharmaceuticals, Inc. and Ms.Vera Anastasoaie for their aid in the preparations of these guidelines. References [1] C.R. Scriver, C.L. Clow, Phenylketonuria: epitome of human biochemical genetics, N. Engl. J. Med. 303 (1980) 1336–1342 (1394–1400). [2] E. Treacy, B. Childs, C.R. Scriver, Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison, Am. J. Hum. Genet. 56 (1995) 359–367. [3] C.R. Scriver, E.P. Treacy, Is there treatment for ‘‘genetic’’ disease? Mol. Genet. Metab. 68 (1999) 93–102. [4] J.H. Walter, F.J. White, Blood phenylalanine control in adolescents with phenylketonuria, Int. J. Adolesc. Med. Health. 16 (2004) 41–45. [5] S. Kaufman, The structure of phenylalanine hydroxylation cofactor, Proc. Natl. Acad. Sci. USA 50 (1963) 1085–1093. [6] S. Milstien, S. Kaufman, Studies on the phenylalanine hydroxylase system in liver slices, J. Biol. Chem. 250 (1975) 4777–4781. [7] S. Kure, D.-Ch. Hou, T. Ohura, H. Iwamoto, S. Suzuki, N. Sugiyama, O. Sakamoto, K. Fujii, Y. Matsubara, K. Narisawa, Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, J. Pediatr. 135 (1999) 375–378. [8] B. Fiege, N. Blau, Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria, J. Pediatr. 150 (2007) 627–630. [9] V. Leuzzi, C. Carducci, F. Chiarotti, C. Artiola, T. Giovanniello, I. Antonozzi, The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency, J. Inherit. Metab. Dis. 29 (2006) 38–46. [10] J.J. Mitchell, B. Wilcken, I. Alexander, C. Ellaway, H. O’Grady, V. Wiley, J. Earl, J. Christodoulou, Tetrahydrobiopterin-responsive phenylketonuria: the New South Wales experience, Mol. Genet. Metab. 86 (2005) S81–S85. [11] A.C. Muntau, W. Roschinger, M. Habich, H. Demmelmair, B. Hoffmann, C.P. Sommerhoff, A.A. Roscher, Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria, N. Engl. J. Med. 347 (2002) 2122–2132. [12] N. Lambruschini, B. Pe´rez-Duen˜as, M.A. Vilaseca, A. Mas, R. Artuch, R. Gassı´o, L. Go´mez, A. Gutierrez, J. Campistol, Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy, Mol. Genet. Metab. 86 (2005) S54–S60. [13] J.B. Hennermann, C. Bu¨hrer, N. Blau, B. Vetter, E. Mo¨nch, Longterm treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria, Mol. Genet. Metab. 86 (2005) S86–S90. [14] H. Shintaku, S. Kure, T. Ohura, Y. Okano, M. Ohwada, N. Sugiyama, N. Sakura, I. Yoshida, M. Yoshino, Y. Matsubara, K. Suzuki, K. Aoki, T. Kitagawa, Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene, Pediatr. Res. 55 (2004) 425–430.
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291 [15] H.L. Levy, A. Milanowski, A. Chakrapani, M. Cleary, P. Lee, F.K. Trefz, C.B. Whitely, F. Feillet, A.S. Feigenbaum, J.D. Bebchuk, H. Christ-Schmidt, A. Dorenbaum, A phase III randomized placebocontrolled study of the efficacy of sapropterin dihydrochloride (tetrahydrobiopterin 6R-BH4) in reducing phenylalanine levels in subjects with phenylketonuria, Lancet 370 (2007) 504–510. [16] PKU-006 Clinical Study Report, BioMarin Pharmaceuticals, Inc., Novato, CA. [17] H.L. Levy, V.E. Shih, V. Karolkewicz, W.A. French, J.R. Carr, V. Cass, J.L. Kennedy, R.A. MacCready, Persistent mild hyperphenylalanemia in the untreated state, N. Engl. J. Med. 285 (1971) 424–429. [18] J. Weglage, M. Pietsch, R. Feldmann, H.-G. Koch, J. Zschocke, G. Hoffmann, A. Muntua-Hegen, J. Denecke, P. Guldberg, F. Guttler, H. Moller, U. Wendel, K. Ullrich, E. Harms, Normal clinical outcome in untreated subjects with mild hyperphenylalaninemia, Pediatr. Res. 49 (2001) 532–536.
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[19] R. Koch, K. Moseley, F. Guttler, Tetrahydrobiopterin and maternal PKU, Mol. Genet. Metab. 86 (2005) S139–S141. [20] N. Blau, H. Erlandsen, The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, Mol. Genet. Metab. 82 (2004) 101–111. [21] H. Erlandsen, A.L. Pey, A. Ga´mez, B. Pe´rez, L.R. Desviat, C. Aguado, R. Koch, S. Surendran, S. Tyring, R. Matalon, C.R. Scriver, W. Ugarte, A. Martinez, R.C. Stevens, Correction of kinetic and stability of defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations, Proc. Natl. Acad. Sci. USA 101 (2004) 16903–16908. [22] S. Kure, K. Sato, K. Fujii, Y. Aoki, Y. Suzuki, S. Kato, Y. Matsubara, Wild-type phenylalanine hydroxylase activity is enhanced by tetrahydrobiopterin supplementation in vivo: an implication for therapeutic basis of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, Mol. Genet. Metab. 83 (2004) 150–156.
Molecular Genetics and Metabolism 92 (2007) 287–291 www.elsevier.com/locate/ymgme
Commentary
Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment Harvey Levy
a,*,1
, Barbara Burton
b,1
, Stephen Cederbaum
c,1
, Charles Scriver
d,1
a Children’s Hospital Boston and Harvard Medical School, Boston, MA, United States Children’s Memorial Hospital and Feinberg School of Medicine, Northwestern University, Chicago, IL, United States Division of Human Genetics and Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States d Department of Human Genetics and Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada b
c
Received 18 September 2007; accepted 18 September 2007
Abstract Some individuals with phenylketonuria (PKU) respond to pharmacologic treatment with tetrahydrobiopterin (BH4) by a reduction in the blood phenylalanine concentration. This can result in increased dietary tolerance for phenylalanine or, in rare instances, replacement of the phenylalanine-restricted diet. BH4 is now available as sapropterin dihydrochloride under the name KUVAN, a formulation of natural BH4. This commentary contains recommendations for determining responsiveness to sapropterin dihydrochloride. The recommendations include challenging with an initial daily dose of 20 mg/kg and blood phenylalanine determinations pre-challenge and on days 1, 7, and 14 with the option of an additional continuation to day 28 if required to clarify whether a response has occurred. An algorithm depicting this recommendation for the challenge is included. The most widely accepted standard of response is P30% reduction in the blood phenylalanine concentration, but a lower degree of response might also be considered clinically meaningful in some individual circumstances. Issues include the potential treatment of those with mild hyperphenylalaninemia who are not on diet, challenging neonates who have hyperphenylalaninemia identified by newborn screening, and the use of sapropterin dihydrochloride in treatment of maternal PKU pregnancies. These recommendations are intended to provide a basis for the use of sapropterin dihydrochloride in the treatment of PKU but may be altered after close observation of treated patients and carefully performed research. Ó 2007 Elsevier Inc. All rights reserved. Keywords: Phenylketonuria; PKU; KUVAN; Tetrahydrobiopterin; BH4; Responsiveness; Sapropterin dihydrochloride
Background Phenylketonuria (PKU) is an inherited disorder in the activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine to tyrosine. In PKU this enzyme is defective, leading to a neurologically toxic accumulation of phenylalanine when a normal amount of protein is ingested. Almost 30 years ago Scriver and Clow characterized PKU as the epitome of human biochemical genetics [1]. Among the several reasons for this characterization, the ability to prevent the phenotype by early die*
1
Corresponding author. Fax: +1 617 730 0907. E-mail address: [email protected] (H. Levy). Writing for the National PKU Advisory Board.
1096-7192/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2007.09.017
tary treatment was key. Even today, PKU remains one of the few inborn errors of metabolism for which there is effective therapy [2,3]. In order to be effective, however, the therapy imposes a substantial burden on the individual with PKU and the family. Most of the foods that are staples must be excluded because they contain too much phenylalanine. Moreover, the phenylalanine-free medical product (‘‘formula’’) that must be ingested three times a day to supply the required amount of protein as well as minerals and vitamins has an unpleasant taste and odor. Although the organoleptic properties of the diet products available today for the treatment of PKU, including ‘‘formulas’’ and low-protein foods, have improved, thereby increasing dietary compliance, adherence to the treatment protocol is still poor in some cases, resulting in suboptimal
288
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
metabolic control and the risk of complications, especially among adolescents and adults [4]. Consequently, the possibility that PKU may be treated without diet or with substantial modification of the diet has great appeal. Enter tetrahydrobiopterin (BH4), a catalytic cofactor for PAH [5]. In 1975, Milstien and Kaufman suggested that BH4 might be effective in treating PKU by stimulating PAH activity in patients with residual activity [6]. Eight years ago, Kure et al. reported that indeed this is so. In four of five patients with mild PKU, BH4 loading produced reductions of 40–70% in the blood phenylalanine concentration while they were on a normal diet [7]. Since then, numerous studies have confirmed this finding [8–11]. From these studies it is clear that the most frequent responders have mild PKU. Nevertheless, even those with classic PKU occasionally respond [8,10]. Beyond response to loading doses of BH4, continued treatment with BH4 in responding patients has been shown to allow substantial easing of dietary restrictions or even replacement of the diet [12–14]. Until now, BH4 has only been available for research, thus severely limiting its use for the treatment of PKU. With the availability of sapropterin dihydrochloride, a formulation of natural BH4 known as KUVANä,2 it is now possible to use BH4 in the treatment of some individuals with PKU. Recommendations Patient selection for sapropterin dihydrochloride responsiveness All patients known to have PKU should be offered a challenge with sapropterin dihydrochloride to determine responsiveness. Large clinics, however, may not be able to initially schedule all patients who are interested. Therefore, a triage system may be required. For this, we suggest the following in order of preference: (a) Younger patients on diet but not in optimal phenylalanine control (b) Patients considered to have mild PKU, based on dietary phenylalanine tolerance and initial confirmatory blood phenylalanine concentration, as these are the most likely to respond [8] (the PAH genotype may be a further clue to identifying these patients) (c) All other patients with PKU, beginning with younger patients on diet, then older patients struggling with diet or not on diet (but experiencing psychological difficulties), and finally, all patients not yet tested.
2 KUVANä is the trade name for sapropterin dihydrochloride manufactured by BioMarin Pharmaceutical Inc., Novato, CA 90907.
Regimen for sapropterin dihydrochloride responsiveness Fig. 1 is a suggested algorithm for determining responsiveness to BH4. The initial test dose should be 20 mg/kg ingested daily (a lower test dose may be used if the patient experiences side effects at the 20 mg/kg/day level). The medication should be taken with food or formula to enhance absorption and minimize the possibility of gastrointestinal side effects. Before the first dose, a blood specimen for phenylalanine determination must be collected. There should be no change in diet. Subsequent specimens for phenylalanine determination should be collected on days 1, 7, 14, and 28 (the last, if needed, to clarify whether a response has occurred). The blood should be collected at the same time of day for each patient. For instance, this could be at 10 a.m. or noon or 2 p.m. but should be consistent for the patient. Sapropterin dihydrochloride has demonstrated a correlation between dose and level of response with the greatest response occurring with the 20 mg/kg/day dose. The dose of sapropterin dihydrochloride may be titrated between 5 and 20 mg/kg/day to achieve the desired results. Determination of responsiveness What constitutes a clinically meaningful blood phenylalanine response to sapropterin dihydrochloride will likely vary depending on individual circumstances. The most widely accepted standard of response to BH4 is a P30% reduction in the blood phenylalanine concentration [10,11]. In the clinical trials of sapropterin dihydrochloride leading to approval of the drug, this was also the standard for responsiveness [15,16]. However, we recognize that a lower degree of responsiveness, e.g. 20%, might also be considered sufficient in some individual circumstances. Dietary phenylalanine tolerance Studies for Europe and Japan have shown that treatment of BH4-responsive patients can result in an increased dietary tolerance for phenylalanine. Lambruschini et al. reported that in 11 of 14 Spanish patients this increase was sufficient to allow for discontinuation of formula [12]. Shintaku et al. found that in Japan long-term therapy with BH4 could replace or modify the phenylalaninerestricted diet in a considerable number of patients with mild PKU [14]. Hennermann et al. reported a two-to-sevenfold increase in dietary phenylalanine tolerance among patients in Germany and Switzerland [13]. Thus, it is clear that in some patients the restrictive low phenylalanine diet can be modified. The degree of permissible dietary modification requires a detailed dietary assessment. Briefly, dietary phenylalanine can be gradually increased by addition of dry milk or egg powder to the diet with frequent monitoring of blood phenylalanine. When the limit of phenylalanine tolerance is achieved, as determined by the maximum amount of
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
289
Fig. 1.
dietary phenylalanine that maintains the blood phenylalanine concentration within the accepted metabolic control range, the amount of formula can be adjusted accordingly and the dry milk or egg powder supplement can be replaced by increased protein intake. Clinical follow-up Continuing careful medical and psychological assessment of sapropterin dihydrochloride-treated patients is important. The standard of follow-up in each clinic should be adhered to, perhaps with more frequent assessments to evaluate the early and still limited experience with sapropterin dihydrochloride therapy. Issues (1) Mild hyperphenylalaninemia Challenging and treating patients with sapropterin dihydrochloride might be considered in those who have mild hyperphenylalaninemia as determined by a blood phenylalanine concentration of 180–
360 lmol/L (2–6 mg/dL) or perhaps up to 600 lmol/L (10 mg/dL) while maintaining a normal diet. These phenylalanine concentrations are 2–5 times above normal and some clinicians might consider them potentially damaging, although there is evidence that such concentrations may be benign [17,18]. In many instances these patients may not have been treated with diet because it was believed that the possible benefit did not justify the intervention of a difficult and life-altering treatment. However, these patients are the most likely to respond to sapropterin dihydrochloride, with a response frequency approaching 90% [8,11], and some might wish to lower the blood phenylalanine concentration with a less interventive therapy than diet to avoid even the possibility of a toxic effect from the hyperphenylalaninemia. This is an area fertile for controlled studies. (2) Neonatal and early childhood treatment with sapropterin dihydrochloride An area of much interest in using sapropterin dihydrochloride cofactor therapy is in the newborn
290
H. Levy et al. / Molecular Genetics and Metabolism 92 (2007) 287–291
identified with PKU by routine screening. It would be valuable to know as early as possible whether the baby responds and thus might be treated without diet or with fewer dietary restrictions. In Europe challenging the neonate with BH4 has been practiced for several years [8]. However, the clinical trials of sapropterin dihydrochloride have not included children younger than 4 years of age. Consequently, the drug has not been approved for younger children. (3) Maternal PKU Another area of interest is the possible use of sapropterin dihydrochloride in pregnant women with PKU who are responsive. Koch and coworkers reported good blood phenylalanine control, no complications of pregnancy, and normal neonatal outcome when BH4 was included in the treatment of a maternal PKU pregnancy but the dose used was only about 10% of that required for the treatment of PKU [19]. Here again, however, the clinical trials of sapropterin dihydrochloride have excluded those with a maternal PKU pregnancy and the drug has not been approved for use during pregnancy. Mechanism of response A positive response is likely to be limited to those genotypes/alleles that change amino acid composition but do not lead to absent or truncated protein products [20]. The mechanism of the response is likely to be complex and will include one or more of the following processes: (1) Overcoming unfavorable kinetics (2) Overcoming the effect of misfolding of the mutant protein [21] (3) An additional mechanism of response may include appropriate saturation of the enzyme by cofactor [22]. Regardless of the molecular mechanism, a positive therapeutic response to a pharmacological dose of BH4 clearly involves enhanced disposal of phenylalanine by conversion to tyrosine and access to the oxidative pathway [11]. Conclusion Stimulation of PAH enzyme activity by the administration of its cofactor, BH4, represents a physiologically direct approach to the treatment of PKU, in contrast to indirect dietary treatment. Until now, however, BH4 has been available for the treatment of PKU only for research. This has been changed by the approval of sapropterin dihydrochloride, a formulation of natural BH4, as a drug for PKU therapy. The use of sapropterin dihydrochloride in treating patients with PKU must be carefully considered. The recommendations provided in this commentary represent an attempt to develop a proper approach to the use of
sapropterin dihydrochloride for treating PKU. We recognize, however, that further experience may alter our understanding of its optimal use and require some changes in the recommendations. This is important and can only be properly done with close observation of cofactor-treated patients and carefully performed research. Acknowledgments The PKU Advisory Board consists of Co-Chairs Harvey L. Levy, MD, and Charles R. Scriver, MDCM, along with members Barbara Burton, MD, Stephen D. Cedarbaum, MD, Linda Marie Randolph, MD, FAAP, FACMG, and Desiree A. White, PhD. We thank Simpson Healthcare Executives, Alex Dorenbaum, MD at BioMarin Pharmaceuticals, Inc. and Ms.Vera Anastasoaie for their aid in the preparations of these guidelines. References [1] C.R. Scriver, C.L. Clow, Phenylketonuria: epitome of human biochemical genetics, N. Engl. J. Med. 303 (1980) 1336–1342 (1394–1400). [2] E. Treacy, B. Childs, C.R. Scriver, Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison, Am. J. Hum. Genet. 56 (1995) 359–367. [3] C.R. Scriver, E.P. Treacy, Is there treatment for ‘‘genetic’’ disease? Mol. Genet. Metab. 68 (1999) 93–102. [4] J.H. Walter, F.J. White, Blood phenylalanine control in adolescents with phenylketonuria, Int. J. Adolesc. Med. Health. 16 (2004) 41–45. [5] S. Kaufman, The structure of phenylalanine hydroxylation cofactor, Proc. Natl. Acad. Sci. USA 50 (1963) 1085–1093. [6] S. Milstien, S. Kaufman, Studies on the phenylalanine hydroxylase system in liver slices, J. Biol. Chem. 250 (1975) 4777–4781. [7] S. Kure, D.-Ch. Hou, T. Ohura, H. Iwamoto, S. Suzuki, N. Sugiyama, O. Sakamoto, K. Fujii, Y. Matsubara, K. Narisawa, Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, J. Pediatr. 135 (1999) 375–378. [8] B. Fiege, N. Blau, Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria, J. Pediatr. 150 (2007) 627–630. [9] V. Leuzzi, C. Carducci, F. Chiarotti, C. Artiola, T. Giovanniello, I. Antonozzi, The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency, J. Inherit. Metab. Dis. 29 (2006) 38–46. [10] J.J. Mitchell, B. Wilcken, I. Alexander, C. Ellaway, H. O’Grady, V. Wiley, J. Earl, J. Christodoulou, Tetrahydrobiopterin-responsive phenylketonuria: the New South Wales experience, Mol. Genet. Metab. 86 (2005) S81–S85. [11] A.C. Muntau, W. Roschinger, M. Habich, H. Demmelmair, B. Hoffmann, C.P. Sommerhoff, A.A. Roscher, Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria, N. Engl. J. Med. 347 (2002) 2122–2132. [12] N. Lambruschini, B. Pe´rez-Duen˜as, M.A. Vilaseca, A. Mas, R. Artuch, R. Gassı´o, L. Go´mez, A. Gutierrez, J. Campistol, Clinical and nutritional evaluation of phenylketonuric patients on tetrahydrobiopterin monotherapy, Mol. Genet. Metab. 86 (2005) S54–S60. [13] J.B. Hennermann, C. Bu¨hrer, N. Blau, B. Vetter, E. Mo¨nch, Longterm treatment with tetrahydrobiopterin increases phenylalanine tolerance in children with severe phenotype of phenylketonuria, Mol. Genet. Metab. 86 (2005) S86–S90. [14] H. Shintaku, S. Kure, T. Ohura, Y. Okano, M. Ohwada, N. Sugiyama, N. Sakura, I. Yoshida, M. Yoshino, Y. Matsubara, K. Suzuki, K. Aoki, T. Kitagawa, Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene, Pediatr. Res. 55 (2004) 425–430.
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