Hyperphenylalaninemia (HPA) has been the source of many fascinating investigations since its discovery in 19341, perhaps due to the difficulty of its study at all levels.
 
 

The uniqueness of the enzyme phenylalanine-4-hydroxylase (PAH), its restriction to liver, the brain damage caused by different mechanisms, and lack of an equivalent animal model for many years, have inspired research in many diverse groups.

Although progress in a major biological frontier, the neurosciences, has been both rapid and broadly based, it has to the present offered little to the practicing pediatrician. Careful study of an old subject, phenylketonuria (PKU), opened a new area of research in 1975 that has great potential significance and target benefits for sick children.

This is primarily for two reasons:

1. the discovery of a variant of HPA involving biosynthesis and regeneration of tetrahydrobiopterin (BH4), the cofactor of PAH; and
2. rapid advances in DNA technology which have allowed successful cloning of PAH and the enzymes involved in the metabolism of BH4.

Today, 60 years after Asbjörn Fölling isolated phenylpyruvic acid (a phenylketone) from 20 liters of urine from two mentally retarded children, and 40 years after Bickel et al.2 initiated dietary treatment by phenylalanine restriction, newborn screening for PKU is virtually established in almost all countries. This became possible after Guthrie and Susi3, in 1963, introduced a simple and sensitive mass screening method for a semiquantitative determination of phenylalanine from a small spot of blood on filter paper. It is now established that early diagnosis and treatment results in normal intellectual development4, and that there is an inverse relationship between the ultimate IQ of the child and the age at which the diet was started5. Nevertheless, there is a group of infants who initially fit the biochemical parameters of classical PKU, however, they do not have this condition and do not appear at risk for neurological damage like the children with classical PKU6. These facts demonstrate clinical and biochemical heterogeneity in PAH deficiency. Use of the complementary DNA of PAH has allowed a restriction fragment length polymorphism (RFLP) haplotype analysis system to be established. This haplotype analysis system provides for the determination of mutant PAH alleles in most families and is the basis for mutation analysis of the PAH locus7. High mutation rates, hitchhiking of PKU alleles through selection at a nearby locus, founder effect, genetic drift, and natural selection for PKU heterozygotes have all been considered as possible mechanisms for the observed high incidence of PKU8,9.

The first patients with BH4 deficiency were identified in 1969 by Tada et al.10. Two siblings with mild HPA were at that time described as "a genetic variant of phenylketonuria", but later characterized as dihydropteridine reductase (DHPR) deficient11. In 1974 in London, Smith et al.12 described three children with "PKU" who had an unusual clinical course. Despite early diagnosis and treatment with a low-phenylalanine diet, these patients developed progressive neurological disease and died. Independently, Bartholomé13 in Heidelberg reported a similar case of "atypical" HPA unresponsive to dietary treatment. The atypical course, high tolerance for phenylalanine and normal PAH activity in liver biopsy in Bartholomé’s patient, led to the speculation that this syndrome was a new form of HPA, probably due to a defect in the metabolism of BH4. Smith et al.12 reasoned that a defect in the metabolism of BH4 in brain tissue would also result in defective turnover of the neurotransmitters L-DOPA, noradrenaline, adrenaline, and serotonin. In the following years a number of cases of BH4 deficiency were described and it was suggested that all these patients suffered from a defect in BH4 metabolism14-22. Because all untreated patients show severe cerebral deterioration and most of them die at an early age, it was suggested that this clinical syndrome should be called "malignant" HPA23,24.

Based on the speculation that pterins might be used in the treatment of PKU, Smith et al.14 proposed that patients with BH4 deficiency might benefit from substitution with reduced pterins. Indeed, Danks et al.20 showed that intravenous administration of synthetic BH4 decreases the serum phenylalanine levels and, therefore, can function as a cofactor substituting for hepatic PAH in vivo. Meanwhile, therapy with L-DOPA, carbidopa, and 5-hydroxytryptophan alone or in combination with BH4, was shown to be beneficial for patients with various forms of BH4 deficiency19,25-32.

REFERENCES

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25. Bartholome K, Byrd DJ.L-dopa and 5-hydroxytryptophan therapy in phenylketonuria with normal phenylalanine-hydroxylase activity. Lancet. 1975;2:1042-1043.
26. Butler IJ, O'-Flynn ME, Seifert WE Jr, Howell RR.Neurotransmitter defects and treatment of disorders of hyperphenylalaninemia. J Pediatr. 1981;98:729-733.
27. Endres W, Niederwieser A, Curtius HC, Ohrt B, Schaub J.Dihydrobiopterin deficiency: monotherapy with tetrahydrobiopterin (BH4) and diacety BH4. Pediatr Res. 1982;16:694.
28. Endres W, Niederwieser A, Curtius HC, Wang M, Ohrt B, Schaub J.Atypical phenylketonuria due to biopterin deficiency. Early treatment with tetrahydrobiopterin and neurotransmitter precursors, trials of monotherapy. Helv Paediatr Acta. 1982;37:489-498.
29. Kaufman S, Kapatos G, McInnes RR, Schulman JD, Rizzo WB.Use of tetrahydropterins in the treatment of hyperphenylalaninemia due to defective synthesis of tetrahydrobiopterin: evidence that peripherally administered tetrahydropterins enter the brain. Pediatrics. 1982;70:376-380.
30. McInnes RR, Kaufman S, Warsh JJ, Van Loon GR, Milstien S, Kapatos G, Soldin S, Walsh P, MacGregor D, Hanley WB.Biopterin synthesis defect. Treatment with L-dopa and 5- hydroxytryptophan compared with therapy with a tetrahydropterin. J Clin Invest. 1984;73:458-469.
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