Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies

Orphanet J Rare Dis. 2020 May 26;15(1):126. doi: 10.1186/s13023-020-01379-8.


Background: Tetrahydrobiopterin (BH4) 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 BH4 biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH4 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 BH4 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 BH4 deficient patients.

Keywords: 6-pyruvoyltetrahydropterin synthase deficiency; BH4; Consensus guidelines; Dihydropteridine reductase deficiency; Guanosine triphosphate cyclohydrolase deficiency; Hyperphenylalaninemia; Neurotransmitter; SIGN; Sepiapterin reductase deficiency, pterin-4-alpha-carbinolamine dehydratase deficiency; Tetrahydrobiopterin deficiency; iNTD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Biopterins / analogs & derivatives
  • Biopterins / therapeutic use
  • Dystonia*
  • Humans
  • Metabolism, Inborn Errors*
  • Phenylketonurias* / diagnosis
  • Phenylketonurias* / drug therapy
  • Phenylketonurias* / genetics


  • Biopterins
  • sapropterin