Different Strategies in the Treatment of Dihydropteridine Reductase Deficiency

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Year: 1996

Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency

Spada, M ; Blau, N ; Meli, C ; Ferrero, G B ; de Sanctis, L ; Ferraris, S ; Ponzone, A

DOI: https://doi.org/10.1515/pteridines.1996.7.3.107

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-155067 Journal Article Published Version

Originally published at: Spada, M; Blau, N; Meli, C; Ferrero, G B; de Sanctis, L; Ferraris, S; Ponzone, A (1996). Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency. Pteridines, 7(3):107-109. DOI: https://doi.org/10.1515/pteridines.1996.7.3.107 Spada et al.: Treatment of DHPR deficiency

Pteridines Vol. 7, 1996, pp. 107 - 109

Different Strategies In the Treatment of Dihydropteridine Reductase Deficiency

2 l M . Spada', N. Blau , C. Meli\ G . B. rerrero', L. de Sanctis\ S. Ferraris 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 mal serum Phe levels. Despite substantial amounts of peripherally ad- Inherited deficiency of dihydropteridine reduc- ministered BH4 can be found in cerebrospinal tase (DHPR, EC 1.66.99.7) impairs the re- fluid (CSr), only some patients respond at the generation of tetrahydrobiopterin (BH 4), the es- central level to BH4 monotherapy (3,4). Most pa- sential cofactor of phenylalanine (Phe), tyrosine tients need neurotransmitter substitutive therapy, (Tyr), and trypthophan (Trp) hydroxylases, which which can be realized by administering the hy- is oxidized to qBH2 during a coupled reaction droxylated precursors, I-Dopa and 5 -0H-Trp, in with these enzymes ( 1). Hyperphenylalaninemia conjunction with an inhibitor of peripheral amino and scarce production of monoamine neu- acid decarboxylases. Also the daily doses and the rotransmitters derived from Tyr and Trp-do- number of administrations of neurotransmitter pamine, norepinephrine, and serotonin-are the precursors have to be individually adjusted. Ran- main metabolic derangements caused by DHPR dom fluctuations in response to this therapy are deficiency. Untreated patients early develp a sev- observed, especially when larger doses of 1- Dopa ere an progressive neurological picture, which is arc required, which can be obviated by the ad- shared by other inborn errors of BH4 metabolism dition of a monoamine oxidase inhibitor (S). (1 ). The control of hyperphenylalaninemia and As a consequence, the best choice of treatment biogenic amine deficiency is necessary to improve must be thoroughly searched for in every patient their prognosis, together with folinic acid sup- affected by DHPR deficiency, as in the case here plementation to avoid folate depiction (2 ). reported. DHPR deficiency, however, is a heterogeneous disease both at clinical and molecular level. The Case Report and Methods dietary tolerance to Phe is highe r than in classical phenyketonuria, but shows interindividual dif- Patient r.M., kmale, was born at term after an ferences, as well as age-dependent increase ( 1 ). uncomplicated preg nancy as the first child of un- The control of hype rphenylalaninemia can be related parents. Routine Guthrie testing on day 4 achieved either by a Phe-restricted diet or by ad- showed slightly elevated blood Phe concentration ministration of synthetic cofactor. As in these pa- (4 mg%) which increased up to 37 mg% on a f<:>r • tients some recycling of BH4 do occur (3), a daily mula diet within the first month . Since then the dosage of 8-20 mg/ kg is sufficient to attain nor- infant was put on a Phe-restricted diet, bur at the age of 4 monthes she developed hvpert()nic crises, § Author to whom correspondence should be addressed. lethargia, and oculogiric crises. DHPR deficiency

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108 Spada et al.: Treatment of DHPR deficiency

Table 1. Clinical and biochemical monitiring in a patient affected by dihydropteridine reductase deficiency during different treatments. Phe=phenylalanine; Tyr=tyrosine; Trp=tryptophan; CSF=cerebrospinal fluid; 5-HlAA=5-hydroxyndole acetic acid; HVA=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 Hypertonic crises Diet only 5 mo 378 91 16 nd 128 nd Oculogiric crises Marked truncal hypotonia

Diet Lethargia BH4(6 mg/kg/day) 7mo Oculogiric crises 180 85 72 nd 474 nd 5-0H-Trp (2.5 mg/kg/day) Truncal hypotonia I-Dopa (3.3 mg/kg/day)

Diet Oculogiric crises 5-0H-Trp (5 mg/kg/day) 8 mo 170 37 156 219 237 17 Reduced truncal hypotonia I-Dopa (5 mg/kg/day)

Lethargia BH monotherapy 4 9mo Oculogiric crises 52 43 28 173 4 (20 mg/kg/day) Marked truncal hypotonia

Diet I-Deprenyl (0.25 mg/kg/day) 9 mo No symptoms 128 32 128 225 216 54 5-0H-Trp (5 mg/kg/day) I-Dopa (5 mg/kg/day) was ascertained at 5 months by enzyme aCtiVIty due to the fact that dopamine and serotonin can measurement on blood spot, urinary pterin and produce agonist and antagonist effects, which can CSF analysis, and combined Phe-BH4 loading test also mimic the symptoms of deficiency (2,8). On ( 6). the other hand, a good clinical result can be Four different therapeutic strategies were then achieved in these patients at CSF levels of HVA sequentially applied (BH4 and neurotransmitter and of 5-HIAA below those of age-matched con- therapy at low doses; diet plus neurotransmitter trols (9). therapy; BH4 monotherapy; diet plus neu- Data shown in Table 1 suggest that the CSF rotransmitter therapy plus monoamine oxidase m- concentration of I-DOPA and of 5-0H-Trp are hibitor), and monitored either clinically or more tightly related to the clinical picture. BH4 biochemically (Table 1). was shown to be peripherally effective in the con- Serum and CSF samples were taken half way trol of hyperphenylalaninemia in this patient; at between two successive drug administrations. Ser- the central level, however, the effect was very um Phe and Tyr were measured chro- poor, even at high cofactor doses, on the basis of matographically with a Kromakon 500 automatic both clinical and biochemical evaluation. analyzer. CSF concentrations of homovanillic acid As previously reported in cases of 6-pyruvoyl (HVA) , 5-hydroxyndole acetic acid (5-HIAA), tetrahydropterin synthase and of DHPR de- and I-DOPA were measured by HPLC with an ficiency (5,10,11) the optimal results were ob- ESA Coulochem 5100A eletrochemical detector. tained by the addition to the classical treatment of I-Deprenyl, a selective monoamine oxidase B in- Results and Discussion hibitor. It should be noted, finally, that on such a therapy the significance of CSF HVA and 5- Monitoring of treatment in BH4 deficiency can HlAA concentration is lessened because of the be implemented either clinically, by evaluating the limiting effect of I-Deprenyl on dopamine and minimal dose effective in relieving symptoms of serotonin degradation. biogenic amine deficiency, or biochemically, by measuring the CSF concentration of neurotrans- Aclmowledgements mitter metabolites, besides the level of blood Phe and Tyr (2,7). Pitfalls in clinical monitoring are The authors thanks Mrs. L. Kierat for analytical

Pteridines / Vol. 7 / No. 3 Spada et aZ.: Treatment of DHPR deficiency 109 work. This study was supported in part by the eshore Pub!. Co., 1989: 325-334. Swiss National Science Foundation grant no. 5 . Schuler A, Blau N , Ponzone A. Monoamine oxidase 3100-043380.95. inhibitors in tetrahydrobiopterin deficiency. Eur J Pediatr 1995; 154: 997. 6. Ponzone A, Guardamagna 0, Spada M, Ferraris S, References Ponzone R Kierat L, Blau N. Differential diagnosis of hyperphenylalaninemia by a combined phenylalan- 1. Blau N, Thony B, Spada M, Ponzone A. Tetrahy- ine-tetrahydrobiopterin loading test. Eur J Pediatr drobiopterin and inherited hyperphenylalaninemias. 1993; 152: 655-661. Turk J Pediatr 1996; 38: 19-35. 7. Ponzone A, Guardamagna 0, Ferraris S, Biasetti S, 2 . Ponzone A, Ferrero GB, Guardamagna 0, Ferraris S, Bracco G , Niederwieser A. Neurotransmitter therapy Curtius H Ch, Blau N. Screening and treatment of and diet in malignant phenylketonuria. Eur J Pediatr tetrahydrobiopterin deficiency. In: Curtius H Ch, 1987; 146: 93-94. Ghisla S, Blau N, eds. Chemistry and Biology of 8 . Dhondt JL, Tetrahydrobiopterin deficiencies: lessons Pteridines and Folic Acid Derivatives. Berlin-New from the compilation of 200 patients. Dev Brain York: Walter de Grujter, 1990: 393-401. Dysf1993; 6: 141-157. 3 . Ponzone A, Guardamagna 0, Spada M, Ferrero GB, 9. Spada M, Parrella T, Ponzone R, Ferraris S, Guar- Ponzone R., Dianzani I, Cotton RGH. Catalytic ac- damagna 0, Ponzone A, Blau N . Monitoring treat- tIVIty of tetrahydrobiopterin in dihydropteridine ment in tetrahydrobiopterin deficiency. Pteridines reductase deficiency and indications for treatemtn. 1992; 3: 13-15. Pediatr Res 1993; 33: 125-128. 10. Spada M, Schuler A, Blau N, Ferraris S, Lanza C, 4. Ponzone A, Biasetti S, Ferraris S, Guardamagna 0 , Ponzone A. Deprend in 6-pyru\·oyl·tetrahvdropterin Curtius h Ch, Kierat L, Blau N. Differential entrance synthase deficiency. Pteridines 1995; 6 : 144-146. of tetrahydrobiopterin into the brain of patients with 11. Spada M, Blau N, Ferraris S, Lanza C, Sanore M , 6-pyruvoyl-tetrahydropterin synthase deficiency. In: Dompe C, de Sanctis L, Perfetto F, Ponzone A. Levine RA, Milstien S, Kuhn DM, Curtius HCh, eds. Monoamine oxidase inhibitors: a new therapeutic ap- Pterins and Biogenic Ami ..es in Neuropsychiatry, proach in dihydropteridine reductase deficiency. Pediatrics and Immunology. Grosse Point: Lak- 1995; 33'" Ann Symp SSIEM, Toledo, Spain.

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