Blau, N.

Ferraris, S.

Guardamagna, O.

Parrella, T.

Ponzone, A.

Ponzone, R.

Spada, M.

RERO DOC Digital Library

Spada et al.: Monitoring treatment in BH4 deficiency 13 Pteridines Voi. 3, pp. 1 3 - 1 5 Short Communication Monitoring Treatment in Tetrahydrobiopterin Deficiency M. Spada, T. Parrella, R. Ponzone, S. Ferraris, O. Guardamagna, A. Ponzone and N. Blau* Istituto di Clinica Pediatrica, Piazza Polonia 94, 10126 Torino, Italy * Department of Pediatrics, University of Zürich, CH-8032 Zürich, Switzerland (Received March 1992) Introduction Tetrahydrobiopterin (BH4) deficiency leads to an im-paired function of phenylalanine (Phe), tyrosine (Tyr) and tryptophan hydroxylases. Consequent hyper-phenylalaninemia and dopamine and serotonin defi-ciency are the main metabolic disturbances on which depend the patient's symptoms and poor prognosis, irrespective of the enzyme defect causing impaired BH4 synthesis or regeneration. Three inborn errors of pterin metabolism are so far known: guanosine triphosphate cyclohydrolase (GTP CH I, EC 3.5.4.16) and 6-pyruvoyl tetrahydropterin synthase (6-PPH4S, Mc Kusick 26164) deficiency inhibit BH4 biosyn-thesis, and dihydropteridine reductase (DHPR, EC 1.66.99.7) deficiency prevents BH4 from being recy-cled after oxidation in the hydroxylating reaction (1). The goals of the treatment are to control the hyper-phenylalaninemia and to restore the homeostasis of neurotransmitters. In synthesis defects, hyperphenyl-alaninemia can be easily corrected by BH4 adminis-tration, while in D H P R deficiency Phe dietary restric-tion is generally applied. With the exception of some milder cases, where BH4 monotherapy or just dietary treatment is affordable, most patients need hydroxy-lated neurotransmitter precursor administration in addition to an inhibitor of peripheral aromatic amino acid decarboxylases to avoid clinical symptoms and to increase brain neurotransmitter levels (2). Enzymes: dihydropteridine reductase (EC 1.66.99.7) guanosine triphosphate cyclohydrolase (EC 3.5.4.16) 6-pyruvoyl tetrahydropterin synthase (Mc Kusick 26164) Pteridines / Vol.3 / No. 1/2 Copyright © 1992 Walter de Gruyter - Berlin · New York The comparison of the biochemical picture in BH4 deficient patients at diagnosis with that observed at the time of optimal clinical response to therapy can be helpful in cases whose clinical monitoring is not sufficient to evaluate the adequacy of treatment. Case Report and Methods Three patients suffering from 6-PPH4S deficiency and three patients suffering from D H P R deficiency have been examined in two opposite conditions: at diag-nosis, when hyperphenylalaninemia and biogenic amine deficiency symptoms were present, and during the follow up, when the hyperphenylalaninemia was controlled and symptoms disappeared (Table 1). As for the treatment, the 6-PPH4S deficient patients were on free diet but received a single daily dose of 5 mg/ kg synthetic BH4, while the D H P R deficient patients were given a Phe-restricted diet adjusted to the indi-vidual tolerance. Both types of patients needed neu-rotransmitter substitutive therapy in three daily di-vided doses (L-dopa: 5 — 6 mg/kg; 5-OH-tryptophan: 4 — 5 mg/kg; Carbidopa: 1 mg/kg). Serum, urine, and cerebrospinal fluid (CSF) samples were taken in the morning after midnight semifasting at diagnosis, and, when patients were on therapy, half way between two successive drug administrations. Serum Phe and Tyr were measured chromatographi-cally with a Kromakon 500 automatic analyzer. Serum, urine and CSF neopterin (N) and biopterin (B) were measured by HPLC after oxidation with manganese dioxide and subsequent deproteinization with trichloroacetic acid; 5-hydroxyindolacetic acid 14 Spada et a!.: Monitoring treatment in BH4 deficiency Table 1. Biochemical findings in 6 tetrahydrobiopterin (BH4) deficient patients, 3 suffering f rom 6-pyruvoyl tetrahydropterin synthase (6-PPH4S) and 3 f rom dihydropteridine reductase ( D H P R ) deficiency. Each patient was evaluated at diagnosis, prior to treatment, and when a good clinical response to the therapy had been obtained. Age Treatment Serum Urine CSF Patients BH4 diet N T Phe Tyr Ν Β N B N B H VA 5-HIAA (μπιοΙ/L) (nmol/L) (mmol/mol C) (nmol/1) 1. 6-PPH4S 7 d — — 1589 34 43 0 28 0 449 0 34 13 4.5 y + — + 70 46 1.3 12.6 1.4 2.4 115 2.1 288 162 2. 6-PPH4S 5 m _ — — 743 52 61 0 27 0 206 6 70 21 4 y + — + 32 68 4.5 19 2.3 1.7 124 5.5 283 202 3. 6-PPH4S 11 m _ — _ 1282 45 229 0 13.4 0 215 9.7 91 15 8 y + — + 161 66 4.6 9.2 1.7 1.3 77 13.7 349 120 I. D H P R 14 m _ — — 1458 66 17 98 2.8 13.8 17 61 71 14 6.5 y — + + 57 72 17 28 1.1 3.1 18 41 123 65 II. D H P R 14 m — — 553 41 24 100 2 6.5 11 57 81 23 2 y — + + 55 51 18 32 1 2.8 20 42 233 164 III. D H P R 1 m — _ — 1993 42 17 35 12.6 9.3 47 117 59 4 3 y — + + 61 69 35 28 0.8 1.2 16 37 168 125 Controls 31 30 12 5 1.1 0.5 9 10 250 110 91 147 24 13 4 3 20 34 880 360 N T = neurotransmitter precursors; Ν — neopterin; Β = biopterin; C = creatinine; HVA = homovanillic acid; 5-HIAA = 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) were meas-ured by HPLC with an ESA Coulochem 5100 A electrochemical detector (3). Results and Discussion Results are summarized in Table 1. As previously reported (4), high serum Phe levels are a limiting factor in the response to neurotransmitter precursor therapy, by interfering with their membrane transport or metabolism, and so altering the dose-effect rela-tionships. Normal serum Phe levels are easily attained in synthesis defects by small doses of synthetic cofac-tor, while D H P R deficient patients need a strict die-tary control. This strategy allows to reduce the dose of neurotransmitter precursors, as well as to avoid most of the clinical fluctuations in symptomatology. In practice, the patient's individual optimal dosage is judged on a clinical basis, with only the monitoring of serum Phe concentration. Unfortunately, dopamine and serotonin can produce agonist and antagonist effects, and side effects, which can also mimic the symptoms of deficiency (4). As a consequence, the direct analysis of neurotransmitter metabolites in CSF might be necessary in some cases to evaluate the adequacy of treatment. Since reference parameters of pterin and neurotrans-mitter metabolism in treated BH4 deficient patients are very scarce in literature, the present investigation offers new insights into the biochemical expression of a favourable outcome. The administration of BH4 and the restriction of Phe dietary intake, respectively applied in 6-PPH4S and in D H P R deficiency, are both able to correct significantly the pattern of pterin me-tabolism at the peripheral level, with only minor mod-ifications of Β and Ν concentrations in CSF (Table 1). Particularly, the urinary pattern of pterin excretion appears to be almost normalized, and this is the reason why the analysis of urinary pterins can miss the diagnosis of D H P R deficiency when serum Phe is low (5). The concentration of CSF neurotransmitter metabo-lites, extremely low prior to hydroxylated precursors administration, increased only up to the lowest nor-mal values on therapy. These findings show that in BH4 deficient patients a good clinical result is achieved at CSF biogenic amine levels below those of age-matched controls. In addition to the low dosage of neurotransmitter precursors required, as compared to other conditions such as Parkinson's disease (2), these data suggest that synaptic receptors are very sensitive in these patients, and that the attempt to reach therapeutically higher values of CSF neuro-transmitter metabolites may result in overdose symp-toms. Acknowledgements This work was supported in part by the Swiss Na-tional Science Foundation (to Ν. B.), project No. 31-28797.90. Pteridines / Vol. 3 / No. 1/2 Spada et al.: Monitoring treatment in BH4 deficiency 15 References 1. Blau, Ν. (1988) Inborn errors of pterin metabolism. Ann. Rev. Nutr. 8, 185 -209 . 2. Ponzone, Α., Ferrerò, G. Β., Guardamagna, Ο., Ferraris, S., Curtius, H. Ch. & Blau, Ν. (1990) in: Chemistry and Biology of Pteridines (Curtius, H. Ch., Ghisla, S. & Blau, N„ eds.) pp. 393 — 401, Walter de Gruyter, Berlin, New York. 3. Blau, N „ Niederwieser, Α., Curtius, H. Ch., Kierat, L., Leimbacher, W., Matasovic, Α., Binkert, F., Lehmann, H., Leupold, D., Guardamagna, O., Ponzone, Α., Schmidt, H., Coskun, T., Ozalp, I., Giugliani, R., Biasucci, G. & Giov-annini, M. (1989) Prenatal diagnosis of atypical phenylke-tonuria. J. Inher. Metab. Dis. 12 (Suppl. 2) 2 9 5 - 2 9 9 . 4. Ponzone, A , Guardamagna, O., Ferraris, S., Biasetti, S., Bracco, G. & Niederwieser, A. (1987) Neurotransmitter ther-apy and diet in malignant phenylketonuria. Eur. J. Pediatr. 146, 9 3 - 9 4 . 5. Kaufman, S. (1986) Unsolved problems in diagnosis and therapy of hyperphenylalaninemia caused by defects in te-trahydrobiopterin metabolism. J. Pediatr. 109, 572 — 578. Pteridines / Vol.3 / No. 1/2 

Monitoring Treatment in Tetrahydrobiopterin Deficiency

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library