Thomas Opladen1, Georg F Hoffmann, Nenad Blau. 1. Division of Inborn Metabolic Diseases, University Childrens Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
Abstract
OBJECTIVES: The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. METHODS: We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. RESULTS: Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. CONCLUSIONS: BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.
OBJECTIVES: The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. METHODS: We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. RESULTS: Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficientpatients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficientpatients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. CONCLUSIONS: BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epilepticseizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.
Authors: D Concolino; G Muzzi; M Rapsomaniki; M T Moricca; M G Pascale; P Strisciuglio Journal: J Inherit Metab Dis Date: 2008-04-15 Impact factor: 4.982
Authors: Mark J Crabtree; Amy L Tatham; Yasir Al-Wakeel; Nicholas Warrick; Ashley B Hale; Shijie Cai; Keith M Channon; Nicholas J Alp Journal: J Biol Chem Date: 2008-11-14 Impact factor: 5.157
Authors: Yair Anikster; Tobias B Haack; Thierry Vilboux; Ben Pode-Shakked; Beat Thöny; Nan Shen; Virginia Guarani; Thomas Meissner; Ertan Mayatepek; Friedrich K Trefz; Dina Marek-Yagel; Aurora Martinez; Edward L Huttlin; Joao A Paulo; Riccardo Berutti; Jean-François Benoist; Apolline Imbard; Imen Dorboz; Gali Heimer; Yuval Landau; Limor Ziv-Strasser; May Christine V Malicdan; Corinne Gemperle-Britschgi; Kirsten Cremer; Hartmut Engels; David Meili; Irene Keller; Rémy Bruggmann; Tim M Strom; Thomas Meitinger; James C Mullikin; Gerard Schwartz; Bruria Ben-Zeev; William A Gahl; J Wade Harper; Nenad Blau; Georg F Hoffmann; Holger Prokisch; Thomas Opladen; Manuel Schiff Journal: Am J Hum Genet Date: 2017-01-26 Impact factor: 11.025