Malignant Hyperphenylalaninemia—Clinical Features, Biochemical Findings, and Experience with Administration of Biopterins

Abstract

Pediat. Res. 13: 1 150-1 155 (1979) Summary has been attributed to defective production of neurotransmitters Four cases of malignant hyperphenylalaninemia (MHPA) are described. Pretreatment serum phenylalanine levels were 1.5, 3.0, 2.4, and 0.9 mmoles/l. Dihydropteridine reductase (DHPR) deficiency was proven in one patient by assays on cultured fibroblastic cells and was presumed in her sibling and in another deceased patient whose parents' fibroblastic cells show approximately 50% of normal enzyme activity. DHPR and phenylalanine hydroxylase deficiency were excluded by assays on liver obtained a t autopsy in the 4th patient. Parenteral administration of tetrahydrobiopterir (BH4) corrected the hyperphenylalaninemia and increased the levels of catecholamines and 5-hydroxy-indoles in the one patient studied in life, but BH4 did not reach the cerebrospinal fluid. A 3-wk course of BH4 therapy had no clinical effect. Oral biopterin was absorbed and excreted in the urine, but did not alter the serum phenylalanine level. The frequency of MHPA in Australia was estimated as 7 in 258 patients with phenylketonuria.derived from hydroxylation of tyrosine and of tryptophan (3, 4). The results of treatment with L-dopa and 5-hydroxytryptophan support this contention (2, 3. 7).Four patients with MHPA seen in Melbourne since 1963 are presented. One patient has been shown to have DHPR deficiency and her sister is presumed to have died of this defect. Both parents of another baby had DHPR levels in the heterozygote range suggesting DHPR deficiency as the cause of her death. The 4th baby had neither PH or DHPR deficiency and defective BH4 synthesis is presumed.Detailed metabolic studies, especially related to BH4 are presented in the one DHPR deficient patient diagnosed in life. The lowering of serum phenylalanine achieved by BH4 administration in this patient is proposed as a test for identification of young babies with MHPA.

Biopterin synthesis defect. Treatment with L-dopa and 5-hydroxytryptophan compared with therapy with a tetrahydropterin.

“…Our results, in combination with reports of decreased 5-HIAA, HVA, or VMA in other BH4-deficient subjects (8)(9)(10)(11)(12)(13), indicate that the defect in monoamine synthesis is very similar in DHPR-deficient and biopterin-deficient patients. Finally, since DA is an established inhibitor of prolactin secretion (46), the hyperprolactinemia of our patient also indicates that a hypothalamic DA deficiency was present before treatment.…”

“…Other DHPR-deficient patients, in contrast, have had evidence of decreased NE synthesis (7). Documentation of the monoamine deficit in additional patients has been generally limited to one or two measurements of 5-hydroxyindoleacetic acid (5-HIAA) and 4-hydroxy-3-methoxyphenylacetic acid (HVA) in cerebrospinal fluid (CSF) or urine (8)(9)(10)(11)(12)(13). As a result, the precise nature of the catecholamine defect in BH4 deficiency remains largely unknown.…”

Biosynthesis of tetrahydrobiopterin by de novo and salvage pathways in adrenal medulla extracts, mammalian cell cultures, and rat brain in vivo.

“…Two developments during the past few years, however, have focused attention on the physiological and biochemical functions of BH4. (i) Although there is no animal model for study of the effects of BH4 deficiency, biopterin cofictor deficiency in man has been observed in atypical forms of hyperphenylalaninemia (lack of dihydropteridine reductase or enzymes at earlier steps in BH4 biosynthesis) (33)(34)(35)(36). Treatment with BH4 restores hepatic metabolism of phenylalanine in these infants but neurotransmitter therapy is also required and these are serious problems in clinical management.…”

Enzymology of the Phenylalanine-Hydroxylating System

“…Despite the sound theoretical basis for pterin therapy in patients with defects in BH4 synthesis, the evidence that adminis tered BH4 does not readily enter the brain from the periphery in either rats [44,45] or humans [46] appeared to dim the prospects for pterin therapy for this variant form of PKU. Although administration of low doses of BH4 (2.5 mg'kg-1*day-1) has been used in the treatment of this disease [41], its princi pal effect when given orally at this dosage is to decrease elevated blood phenylalanine levels, thus providing an alternative in this respect to dietary restriction of phenylala nine intake.…”