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Tetrahydrobiopterin deficiency
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

Tetrahydrobiopterin deficiency

Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage of tetrahydrobiopterin (BH4), leading to altered levels of phenylalanine and neurotransmitters, and a range of medical problems from mild to severe.

Overview

Tetrahydrobiopterin deficiency is a rare disorder characterized by a shortage (deficiency) of a molecule called tetrahydrobiopterin or BH4. This condition alters the levels of several substances in the body, including phenylalanine. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in foods that contain protein and in some artificial sweeteners. High levels of phenylalanine are present from early infancy in people with untreated tetrahydrobiopterin deficiency. This condition also alters the levels of chemicals called neurotransmitters, which transmit signals between nerve cells in the brain.

Infants with tetrahydrobiopterin deficiency appear normal at birth, but medical problems ranging from mild to severe become apparent over time. Signs and symptoms of this condition can include intellectual disability, progressive problems with development, movement disorders, difficulty swallowing, seizures, behavioral problems, and an inability to control body temperature.

Frequency

This condition is rare, affecting an estimated 1 in 500,000 to 1 in 1 million newborns. In most parts of the world, tetrahydrobiopterin deficiency accounts for 1 to 3 percent of all cases of elevated phenylalanine levels. The remaining cases are caused by a similar condition called phenylketonuria (PKU). In certain countries, including Saudi Arabia, Taiwan, China, and Turkey, it is more common for elevated levels of phenylalanine to be caused by tetrahydrobiopterin deficiency than by PKU.

Causes

Tetrahydrobiopterin deficiency can be caused by mutations in one of several genes, including GCH1, PCBD1, PTS, and QDPR. These genes provide instructions for making enzymes that help produce and recycle tetrahydrobiopterin in the body. Tetrahydrobiopterin normally helps process several amino acids, including phenylalanine. It is also involved in the production of neurotransmitters.

If one of the enzymes fails to function correctly because of a gene mutation, little or no tetrahydrobiopterin is available to help process phenylalanine. As a result, phenylalanine can build up in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage. Tetrahydrobiopterin deficiency can also alter the levels of certain neurotransmitters, which disrupts normal brain function. These abnormalities underlie the intellectual disability and other characteristic features of the condition.

Inheritance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • BH4 deficiency
  • Hyperphenylalaninemia caused by a defect in biopterin metabolism
  • Hyperphenylalaninemia, non-phenylketonuric
  • Non-phenylketonuric hyperphenylalaninemia

Frequently Asked Questions

Most state newborn screening panels include a measurement of blood phenylalanine. An elevated phenylalanine level that does not respond to a standard low‑phenylalanine diet prompts reflex testing for BH4 deficiency using a pterin profile and dihydropteridine reductase activity. Early detection allows prompt treatment before neurologic damage occurs.
cute neurological changes such as new seizures, sudden loss of motor control, severe irritability, or a rapid rise in blood phenylalanine (≥ 600 µmol/L) despite adherence to diet and medication indicate possible treatment failure or infection. Seek emergency care, obtain a phenylalanine level, and inform the metabolic team.
BH4 deficiency is inherited in an autosomal‑recessive pattern for most gene defects (GCH1, PCBD1, PTS, QDPR). Each subsequent pregnancy carries a 25 % risk if both parents are carriers. Offer carrier testing to the parents and consider prenatal diagnostic testing (chorionic villus sampling or amniocentesis) with targeted gene analysis if they desire.
In addition to a phenylalanine‑restricted diet, patients with BH4 deficiency receive pharmacologic BH4 (sapropterin dihydrochloride) to restore enzyme cofactor activity, and often need supplementation of neurotransmitter precursors such as L‑tyrosine, L‑tryptophan, and sometimes 5‑hydroxytryptophan or L‑dopamine agonists. Classic PKU is managed with diet alone.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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