Shintaku et at.: Tetrahydrobiperin responsiYe hyperphen yl8. 1 8.r. : ~e7_l':' " ::;"'"Y.1t b;-te~ :-. ,: ":1C1,, r:.:::- 83
Pteridines Vol. 11 , 2000, pp. 83 - 84
Tetrahydrobiopterin, responsive! hyperphenylalaninemia without biopterin defi CIency
l 2 l Haruo Shintaku , Minoru Asada', Yoshitomo S.lwada , and Tsunekazu Yamano
Dept of Pediatrics, Osaka City University Medica l School, Osaka 545 Japan I and Dept of Pediatrics, Osaka City General Hospital, Osaka 534 Japan2
Introduction Results
Hyperphenylalaninemia (HPA) results from " All patients with classical PKU (serum phenyl deficiency of the enzyme phenylalanine hydroxylase alanine > 20 mgldL) showed no response to BH4 • (PAH) or its cofactor, tetrahydrobiopterin (BH4 ), However, in five patients among fifteen identified with Prompt diagnosis of neonates with HP A discovered by HPA (serum phenylalanine < 20 mg/dL), the serLim a newborn screening for phenylketonuria (PKU) is phenylalanine levels gradually decreased and the final necessary, because early treatment by administration pl, enylalanine concentrations after 24 hours were 2 to of BH4 and neurotransmitter precursors helps to 5 mgldL lower than the initial phenylalanine prevent neurological injuryl . It is essential for the concentrations. These five patients did not have diffe-rential diagnosis to measure urinary pterin or abnormalities in serum pteridine levels or DHPR specific enzyme activity. A BH4 loading test based on activj 'Y. the lowering of serum phenylalanine is not essentia l but recommended as the simplest method. Recently, it Discussion has been reported that serum pheny lalanine concentrations decreased in some patients with PAH It is well known that an oral dose of BH4 (10 mg/kg) deficient HPA after loading with BH4 . By measuring normalizes serum phenylalanine in patients with BH4 serum pteridine levels and dihydropteridine reductase deficiency within 4-6 hours after loading unlike those (DHPR) activities in all patients with HPA detected by with PKU. As PAH is normal in BH4 deficiency, it is the neonatal mass screening for PKU, we found some possible that administered BH4 activates PAH in the BPA patients without BH4 deficiency decreased their liver and converts to tyrosine, thereby the blood serum phenylalanine concentrations by the BH4 phenylalanine level decreases and the blood tyrosine loading test. level increases. In PKU and HPA, which result from an abnormality in PAH production, it is not possible to
Patients and Method activate P AH by administering BH4 , and the blood phenylalanine level does not fall. Based on this Twenty-five patients with HP A detected by neonatal principle, the BH4 loading test differentiates between mass-screening for PKU were examined from 1997 to the cofactor (BH4) deficiency and apoenzyme (PAH) 2000. An oral BH4 loading test (10 mg/kg) was deficiency. performed before starting a Phe-restricted diet. Blood Tn this study five patients with HP A had decreased samples were obtained at 0, I, 2, 3, 4, 8, and 24 hours serum phenylalanine levels at 24 hours after loading after loading. Serum phenylalanine concentrations with BH4. Their serum phenylalanine va-lues did not were determined by using an automated amino acid decrease more than 3 mgldL during the first 4 hours, analyzer. Serum pteridine levels were measured by decreased 2 mgldL in one patient, and more than 3 using high performance liquid chromatography after mgldL in four patients from the initial value at 24 iodine oxidation. DHPR activity was measured in hours after loading. These responses differed from 2 Guthrie card specimens as described • patients with BH4 defi-ciency. These patients had no abnormalities in serum pteridine levels or DHPR activity, and were diagnosed with PAH deficiency.
Pteridines/Vol. JJlNo. 3
84 Shintaku et at. : Tetrahydrobiperin responsive hyperpheny\alaninemia without bipterin deficiency
Fig.! : Response of serum phenylalanine concen Recently, it has been reported that the mechanism of trations after the BH4 loading test (10 mg/kg) in BH4 responsivfmess may be explained by distinct 3 patients with PKU (>20 mg/dL). mutations in th ~ PAH gene • To summarize, a lowering of the serum phenylala
70r------~ nine value mc.y occur by administering BH4 which exceeds the M ichaelis constant (Km) when the rise of the Km value by the mutation in the P AH gene may 60 be a cause. It \s important to confirm the response of ,..... BH4 loading \\'ith a second test. If the decrease of ~ 50 serum phenylalanine is more than 5mg/dL from the 5c: initial value, BR., can be used for the treatment of .9 40 HP A with P AH deficiency. ~c: 30 r------, 25 ~------~-1 '. ~ ~'. ~ .,.... ",' S 20 1---____---.,.0.:- ____-'":..:-,;., • •'-'.. ""c.;..... ---j Lh; ... ' -"'i ···'-··....;:::.... ~::;;;:_· :··-·~· ·-·~·-:· J-"·-~·=:.'-'-- : -~·~'-·:;,...... ,...... ------1 § "0 u ( ~Il. 10 I-I~~~~~~~--~~==~ E ...2 VJ o 3 24 Time after loading(hours) PteridinesNol. IlINo. 3