Blau, N.

de Sanctis, L.

Ferraris, S.

Ferrero, G. B.

Meli, C.

Ponzone, A.

Spada, M.

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 Spada et al .: Treatment of DHPR deficiency Pteridines Vol. 7, 1996, pp. 107 - 109 Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency M . Spada', N. Blau2 , C. Meli\ G . B . rerrero', L. de Sanctis\ S . Ferraris l and A. Ponzone' · 4§ IDipartimento di Scienze Pediatriche e dell'Adolcscenza, Universita'degli Studi di Torino, Italy 2Division of Clinical Chemistry, University Children's Hospital, Zurich, Switzerland 3 C linica Pediatrica, Universita'di Catania, Italy 4Facolta' di Magistero, Universita'di Messina, Italy (Received July IS, 1996) Introduction Inherited deficiency of dihydropteridine reduc-tase (DHPR, EC 1.66.99.7) impairs the re-generation of tetrahydrobiopterin (B H 4), the es-sential cofactor of phenylalanine (Phe) , tyrosine (Tyr), and trypthophan (Trp) hydroxylases, which is oxidized to qBH2 during a coupled reaction with these enzymes ( 1). Hyperphenylalaninemia and scarce production of monoamine neu-rotransmitters derived from Tyr and Trp-do-pamine, norepinephrine, and serotonin-are the main metabolic derangements caused by DHPR deficiency. Untreated patients early develp a sev-ere an progressive neurological picture , which is shared by other inborn errors of BH4 metabolism (1 ). The control of hyperphenylalaninemia and biogenic amine deficiency is necessary to improve their prognosis, together with folinic acid sup-plementation to avoid folate depiction (2 ) . DHPR deficiency, however, is a heterogeneous disease both at clinical and molecular level. The dietary tolerance to Phe is highe r than in classical phenyketonuria, but shows interindividual dif-ferences, as well as age-dependent increase ( 1 ). The control of hype rphenylalaninemia can be achieved either by a Phe-restricted diet or by ad-ministration of synthetic cofactor. As in these pa-tients some recycling of BH4 do occur (3), a daily dosage of 8-20 mg/ kg is sufficient to attain nor-§ Author to whom correspondence should be addressed. mal serum Phe levels. Despite substantial amounts of peripherally ad-ministered BH4 can be found in cerebrospinal fluid (CSr), only some patients respond at the central level to BH4 monotherapy (3,4). Most pa-tients need neurotransmitter substitutive therapy, which can be realized by administering the hy-droxylated precursors, I-Dopa and 5 -0H-Trp, in conjunction with an inhibitor of peripheral amino acid decarboxylases. Also the daily doses and the number of administrations of neurotransmitter precursors have to be individually adjusted . Ran-dom fluctuations in response to this therapy are observed, especially when larger doses of 1- Dopa arc required, which can be obviated by the ad-dition of a monoamine oxidase inhibitor (S ). As a consequence, the best choice of treatment must be thoroughly searched for in every patient affected by DHPR deficiency, as in the case here reported . Case Report and Methods Patient r.M., kmale, was born at term after an uncomplicated preg nancy as the first child of un -related parents. Routine Guthrie testing on day 4 showed slightly elevated blood Phe concentration (4 mg%) which increased up to 37 mg% on a f<:>r -mula diet within the first month . Since then the infant was put on a Phe -restricted diet , bur at the age of 4 monthes she developed hvpert()nic crises, lethargia, and oculogiric crises. DHPR deficiency Pteridines/ VoL 7 / No. 3 108 Spada et al.: Treatment of DHPR deficiency Table 1 . Clinical and biochemical monitiring in a patient affected by dihydropteridine reductase deficiency during dif-ferent treatments. Phe=phenylalanine; Tyr=tyrosine; Trp=tryptophan; CSF=cerebrospinal fluid; 5-HlAA=5-hy-droxyndole acetic acid; HV A=homovanillic acid; BH4 =tetrahydrobiopterin; nd=not done. Serum (umol/l) CSF (nmol/l) Treatment Age Clinical symptoms Phe Tyr 5-HIAA 5-OH-Trp HVA I-Dopa Lethargia Diet only 5 mo Hypertonic crises 378 91 16 nd 128 nd Oculogiric crises Marked truncal hypotonia Diet Lethargia BH4(6 mg/kg/day) 5-0H-Trp (2.5 mg/kg/day) 7mo Oculogiric crises 180 85 72 nd 474 nd I-Dopa (3.3 mg/kg/day) Truncal hypotonia Diet Oculogiric crises 5-0H-Trp (5 mg/kg/day) 8 mo 170 37 156 219 237 17 I-Dopa (5 mg/kg/day) Reduced truncal hypotonia BH4monotherapy Lethargia 9mo Oculogiric crises 52 43 28 173 4 (20 mg/kg/day) Marked truncal hypotonia Diet I-Deprenyl (0.25 mg/kg/day) 5-0H-Trp (5 mg/kg/day) I-Dopa (5 mg/kg/day) 9 mo No symptoms was ascertained at 5 months by enzyme aCtiVIty measurement on blood spot, urinary pterin and CSF analysis, and combined Phe-BH4 loading test ( 6). Four different therapeutic strategies were then sequentially applied (BH4 and neurotransmitter therapy at low doses; diet plus neurotransmitter therapy; BH4 monotherapy; diet plus neu-rotransmitter therapy plus monoamine oxidase m-hibitor), and monitored either clinically or biochemically (Table 1). Serum and CSF samples were taken half way between two successive drug administrations. Ser-um Phe and Tyr were measured chro-matographically with a Kromakon 500 automatic analyzer. CSF concentrations of homovanillic acid (HVA) , 5-hydroxyndole acetic acid (5-HIAA), and I-DOPA were measured by HPLC with an ESA Coulochem 5100A eletrochemical detector. Results and Discussion Monitoring of treatment in BH4 deficiency can be implemented either clinically, by evaluating the minimal dose effective in relieving symptoms of biogenic amine deficiency, or biochemically, by measuring the CSF concentration of neurotrans-mitter metabolites, besides the level of blood Phe and Tyr (2,7). Pitfalls in clinical monitoring are Pteridines / Vol. 7 / No. 3 128 32 128 225 216 54 due to the fact that dopamine and serotonin can produce agonist and antagonist effects, which can also mimic the symptoms of deficiency (2,8). On the other hand, a good clinical result can be achieved in these patients at CSF levels of HV A and of 5-HIAA below those of age-matched con-trols (9). Data shown in Table 1 suggest that the CSF concentration of I-DOPA and of 5-0H-Trp are more tightly related to the clinical picture. BH4 was shown to be peripherally effective in the con-trol of hyperphenylalaninemia in this patient; at the central level, however, the effect was very poor, even at high cofactor doses, on the basis of both clinical and biochemical evaluation. As previously reported in cases of 6-pyruvoyl tetrahydropterin synthase and of DHPR de-ficiency (5,10,11) the optimal results were ob-tained by the addition to the classical treatment of I-Deprenyl, a selective monoamine oxidase B in-hibitor. It should be noted, finally, that on such a therapy the significance of CSF HV A and 5-HlAA concentration is lessened because of the limiting effect of I-Deprenyl on dopamine and serotonin degradation. Aclmowledgements The authors thanks Mrs. L. Kierat for analytical  Spada et aZ.: Treatment of DHPR deficiency work. This study was supported in part by the Swiss National Science Foundation grant no. 3100-043380.95 . References 1. Blau N, Thony B, Spada M, Ponzone A. Tetrahy-drobiopterin and inherited hyperphenylalaninemias. Turk J Pediatr 1996; 38: 19-35. 2 . Ponzone A, Ferrero GB, Guardamagna 0, Ferraris S, Curtius H Ch, Blau N. Screening and treatment of tetrahydrobiopterin deficiency. In: Curtius H Ch, Ghisla S, Blau N, eds. Chemistry and Biology of Pteridines and Folic Acid Derivatives. Berlin-New York: Walter de Grujter, 1990: 393-401. 3 . Ponzone A, Guardamagna 0, Spada M, Ferrero GB, Ponzone R., Dianzani I, Cotton RGH. Catalytic ac-tIVIty of tetrahydrobiopterin in dihydropteridine reductase deficiency and indications for treatemtn. Pediatr Res 1993; 33: 125-128. 4. Ponzone A, Biasetti S, Ferraris S, Guardamagna 0 , Curtius h Ch, Kierat L, Blau N. Differential entrance of tetrahydrobiopterin into the brain of patients with 6-pyruvoyl-tetrahydropterin synthase deficiency. In : Levine RA, Milstien S, Kuhn DM, Curtius HCh, eds . Pterins and Biogenic Ami .. es in Neuropsychiatry, Pediatrics and Immunology. Grosse Point: Lak-109 eshore Pub!. Co., 1989: 325-334. 5 . Schuler A, Blau N , Ponzone A. Monoamine oxidase inhibitors in tetrahydrobiopterin deficiency. Eur J Pediatr 1995; 154: 997 . 6. Ponzone A, Guardamagna 0, Spada M, Ferraris S, Ponzone R Kierat L, Blau N. Differential diagnosis of hyperphenylalaninemia by a combined phenylalan-ine-tetrahydrobiopterin loading test. Eur J Pediatr 1993; 152: 655 -661. 7. Ponzone A, Guardamagna 0, Ferraris S, Biasetti S, Bracco G , Niederwieser A. Neurotransmitter therapy and diet in malignant phenylketonuria. Eur J Pediatr 1987; 146: 93-94. 8 . Dhondt JL, Tetrahydrobiopterin deficiencies: lessons from the compilation of 200 patients. Dev Brain Dysf1993; 6: 141 -157. 9. Spada M, Parrella T, Ponzone R, Ferraris S, Guar-damagna 0, Ponzone A, Blau N . Monitoring treat-ment in tetrahydrobiopterin deficiency. Pteridines 1992; 3: 13-15 . 10. Spada M, Schuler A, Blau N, Ferraris S, Lanza C, Ponzone A . Deprend in 6-pyru\·oyl·tetrahvdropterin synthase deficiency. Pteridines 1995; 6 : 144-146. 11. Spada M, Blau N, Ferraris S, Lanza C, Sanore M , Dompe C, de Sanctis L, Perfetto F, Ponzone A. Monoamine oxidase inhibitors: a new therapeutic ap-proach in dihydropteridine reductase deficiency. 1995; 33'" Ann Symp SSIEM, Toledo, Spain. Pteridines / Vo!' 7 / No.3 

Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency

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