Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies
Thomas OpladenEduardo López‐LasoElisenda Cortès‐SaladelafontToni S. PearsonSerap SivriYılmaz YıldızBirgit AssmannManju A. KurianVincenzo LeuzziSimon HealesSimon PopeFrancesco PortaÁngeles García‐CazorlaTomáš HonzíkRoser PonsLuc RégalHelly GoezRafael ArtuchGeorg F. HoffmannGabriella HorváthBeat ThönySabine Scholl‐BürgiAlberto BurlinaMarcel M. VerbeekMario MastrangeloJennifer FriedmanTessa WassenbergKathrin JeltschJan KulhánekOya Kuseyri Hübschmann
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Abstract Background Tetrahydrobiopterin (BH 4 ) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH 4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH 4 deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH 4 deficiencies. Conclusion Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH 4 deficient patients.Keywords:
Hyperphenylalaninemia
Guideline
Biopterin
To show the incidence of 6-Pyruvoyl-tetrahydrobiopterin synthase (PTPS) deficiency among hyperphenylalaninemia and conclude the clinical outcome of patients with PTPS deficiency.The urinary neopterin (N) and biopterin (B) were determined by HPLC in 69 PKU cases. BH(4) loading test and mutation analysis of PTPS were performed in patients who had abnormal urinary pterin patterns. Three patients with PTPS deficiency were placed on treatment with combined synthetic BH(4) and neurotransmitter precursors such as Dopa and 5-hydroxytryptophan.9 out of 69 patients, whose urinary N/B exceed 38 [normal: 1.17 (1.4)] and B% were less than 5% [normal: 55.9 (18.6)], were diagnosed as having PTPS deficiency. Four kinds of PTPS gene mutations (P87S, N52S, D96N and G144R) were detected from 4 out of 9 cases with PTPS deficiency. The last mutation was a new mutation. The three typical PTPS-deficient patients had satisfactory physical development, their intelligence quotient (IQ) were 70 approximately 80 after treatment and one partial PTPSD had normal growth and mental development.The screening for BH(4) deficiency should be carried out among all patients with hyperphenylalaninemia in order to avoid misdiagnosis.
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Hyperphenylalaninemia due to dihydropteridine reductase deficiency results from the inability to maintain the aromatic amino acid hydroxylase cofactor, tetrahydrobiopterin, in its reduced or active form. Diagnosis of the disease is usually made by direct enzymatic assay on liver biopsies or in cultured skin fibroblasts. Evidence is presented that normal children and classic phenylketonuric children excrete mainly tetrahydrobiopterin in their urines, whereas children with dihydropteridine reductase deficiency excrete only oxidized forms of biopterin. Details of a rapid high performance liquid chromatographic assay for the measurement of the various forms of biopterin in urine are presented. This assay can be used to screen for suspected dihydropterine reductase mutants.
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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 diagnosis 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 (N/B) 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 N/B 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/B is useful for the diagnosis of homozygotes and heterozygotes for PTPS deficiency.
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Substantial amounts of tetrahydrobiopterin and 6-methyltetrahydropterin can be detected in CSF when these pterins are given peripherally to patients with hyperphenylalaninemia due to defective biopterin synthesis. Results of this study suggest that administration of either of these pterins in proper doses may prove to be a treatment not only for the impaired peripheral phenylalanine metabolism, but also for the neurologic disorders that are characteristic of the variant forms of hyperphenylalaninemia due to defective tetrahydrobiopterin synthesis or metabolism.
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To find out the incidence of tetrahydrobiopterin deficiency(BH4D) among patients with hyperphenylalaninemia in Southern Chinese and evaluate the clinical outcome and gene mutations of tetrahydrobiopterin deficient patients.Analyses of urinary neopterin(N) and biopterin(B) were done in 87 patients with hyperphenylalaninemia by high-performance liquid chromatography. The patients with BH4 deficiency and their parents were asked to undergo the gene mutation analysis and the patients were treated and followed up.Eleven cases of which the urinary N/B ratio was higher than 38 and B% lower than 5% were diagnosed as BH4 deficiency caused by 6-pyruvoyl-tetrahydropterin synthase(PTPS) deficiency. The incidence of BH4 deficiency among patients with hyperphenylalaninemia is 12% in Southern Chinese. PTPS gene mutations (P87S, N52S, D96N and G144R) were detected from 5 PTPS deficient families. The G144R mutation is a new mutation. The five PTPS-deficient patients were treated with synthetic BH4, neurotransmitter precursors L-dopa and 5-hydroxytryptophan. They had satisfactory physical and mental development after treatment, and 4 of them scored their IQ 70-80.The screening for BH4 deficiency should be carried out in all patients with hyperphenylalaninemia in order to minimize the misdiagnoses.
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Screening for tetrahydrobiopterin deficiency among hyperphenylalaninemia patients in Southern China.
To assess the incidence of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in southern Chinese and evaluate clinical outcome and gene mutations in tetrahydrobiopterin deficient patients.Urinary neopterin (N) and biopterin (B) was analyzed in 87 patients with hyperphenylalaninemia by high-performance liquid chromatography. Further combined loading tests with phenylalanine (Phe) (100 mg/kg) and tetrahydrobiopterin (BH4) (7.5 mg/kg) were performed in suspected patients with abnormal urinary pterin profiles. Gene mutation analysis was performed for patients with BH4 deficiency and their parents. BH4 deficient patients were treated with BH4 and neurotransmitter precursors after diagnosis. Blood phenylalanine levels, clinical symptoms and mental development were followed up.Eleven patients were diagnosed as having BH4 deficiency caused by 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency. The incidence of tetrahydrobiopterin (BH4) deficiency among patients with hyperphenylalaninemia (HPA) in southern Chinese was 10%. Combined loading tests with phenylalanine and oral BH4 were done in 4 of 11 patients and their phenylalanine levels were decreased to normal 4 - 6h after BH4 administration. Four different mutations (P87S, N52S, D96N and G144R) in the PTPS gene were detected in 5 families. Five PTPS-deficient patients were treated with synthetic BH4, neurotransmitter precursors (L-dopa plus carbidopa, and 5-hydroxytryptophan). They had satisfactory physical and mental development after treatment. One patient with partial PTPS deficiency had normal growth and mental development without treatment.Our results emphasize that screening for BH4 deficiency should be carried out in all patients with hyperphenylalaninemia in order to minimize the misdiagnosis. Patients with BH4 deficiency should be treated early with BH4 and a combination of neurotransmitter precursors.
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