Correspondence
Tetrahydrobiopterin and Mild Phenylketonuria
N Engl J Med 2003; 348:1722-1724April 24, 2003
- Article
To the Editor:
The concept that phenylketonuria may be cured by tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase, rather than by dietary protein restriction, has generated a number of therapeutic attempts. Muntau et al. (Dec. 26 issue)1 offer a more extensive study and claim that the majority of mild cases of phenylalanine hydroxylase deficiency are variably responsive to tetrahydrobiopterin. Major issues concerning the selection of patients and the experimental design, however, weaken the significance of their findings. Patients were classified according to their pretreatment plasma phenylalanine concentration instead of their phenylalanine tolerance, but only the latter permits the definite identification of the phenotype.2 The combined phenylalanine–tetrahydrobiopterin loading test was accomplished at variable basal phenylalanine concentrations, with a procedure that might lead to erratic results.3 Phenylalanine tolerance was reported to increase during long-term tetrahydrobiopterin administration from a mean value of 18.7 mg per kilogram of body weight to 61.4 mg per kilogram, but a phenylalanine tolerance above 100 mg per kilogram is characteristic of benign forms of phenylketonuria.2
The safest conclusion to be drawn from this study is that severe phenylketonuria is not responsive to tetrahydrobiopterin, whereas consistent phenylalanine hydroxylation after phenylalanine loading is shared by variants of phenylketonuria with high residual phenylalanine hydroxylase activity — points that have already been elucidated.2,4 Whatever activity might be exerted by tetrahydrobiopterin in individual cases of phenylketonuria awaits demonstration, notwithstanding the strong biopterin response elicited by acute or chronic hyperphenylalaninemia in patients with intact cofactor metabolism.5
5 ReferencesAlberto Ponzone, M.D.
Antonella Peduto, M.D.
Marco Spada, M.D., Ph.D.
University of Turin, 10126 Turin, Italy
alberto.ponzone@unito. it 1
Muntau AC ,Roschinger W ,Habich M , et al. Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 2002;347:2122-2132
Full Text | Web of Science | Medline2
Guttler F . Hyperphenylalaninemia: diagnosis and classification of the various types of phenylalanine hydroxylase deficiency in childhood. Acta Paediatr Scand Suppl 1980;280:1-80
Medline3
Ponzone A ,Guardamagna O ,Spada M , et al. Differential diagnosis of hyperphenylalaninaemia by a combined phenylalanine-tetrahydrobiopterin loading test. Eur J Pediatr 1993;152:655-661
CrossRef | Web of Science | Medline4
Ponzone A ,Guardamagna O ,Ferraris S ,Ferrero GB ,Dianzani I ,Cotton RGH . Tetrahydrobiopterin loading test in hyperphenylalaninemia. Pediatr Res 1991;30:435-438
CrossRef | Web of Science | Medline5
Ponzone A ,Guardamagna O ,Spada M , et al. Hyperphenylalaninemia and pterin metabolism in serum and erythrocytes. Clin Chim Acta 1993;216:63-71
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To the Editor:
Muntau et al. infer that tetrahydrobiopterin may be an alternative treatment for certain variants of phenylketonuria related to phenylalanine hydroxylase deficiency but not for classic phenylketonuria. The distribution of phenylketonuria phenotypes they report is unusual. Most phenylketonuria treatment centers report that 50 to 70 percent of their patients have classic phenylketonuria and that the majority of the variants involve mild hyperphenylalaninemia. For example, Clemens et al.1 in Hamburg, Germany, report that of 14 consecutive patients with newly diagnosed phenylketonuria, 8 had classic phenylketonuria, 2 had mild phenylketonuria, and 4 had mild hyperphenylalaninemia. This difference in distribution suggests some selection bias in the study by Muntau et al. It is now clear that patients with mild hyperphenylalaninemia do not need treatment,2 possibly even during pregnancy.3 This conclusion leaves a small number of patients — those with mild phenylketonuria — who may be good candidates for therapy. It is of interest that Weglage et al.,4 in Münster, Germany, found that only 3 of 87 patients with newly diagnosed phenylketonuria had a response to tetrahydrobiopterin, and in these 3, the response was only temporary, necessitating the reintroduction of dietary therapy. Treatment with tetrahydrobiopterin is very expensive — as high as $30,000 per year for an adolescent or an adult, as compared with $6,000 for phenylalanine-restricted dietary therapy.
4 ReferencesWilliam B. Hanley, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
whanley@sickkids.ca 1
Clemens PC ,Neumann SJ ,Wulke AP ,Burmester JG . Newborn screening for hyperphenylalaninemia on day 5: is 240 μmols/liter the most appropriate cut-off level? Prev Med 1990;19:54-60
CrossRef | Web of Science | Medline2
Smith ML ,Saltzman J ,Klim P ,Hanley WB ,Feigenbaum A ,Clarke JTR . Neuropsychological function in mild hyperphenylalaninemia. Am J Ment Retard 2000;105:69-80
CrossRef | Web of Science | Medline3
Levy HL ,Waisbren SE ,Lobbregt D , et al. Maternal mild hyperphenylalaninaemia: an international survey of offspring outcome. Lancet 1994;344:1589-1594
CrossRef | Web of Science | Medline4
Weglage J ,Grenzebach M ,von Teeffelen-Heithoff A , et al. Tetrahydrobiopterin responsiveness in a large series of phenylketonuria patients. J Inherit Metab Dis 2002;25:321-322
CrossRef | Web of Science | Medline
To the Editor:
Currently, the standard treatment for patients with hyperphenylalaninemia is dietary protein restriction. This treatment is of paramount importance, especially during pregnancy, since high levels of phenylalanine may result in intrauterine retardation of brain development. Since a low-protein diet during pregnancy may result in retarded renal development, a subsequent reduction in the number of nephrons and, potentially, hypertension in adulthood, and since we treat pregnant women who have hyperphenylalaninemia with a protein-restricted diet, it would be interesting to know whether their offspring have an increased incidence of hypertension in adulthood due to a reduction in the number of nephrons. Patients with hyperphenylalaninemia are, in general, followed closely in metabolic clinics throughout the country and thus would be subjects for this type of analysis. Therefore, researchers who are interested in exploring further the concept of a low-protein diet during pregnancy with the potential consequence of reduced numbers of nephrons and the development of hypertension in adulthood might want to study this cohort of patients who are treated with protein restriction during pregnancy for hyperphenylalaninemia.
Ronald D. D'agostino, D.O.
Long Island Cardiovascular Imaging Consultants, Manhasset, NY 11030Author/Editor Response
Ponzone et al. question our experimental design. The definite identification of the phenotype by a single method, which they request, is unachievable, considering the complexity and multifactorial nature of the condition.1 However, both pretreatment plasma phenylalanine concentrations and the dietary phenylalanine tolerance are widely accepted, albeit rough, measures of the metabolic phenotype.2 In any case, the choice of classification is unlikely to weaken our findings.
We deliberately deviated from previous loading-test protocols that have been standardized to detect tetrahydrobiopterin deficiencies — conditions that are entirely different from those we investigated. Notably, such tests failed to uncover the high prevalence of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, despite their application for decades. Only a recent reinterpretation of test results has permitted 70 percent of cases involving milder phenotypes to be tentatively reclassified as tetrahydrobiopterin-responsive.3 This proportion comes close to the 87 percent we found prospectively using a loading test specifically designed to detect tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. In addition, we cross-validated data by independent oxidation testing in vivo. Any hypothetical influence on enzyme activity by phenylalanine loading, as discussed by Ponzone et al., cannot explain the significant effects of supplemental tetrahydrobiopterin on phenylalanine oxidation that we observed. First, only minimal amounts of labeled phenylalanine were involved. Second, and more important, the criterion of sensitivity remains unaffected, since it was defined as the difference in the rate of phenylalanine oxidation between two separate tests, one performed without treatment and one during treatment. Full concordance between the loading and oxidation tests in 33 of 38 patients also validates our experimental procedures.
Our study was not designed to address Hanley's question about the number of patients with tetrahydrobiopterin-responsive phenylketonuria in a representative cohort of all hyperphenylalaninemia phenotypes. We specifically aimed to evaluate tetrahydrobiopterin responsiveness in milder phenotypes, and seven patients with classic phenylketonuria were included only as controls. Some of them had a weak response that did not meet the study criteria for tetrahydrobiopterin responsiveness (Figure 4 of our article). Accordingly, we explicitly stated that we cannot rule out a possible response in certain patients with classic phenylketonuria. The general statement by Ponzone et al. on this issue is premature and misleading.
We share Hanley's concern about the compound's prohibitive price. This and other obstacles outlined in our article suggest that we exercise caution with respect to this therapy at the present time.
D'agostino refers to pathologic mechanisms not yet investigated in maternal phenylketonuria. Hyperphenylalaninemia and inadequate intake of protein during pregnancy can act additively, resulting in congenital heart defects and low birth weight.4 If the safety issues can be resolved, tetrahydrobiopterin may complement preventive strategies for maternal phenylketonuria.
4 ReferencesAdelbert A. Roscher, M.D.
Ania C. Muntau, M.D.
Wulf Röschinger, M.D.
Dr. von Hauner Children's Hospital, D-80337 Munich, Germany
adelbert.roscher@kk-i. med. uni-muenchen. de 1
Guldberg P ,Rey F ,Zschocke J , et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet 1998;63:71-79[Erratum, Am J Hum Genet 1998;63:1252-3.]
CrossRef | Web of Science | Medline2
Scriver CR ,Waters PJ . Monogenic traits are not simple: lessons from phenylketonuria. Trends Genet 1999;15:267-272
CrossRef | Web of Science | Medline3
Bernegger C ,Blau N . High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 pa-tients observed from 1988 to 2002. Mol Genet Metab 2002;77:304-313
CrossRef | Web of Science | Medline4
Michals-Matalon K ,Platt LD ,Acosta PP ,Azen C ,Walla CA . Nutrient intake and congenital heart defects in maternal phenylketonuria. Am J Obstet Gynecol 2002;187:441-444
CrossRef | Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Alberto Ponzone, Francesco Porta, Alessandro Mussa, Alessandra Alluto, Silvio Ferraris, Marco Spada. (2010) Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency. Metabolism 59:5, 645-652
CrossRef2
Angel L. Pey, Bel
n P
CrossRef
