BH4 Deficiency (Tetrahydrobiopterin Deficiency) Treatment & Management

Updated: Sep 28, 2018
  • Author: Anna V Blenda, PhD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Medical Care

Most patients are treated in a specialty metabolic clinic, usually under the direction of a geneticist or a pediatric endocrinologist.

In some cases, gene therapy has been used, with a possible effect. [43, 44, 45, 46] Gene therapy is not widely used, and its use is purely experimental.

Treatment of tetrahydrobiopterin (BH4) deficiencies consists of BH4 supplementation [47, 48, 49] or dietary changes to control blood Phe concentration and replacement therapy with neurotransmitter precursors (eg, levodopa and carbidopa, 5-hydroxytryptophan [5HT]). In dihydropteridine reductase (DHPR) deficiency, folinic acid is supplemented. In Japan, sapropterin dihydrochloride is used as a treatment. [37]

In patients with BH4 deficiency, levodopa replacement therapy (to increase dopamine levels) should be started in the first weeks or months of life. Patients diagnosed before age 2 years and 6 months can obtain normal executive functions and prevent development of motor and cognitive symptoms with levodopa supplementation. [50] This finding suggests dopamine may play a critical role in ensuring stable development of executive functions in early life. While treating BH4 deficiency, there is a target prolactin range. [51]

Depending on the variant, levels of the relevant enzymes are checked.

In DHPR, some positive reports have documented the use of monoamine oxidase (MAO) B inhibitor.

A 2016 report described safe and clinically effective long-term use of low-dose pramipexole (~0.010 mg/kg/day) for the most common causes of BH4 deficiency, which are PTPS and DHPR deficiencies. [52]

Treatment is determined on the basis of enzyme-defect phenotype, as follows:

  • Severe guanosine triphosphate (GTP) cyclohydrolase I (GTPCH) - Levodopa, 5HT, BH4
  • Severe 6-pyruvoyl-tetrahydropterin synthase (PTPS) - Levodopa, 5HT, BH4
  • Mild PTPS - BH4
  • Transient PTPS - BH4 in the neonatal period
  • Severe DHPR - Levodopa, 5HT, low-Phe diet, folinic acid
  • Mild DHPR - Low-Phe diet
  • Transient carbinolamine-4a-dehydratase (PCD) - BH4 in the neonatal period


A psychologist should perform developmental testing at regular intervals. Whenever possible, the patient and his or her parents should work with a nutritionist and a geneticist experienced in BH4 deficiency.



Treatment of BH4 deficiencies consists of BH4 supplementation (2-20 mg/kg/d) or diet to control blood Phe and, in DHPR deficiency, supplements of folinic acid (10-20 mg/d).



BH4 deficiencies are heterogeneous. They range from mild forms that require only marginal, if any, treatment to severe forms that are sometimes difficult to treat. In many cases, normal activity can be expected if the patient adheres to treatment.



Avoid substances containing aspartame. Avoid drugs that effect folate metabolism such as methotrexate and trimethoprim-sulfamethoxazole.