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Early Diagnosis of 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency

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Early Diagnosis of 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency Shintaku: Early diagnosis of 6-pyruvoyl-tetrahydropterin synthase deficiency Pteridines Vol. 5, 1994, pp. 18-27 Early Diagnosis of 6-Pyruvoyl-tetrahydropterin Synthase Deficiency Haruo Shintaku Department of Pediatrics, Osaka City University Medical School, Osaka 545, Japan (Received December 10, 1993) Summary 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, which used to be called dihydrobiopterin synthase deficiency, is the most common kind of tetrahydrobiopterin deficiency. Early treatment by administration of tetrahydrobiopterin and neurotransmitter precursors helps to prevent neurological injury, so prompt diag­ nosis of neonates with hyperphenylalaninemia discovered by screening for phenylketonuria is necessary. Three patients with PTPS deficiency were diagnosed by pteridine analysis. All patients had low biopterin and high neopterin levels in the urine, resulting in a neopterin to biopterin ratio (NIB) much higher than that of age-matched controls. The mean NIB in the parents of these patients was twice that of healthy unrelated adults. PTPS activity was measured in one of these patients with PTPS deficiency and in his family members; the patient was homozygous and his parents were heterozygous for PTPS deficiency. This result meant that NIB could be used as an index of PTPS activity. In healthy subjects studied cross­ sectionally, urinary levels of pteridine decreased in groups of increasing age, and the same change was found in subjects with hyperphenylalaninemia studied cross-sectionally. Thus, pteridine values of patients can be compared meaningfully only with age-matched controls. The urinary N IB is useful for the diagnosis of homozygotes and heterozygotes for PTPS deficiency. Key words: Phenylketonuria, Tetrahydrobiopterin, Malignant hyperphenylalaninemia, 6-pyruvoyl-tetrahy­ dropterin synthase deficiency Abbreviations Introduction PKU: phenylketonuria BH4: tetrahydrobiopterin Phenylketonuria (PKU) is an inherited metabolic DHPR: dihydropteridine reductase disease once thought to be caused only by a defect L-DO P A: L-3,4-dihydroxyphenylalanine of phenylalanine hydroxylase (phenylalanine 4-mon­ 5-HTP: 5-hydroxytryptophan oxygenase; EC 1.14.16.1), as described by Jervis (1) BH2: dihydrobiopterin in 1953. Patients with PKU were at first thought NH2P3: dihydroneopterin triphosphate to develop normally if they are kept from early infan­ PTPS: 6-pyruvoyl-tetrahydropterin synthase cy on a low-phenylalanine diet. as Bickel et al. N: neopterin (2) proposed in 1953. In 1975, Smith et al. (3) repor­ B: biopterin ted three patients with progressive neurological ill­ EEG: electroencephalogram ness that was unlike classical PKU and did not res­ SD: standard deviation pond to a low-phenylalanine diet. Since then many CT: computerized tomography such patients have been identified, and the phenyl­ HPLC: high-pressure liquid chromatography alanine hydroxylase system in patients with PKU has Hb: hemoglobin heen ree\aluated. Kaufman (4) reported in 1963 that tetrahydrobio­ rterin (BH ~ ) is a cofactor for phenylalanine hydrox- Ptcridines / Vol. 5 / No.1 Shintaku: Early diagnosis of 6-pyruvoyl-tetrahydropterin synthase deficiency 19 Guanosine triphosphate (GTP) ~ GTP cyclohydrolase I (GTPCH) Pi Dihydroneopterin triphosphate (NH2 P 3) ~ Dihydroneopterin (NH 2) __ Neopterin (N) l 6-Pyruyoyl-tetrahydropterin synthase (PTPS) 6-Pyruvoyl-tetrahydropterin (PTP) ~ Sepillpterin reductase (SPR) or PTP reductase 6-Lactoyl-tetrahydropterin (dihYdrosepiap:te:::.n:·n:) _----------_ SPR NADPH+H+ Dihydropteridine + reducUJse (DHPR) NADH+H TO''''''''Obl,,"\: (BH ,) 0, 2':: "')""'OOP.ri" (qBH,) - D(hY"'trb~p.ri" (BH,r---- Blop",," (B) . Phenylalanine-~--.;::==-_'>....;:::.,. __:!:....-..===::::::::=.=- __~ Tyrosine Phenylalanine hydroxylase. Tyrosine • Dopa -- Dopamine -- Norepinephrine ___ Epinephrine Tyrosine hydroxylase. Tryptophan ------------...~ 5-Hydroxytryptophan (5-HTP) ---.~ Serotonin Tryptophan hydroxylase. Figure 1. Tetrahydrobiopterin (BH4) biosynthetic pathway and aromatic amino acid hydroxylase system. ylase (3), and later it was found that BH4 is a cofac­ of the seventeen patients had already died. Of the ro r of tyrosine 3-hydroxylase (EC 1.14.16.2) and tryp­ six survivors, three were younger than 1 year old tophan 5-hydroxylase (EC 1.14.16.4), as well (5, 6). and the oldest was 6 years old. The miserable clini­ i Fig. 1). cal outcomes arose because the BH4 deficiency led Kaufman et af. recommended that patients with to dysfunction of the aromatic amino acid hydroxy­ PKU resembling that reported by Smith et at. be lase system, which produces neurotransmitters from ~xamined not only for · phenylalanine hydroxylase tyrosine and tryptophan, so that serotonin and cate­ but also for BH4 and dihydropteridine reductase cholamine are not synthesized. Bartholome et af. (10) (DHPR; EC 1.6.99.7). In one of the patients reported reported that neurological signs in these patients are by Smith et at. (3), phenylalanine hydroxylase was treatable by the oral administration of the neurotrans­ normal but DHPR was deficient, so no BH4 was mitter precursors 3,4-dihydroxyphenylalanine (L­ detected in the liver (7). In DHPR deficiency, biop­ DOPA) and 5-hydroxytryptophan (5-HTP), which terin levels are higher than normal, but BH4, the both pass the blood-brain barrier, and Curtius et active form of biopterin, is deficient, so serum phenyl­ af. (11) recommend that this treatment be started alanine increases. In 1978, Kaufman et af. (8) repor­ within 1 month after birth to help prevent neurolo­ ted that a child with PKU who had neurological gical damage. Therefore, a noninvasive diagnostic impairment despite early dietary control of elevated method for malignant hypei-phenylalaninemia for use blood phenylalanine levels had normal levels of during neonatal mass-screening for PKU is need­ phenylalanine hydroxylase and DHPR activity, but ed. a very low level of BH4, which pattern suggested Before 1985, it was believed that dihydrofolate re­ a deficiency of biopterin biosynthesis. Seventeen pa­ ductase produced BH4 from dihydrobiopterin, which tient<; who developed neurological illness in spite was thought to be synthesized from dihydroneo­ of a low-phenylalanine diet were reported at a work­ pterin triphosphate (NH2P3) (11). For that reason, pa­ shop in Lausanne in 1977 (9), and their disorder tients with BH4-defective biosynthesis from NH2P3 was named "malignant hyperphenylalaninemia". were said to have "dihydrobiopterin synthetase defi­ There were nine patients with DHPR deficiency, two ciency." The BH4 biosynthetic pathway as it is cur­ patients with normal DHPR but BH4 deficiency, rently understood is shown in Fig. 1. The deficiency and six patients with an unclear diagnosis. Eleven is generally believed to involve a defect in 6-pyru- Pteridines / Vol. 5 / No. I 20 Shintaku: Early diagnosis of 6-pyruvoyl-tetrahydropterin synthase deficiency voyl-tetrahydropterin synthase (PTPS) (12). There­ sions continued. When the patient was 18 months fore, the expression "BH4 deficiency" should be used old, his cultured fibroblasts were sent to Dr. S. Kauf­ rather than the terms "malignant PKlJ or "malig­ man (NIH) for measurement of DHPR activity, be­ nant hyperphenylalaninemia" (13). cause of the report that "malignant PKU" involves I have seen three patients with PTPS deficiency, DHPR deficiency (7). The test results showed nor­ including the first patient to be diagnosed in Japan, mal activity, so the patient did not have DHPR de­ and diagnosed these patients by BH4 loading tests, ficiency. When the child was 3 and a half years phenylalanine loading tests, and assays of urinary old, a report was published that among patients with pteridines. The results of assays of urinary pteridines malignant PKU, some have normal DHPR activity, showed that the neopterin to biopterin ratio (NIB) although the clinical signs in such patients improve was useful not only for the diagnosis of PTPS defi­ when the same treatment as for DHPR deficiency ciency but also for the detection of heterozygotes is given. The patient was therefore given 160 mglkg for PTPS deficiency. L-DOPA and 20 mglkg 5-HTP. His convulsions be­ came less frequent and the hypsarrthythmia disap­ peared. In the meantime, the serum level of pheny­ Case reports lalanine was maintained at about 4 mg/dl (0.24 mmol/l) without a low-phenylalanine diet. The hypo­ Case 1. The first patient, a boy, was born on Oct. tonia was unchanged and speech did not begin, 12, 1973 at term after an uncomplicated pregnancy, but the child's facial expression improved. The child as the second child of unrelated healthy parents. weighed 9 kg when he reached 6 years of age, and Birth weight was 2650 g. The infant developed nor­ he never weighed more than 10 kg because of feed­ mally until 3 months of age. He could not control ing difficulties and recurrent respiratory infections. his head movements at the age of 4 months, and Mild brain atrophy in the frontal and tc:!mporal starting then, convulsions occurred every 7 to 10 lobes was found by computerized tomography scan­ days. At the age of 6 months, anticonvulsant drugs ning. (phenobarbital and diphenylhydantoin) were started Case 2. The patient, a boy, was born March 16, because of hypsarrthythmia in the electroencephalog­ 1980, at term after an uneventful pregnancy, as the rams (EEG), but the convulsions were not well con­ first child of healthy parents who were second cous­ trolled. At the age of 8 months, the patient was ins. Birth weight was 2850 g. The Guthree test for
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