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An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia

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Journal of Inherited Metabolic Disease



The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH4) deficiencies.


We analyzed the clinical, biochemical and treatment data of 626 patients with BH4 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.


Up to 57 % of neonates with BH4 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 BH4 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 BH4 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.


BH4 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 BH4 deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.

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We would like to thank all contributing medical centers and their physicians for providing biochemical, clinical, and follow-up date to the BIODEF database. This work was supported by the Swiss National Science Foundation grant no. 31003A-119982, by the BIOPKU, Switzerland, and by the “Forschungsförderung” of the German Metabolic Society (APS).

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Correspondence to Nenad Blau.

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Communicated by: Alberto B. Burlina

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Opladen, T., Hoffmann, G.F. & Blau, N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 35, 963–973 (2012).

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