AMERICAN ACADEMY OF PEDIATRICS. New Developments in Hyperphenylalaninemia. Committee on Nutrition

Transcription

1 AMERICAN ACADEMY OF PEDIATRICS Committee on Nutrition New Developments in Hyperphenylalaninemia In recent years it has become apparent that hyperphenylalaninemia in newborn infants may be caused by a variety of defects in the enzyme phenylalanine hydroxylase or by an abnormality in either the enzyme dihydropteridine reductase (DHPR) or the synthesis of dihydrobiopterin (BH2) (Figure). Despite the rarity of the latter conditions there are important implications for management in making this diagnosis. It has been suggested that all new cases of hyperphenylalaninemia now be screened for these variants.2 The purpose of the Task Force was to define the feasibility of this course at the present time. BACKGROUND The hepatic system for conversion of phenylalanine to tyrosine is complex and consists of at least two essential enzymes, phenylalanine hydroxylase (catalyzing reaction 1) and dihydropteridine reductase (catalyzing reaction 2), and an essential, nonprotein cofactor, tetrahydrobiopterin3: ( 1) Phenylalanine tetrahydrobiopterin -* tyrosine + H20 + quinonoid dihydrobiopterin; (2) nicotinamide adenine dinucleotide (reduced form) + H + quinonoid dihydrobiopterin - nicotinamide adenine dinucleotide (oxidized form) + tetrahydrobiopterin. Most cases of hyperphenylalaninemia detected by newborn infant screening programs are caused by deficiencies of phenylalanine hydroxylase ranging from the severe classic phenylketonuria (PKU) to the more benign hyperphenylalaninemic variant. The patients with classic PKU usually respond to a diet low in phenylalanine. However, of the estimated 400 cases of classic PKU detected annually in the United States, up to 3% may show progressive neurologic deterioration despite adequate dietary treatment. The elevated phenylalanine in these infants may be caused by PEDIATRICS (ISSN ). Copyright 1980 by the American Academy of Pediatrics. either DHPR deficiency or a deficient synthesis of BH2 or to other stifi unidentified causes. TERMINOLOGY In a workshop held at the Centre Hospitalier Universitaire, Lausanne, Switzerland, the term malignant hyperphenylalaninemia was chosen to describe patients who showed neurologic deterioration despite adequate, early treatment. However, the Task Force prefers the following terminology until the enzyme defects can be precisely defined in molecular terms: 1. Hyperphenylalamnemia caused by phenylalanine hydroxylase deficiency: (a) severe deficiency of the enzyme (classic PKU); (b) less severe deficiency of the enzyme (milder hyperphenylalaninemia); 2. Hyperphenylalaninemia caused by DHPR deficiencies; 3. Hyperphenylalaninemia caused by defects in the synthesis of dihydrobiopterin. DIAGNOSIS There is a need to identify the latter two variants of hyperphenylalaninemia because their treatment is not the same as that for classic PKU. The first cases of hyperphenylalaninemia caused either by DHPR deficiency4 5 or a defect in the synthesis of biopterin6 were diagnosed by direct determination of levels of phenylalanine hydroxylase, DHPR, and biopterin in liver biopsy samples. Suggestive evidence for the severe condition was also provided by the finding of low levels of biopterm-like compounds in the blood and urine of a child with hyperphenylalaninemia.5 Since then, many methods have become available that are useful in discriminating between classic PKU and the newer variants.7 One of the tests involves administering BR, to the patient, and it is based on the observation that BR, will lower blood phenylalanine levels in patients with hyperphenylalaninemia caused by either defects in biopterin synthesis8 9 or DHPR deficiency.8 #{176} 844 PEDIATRICS Vol. 65 No. 4 April 1980

2 snine BH4q-BH2 02 PH DHPR tyrosin NAD NADH Figure. Phenylalanine hydroxylating system. PH, Phenylalanine hydroxylase; BH4, tetrahydrobiopterin; q- BH2, quinonoid dihydrobiopterin; DHPR, dihydropteridine reductase; NAD, nicotinamide adenine clinucleotide (oxidized form); NADH, nicotinamide adenine dinucleotide (reduced form). In one patient the oral administration of BH4 was not effective in reducing serum phenylalanine levels in DHPR deficiency, whereas a dose of 2 mgi kg given intravenously or intramuscularly was. There was further evidence that biopterin did not enter the cerebrospinal fluid and produced no dinical effect in a three-week trial. Although the administration of BH. will distinguish hyperphenylalaninemia caused by biopterin abnormalities from that caused by phenylalanine hydroxylase deficiencies, several unanswered questions concerning the administration of BH4 remain: 1. The BR, administration test and biopterin analyses of urine will reflect only peripheral phenylalanine metabolism and wifi not be useful in evaluating central nervous system status. 2. The currently available form of tetrahydrobiopterin is the DL isomer. The fate of the D isomer and its long-term effects are not known at this time. 3. The patient s phenylalanine level must be permitted to rise before the BH4 loading test. This might be harmful, but it might be done in the newborn period before treatment is begun. 4. It may be difficult to distinguish a false-positive test for BR, deficiency from partial deficiency of phenylalanine hydroxylase. In certain instances the differential diagnosis would require a liver biopsy or some other test for complete analysis of the component of the hydroxylase system. RECOMMENDATIONS In view of the recent developments, the Task Force recommends the following: 1. At the present time, the screening of all newborn infants with hyperphenylalamnemia for biopterm disorders is not practical in the United States because neither adequate laboratory facilities nor supplies of BH4 for human use are available. Investigation for these conditions should be confined to children with classic PKU or hyperphenylalaninemia who show neurologic deterioration despite an adequate dietary regimen. 2. One or more central reference laboratories should be established or designated for the determination of biopterin and its metabolites, 5-hydroxyindoleacetic acid (5HIAA), homovanilhic acid (HVA), and vanillylmandelic acid (VMA) and related metabolites, in all newly diagnosed patients with classic PKU. 3. The Society for Inherited Metabolic Diseases (Selma E. Snyderman, MD, President, Society for Inherited Metabolic Diseases, New York University School of Medicine, 550 First Avenue, New York, New York 10016) should be asked to submit an Investigational New Drug Application to the Food and Drug Administration for the use of BR, as a loading test in the diagnosis of hyperphenylalaninemia caused by inborn errors of biopterin metabolism. 4. Once BR, is available for human use, the following collaborative research projects should be undertaken: (a) further definition of the use of BH4 by the oral or parenteral route in the diagnosis of DHPR and biopterin synthesis defects; (b) further studies on the value, if any, oflong-term BH4 in the therapy of these hyperphenylalaninemic variants; (c) studies on the value of urinary excretion coefficients or creatinine ratios of 5HIAA, HVA, and VMA in the screening diagnosis of DHPR and biopterin synthesis defects. ACKNOWLEDGMENT This work was supported by grant DHEW-FDA from the Food and Drug Administration. REFERENCES TASK FORCE ON BIOPTERIN Donough O Brien, MD, Chairman Stanley Berlow, MD George Donnell, MD Parvin Justice, PhD Seymour Kaufman, PhD Harvey L. Levy, MD Edward R. B. McCabe, MD, PhD Selma Snyderman, MD 1. Danks DM, et al: Malignant hyperphenylalaninemia-current status. J Inher Metab Dis 1:49, Danks DM, Cotton RGH, Schlesinger P: Diagnosis of malignant hyperphenylalaninemia. Arch Dis Child 54:329, Kaufman 5: The phenylalanine hydroxylating system from mammalian liver. Adv Enzymol 35:245, Kaufman 5, Holtzman NA, Milstien 5, et al: Phenylketonuna due to a deficiency ofdihydropteridine reductase. N Engi JMed293:785, Rey F, Harpey JP, Leeming Ri, et al: Les hyperphenylalaninemies avec activit#{233} normale de la phenylalanine hydrox- AMERICAN ACADEMY OF PEDIATRICS 845

3 ylase. Arch Fr Pediatr 34(suppl): 109, Kaufman S, Berlow S, Summer GK, et al: Hyperphenylalaninemia due to a deficiency of biopterin. N Engl J Med 299: 673, Kaufman S: Differential diagnosis of variant forms of hyperphenylalaninemia. Pediatrics 65:840, Curtius H-Ch, Niederwieser A, Viscontini M, et al: Atypical phenylketonuria due to tetrahydrobiopterin deficiency: Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiaterin. Clin Chim Acta 93:251, Mclnnes R, Kaufman 5, Warsh JJ, et al: Neurotransmitter metabolites (NTM) and plasma catechols in biopterin (BP) deficiency, abstracted. Pediatr Res 13:422, Danks DM, Cotton RG, Schlesinger P: Tetrahydrobiopterin treatment of a variant form of phenylketonuria. Lancet 2: 1043, Danks DM, Schlesinger P, Firgaira F, et al: Malignant hyperphenylalaninemia-clinical features, biochemical findings and experience with administration ofbiopterin. Pediatr Res 13:1150, 1979 EXPERTS MEET, DRAW UP MODEL LIST OF ESSENTIAL DRUGS In the light of present scientific knowledge, approximately 200 drugs are indispensable for the health care of the vast majority of the world s population. This was the conclusion of the WHO Expert Committee on the Selection of Essential Drugs, which met in Geneva from 17 to 22 October. The Committee s full report will be submitted, together with other Expert Conunittee reports, to the Executive Board of WHO during its January 1978 session. In its deliberations the Committee benefited from the worldwide response to a preliminary model list issued after a consultation held in Geneva in October Comments and suggestions were received from the six regional offices of WHO, more than 100 experts from over 40 countries, and nongovernmental organizations in official relations with WHO. The Committee drew attention to the fact that drug costs account for up to 40% of the total health budget in some developing countries. In affluent nations as well, governments appear to be increasingly worried by the rising expenditure for pharmaceutical products. In the least developed countries, where communicable disease control and elementary health care are the major concerns, large segments of the population are in urgent need of essential drugs and vaccines. For their limited financial resources to be put to optimal use, the drugs available must be restricted to those proven to be therapeutically effective, to have acceptable safety, and to satisfy the health needs of the population. WHO News Release 846 HYPERPHENYLALANINEMIA

4 New Developments in Hyperphenylalaninemia Donough O'Brien, Stanley Berlow, George Donnell, Parvin Justice, Seymour Kaufman, Harvey L. Levy, Edward R. B. McCabe and Selma Snyderman Pediatrics 1980;65;844 Updated Information & Services Permissions & Licensing Reprints including high resolution figures, can be found at: Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online:

5 New Developments in Hyperphenylalaninemia Donough O'Brien, Stanley Berlow, George Donnell, Parvin Justice, Seymour Kaufman, Harvey L. Levy, Edward R. B. McCabe and Selma Snyderman Pediatrics 1980;65;844 The online version of this article, along with updated information and services, is located on the World Wide Web at: Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 1980 by the American Academy of Pediatrics. All rights reserved. Print ISSN: