New Developments in Hyperphenylalaninemia

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844 PEDIATRICS Vol. 65 No. 4 April 1980

AMERICAN

ACADEMY

OF

PEDIATRICS

Committee on Nutrition

New

Developments

in Hyperphenylalaninemia

In recent years it has become apparent that hy-perphenylalaninemia in newborn infants may be caused by a variety of defects in the enzyme phen-ylalanine 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 phenylala-nine to tyrosine is complex and consists of at least two essential enzymes, phenylalanine hydroxylase

(catalyzing reaction 1) and dihydropteridine reduc-tase (catalyzing reaction 2), and an essential, nonprotein cofactor, tetrahydrobiopterin3: ( 1) Phenylalanine + 02 + tetrahydrobiopterin -* tyro-sine + H20 + quinonoid dihydrobiopterin; (2) nic-otinamide adenine dinucleotide (reduced form) +

H + quinonoid dihydrobiopterin - nicotinamide

adenine dinucleotide (oxidized form) + tetrahydro-biopterin.

Most cases of hyperphenylalaninemia detected

by newborn infant screening programs are caused

by deficiencies of phenylalanine hydroxylase rang-ing from the severe “classic phenylketonuria (PKU)” to the more benign “hyperphenylalani-nemic variant.” The patients with classic PKU usu-ally respond to a diet low in phenylalanine. How-ever, of the estimated 400 cases of classic PKU detected annually in the United States, up to 3% may show progressive neurologic deterioration de-spite adequate dietary treatment. The elevated phenylalanine in these infants may be caused by

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 deterio-ration 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 phenylala-nine hydroxylase deficiency: (a) severe deficiency of the enzyme (classic PKU); (b) less severe

defi-ciency of the enzyme (milder hyperphenylalanine-mia);

2. Hyperphenylalaninemia caused by DHPR

de-ficiencies;

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 hydroxy-lase, DHPR, and biopterin in liver biopsy samples. Suggestive evidence for the severe condition was also provided by the finding of low levels of biop-term-like compounds in the blood and urine of a child with hyperphenylalaninemia.5 Since then, many methods have become available that are use-ful in discriminating between classic PKU and the newer variants.7 One of the tests involves adminis-tering BR, to the patient, and it is based on the observation that BR, will lower blood phenylala-nine levels in patients with hyperphenylalaninemia

caused by either defects in biopterin synthesis8’9 or DHPR deficiency.8”#{176}

at Viet Nam:AAP Sponsored on September 7, 2020 www.aappublications.org/news

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AMERICAN ACADEMY OF PEDIATRICS 845 02 PH snine tyrosin BH4q-BH2 DHPR NAD NADH

Figure. Phenylalanine hydroxylating system. PH,

Phenylalanine hydroxylase; BH4, tetrahydrobiopterin;

q-BH2, quinonoid dihydrobiopterin; DHPR,

dihydropteri-dine reductase; NAD, nicotinamide adenine clinucleotide

(oxidized form); NADH, nicotinamide adenine

dinucleo-tide (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 din-ical effect in a three-week trial.

Although the administration of BH. will distin-guish hyperphenylalaninemia caused by biopterin abnormalities from that caused by phenylalanine hydroxylase deficiencies, several unanswered ques-tions concerning the administration of BH4 remain:

1. The BR, administration test and biopterin

analyses of urine will reflect only peripheral phen-ylalanine metabolism and wifi not be useful in eval-uating central nervous system status.

2. The currently available form of tetrahydro-biopterin 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 per-mitted 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-posi-tive test for BR, deficiency from partial deficiency of phenylalanine hydroxylase. In certain instances the differential diagnosis would require a liver bi-opsy 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

new-born infants with hyperphenylalamnemia for biop-term disorders is not practical in the United States because neither adequate laboratory facilities nor

supplies of BH4 for human use are available. Inves-tigation for these conditions should be confined to children with classic PKU or

hyperphenylalanine-mia who show neurologic deterioration despite an adequate dietary regimen.

2. One or more central reference laboratories

should be established or designated for the deter-mination of biopterin and its metabolites, 5-hydrox-yindoleacetic acid (5HIAA), homovanilhic acid

(HVA), and vanillylmandelic acid (VMA) and re-lated 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 hyperphenylalani-nemia caused by inborn errors of biopterin metab-olism.

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 coeffi-cients 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

223-72-2304 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-Cur-rent status. J Inher Metab Dis 1:49, 1978

2. Danks DM, Cotton RGH, Schlesinger P: Diagnosis of

malig-nant hyperphenylalaninemia. Arch Dis Child 54:329, 1979

3. Kaufman 5: The phenylalanine hydroxylating system from

mammalian liver. Adv Enzymol 35:245, 1971

4. Kaufman 5, Holtzman NA, Milstien 5, et al: Phenylketonu-na due to a deficiency ofdihydropteridine reductase. N Engi JMed293:785, 1975

5. Rey F, Harpey JP, Leeming Ri, et al: Les hyperphenylala-ninemies avec activit#{233} normale de la phenylalanine

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846 HYPERPHENYLALANINEMIA

ylase. Arch Fr Pediatr 34(suppl): 109, 1977

6. Kaufman S, Berlow S, Summer GK, et al: Hyperphenylala-ninemia due to a deficiency of biopterin. N Engl J Med 299: 673, 1978

7. Kaufman S: Differential diagnosis of variant forms of hyper-phenylalaninemia. Pediatrics 65:840, 1980

8. Curtius H-Ch, Niederwieser A, Viscontini M, et al: Atypical

phenylketonuria due to tetrahydrobiopterin deficiency:

Di-agnosis and treatment with tetrahydrobiopterin, dihydro-biopterin and sepiaterin. Clin Chim Acta 93:251, 1979

9. Mclnnes R, Kaufman 5, Warsh JJ, et al: Neurotransmitter metabolites (NTM) and plasma catechols in biopterin (BP) deficiency, abstracted. Pediatr Res 13:422, 1979

10. Danks DM, Cotton RG, Schlesinger P: Tetrahydrobiopterin treatment of a variant form of phenylketonuria. Lancet 2: 1043, 1975

11. Danks DM, Schlesinger P, Firgaira F, et al: Malignant hy-perphenylalaninemia-Clinical features, biochemical find-ings 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 11-27 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 1976. 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

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1980;65;844

Pediatrics

Harvey L. Levy, Edward R. B. McCabe and Selma Snyderman

Donough O'Brien, Stanley Berlow, George Donnell, Parvin Justice, Seymour Kaufman,