Infants with BH4 deficiency appear normal at birth.
Infants with BH4 deficiency appear normal at birth.

Tetrahydrobiopterin (BH4) deficiency is a neurological condition characterized by abnormalities in the production and regeneration of tetrahydrobiopterin. Tetrahydrobiopterin, a naturally occurring chemical substance, which helps to enhance the functions of certain enzymes. Deficiency of BH4 leads to abnormally high levels of the amino acid, phenylalanine, and low levels of certain neurotransmitters in the blood. Phenylalanine (amino acid), obtained from the diet, is the building block of several proteins essential for proper growth and development. If BH4 deficiency is left untreated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health issues.

What causes BH4 deficiency?

BH4 deficiency is caused due to mutation in any of these genes: GCH1, PCBD1, PTS, and QDPR. Mutation in any of these genes affects the production and regeneration of tetrahydrobiopterin.

Tetrahydrobiopterin has the following function in our bodies:

  • Breaking down or processing certain amino acids
  • Proper development of amine neurotransmitters, such as catecholamines and serotonin

BH4 deficiency is acquired in an autosomal recessive manner, which means the disease will manifest when both the copies of the gene obtained from parents have mutations. Both the parents may carry one copy of mutated genes (carriers), although they do not show any signs or symptoms. When two carriers of an autosomal recessive condition have children, there is a 25% chance to have a child with BH4 deficiency.

What are the signs and symptoms of BH4 deficiency?

Infants with BH4 deficiency appear normal at birth. Over time, the symptoms become apparent and range from mild to severe. The sign and symptoms include:

  • Intellectual disability
  • Difficulty swallowing
  • Seizures
  • Behavioral problems
  • Progressive problems with development
  • Inability to control body temperature
  • Microcephaly (a condition defined as having a head circumference smaller than the normal)
  • Truncal hypotonia (poor muscle tone of the trunk of the body)
  • Limb hypertonia (excess muscle tone of the arms and legs)
  • Bradykinesia (abnormal slowness of movement)
  • Chorea (rapid, involuntary, purposeless movements)
  • Athetosis (slow, involuntary writhing movements)
  • Opisthotonus (muscle spasm causing backward arching of the head, neck, and spine)
  • Oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upwards)
  • Excessive production of saliva
  • Lethargy
  • Irritability
  • Gait abnormalities (abnormal manner of walking)
  • Dystonia (abnormal, painful movements and positions)

How is BH4 deficiency treated?

Early recognition and treatment of BH4 deficiency are necessary to prevent severe neurological complications.

The focus of BH4 deficiency treatment includes:

  • Control the level of phenylalanine in the body
  • Restore the proper balance of neurotransmitters in the brain

Treatment for BH4 deficiency includes:

  • Treatment with synthetic BH4
  • Additional therapy with Folinic acid
  • Treatment with a regimen of amine neurotransmitter precursors, such as 5-Hydroxytryptophan and Levodopa

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Medically Reviewed on 10/12/2020
References
https://www.medicinenet.com/tetrahydrobiopterin_deficiency/article.htm

https://rarediseases.info.nih.gov/diseases/7751/tetrahydrobiopterin-deficiency

https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/

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