BH4-Deficient Hyperphenylalaninemia A

BH4-deficient hyperphenylalaninemia A is an inherited disorder caused by a defective enzyme called 6-pyruvoyltetrahydropterin synthase that results in increased levels of a protein building block called phenylalanine. As a result, it alters levels of molecules called neurotransmitters, which are necessary for communication between nerve cells in the brain. Affected individuals appear normal at birth or may be smaller than normal at birth. Symptoms begin to appear within a few days to a few months after birth. Symptoms can range from mild to severe and become more evident over time. They include low muscle tone, progressive problems with development, difficulty swallowing, seizures, movement disorders, behavioral problems, an inability to control body temperature, and intellectual disability. Initiation of treatment of dietary restrictions, along with supplementation of BH4 and other compounds is able to prevent motor and intellectual decline and a normal life expectancy is expected. Without treatment, early death is possible. BH4-deficient hyperphenylalaninemia is caused by pathogenic variants in the PTS gene.

BH4-deficient hyperphenylalaninemia is inherited in an autosomal recessive manner. This type of inheritance requires the presence of two copies of a pathogenic variant in the gene for a person to have the genetic disease. Both parents must be carriers of a pathogenic variant in the gene in order to be at risk to have an affected child. The child must inherit a pathogenic variant from each carrier parent in order to be affected. There is a 1 in 4 chance that a baby will inherit two mutated copies of the gene and be affected when both parents are carriers.

There are generally no signs or symptoms associated with being a carrier for BH4-deficient hyperphenylalaninemia. However, the risk to have a child affected with BH4-deficient hyperphenylalaninemia is increased. Testing of reproductive partners is recommended for carriers of BH4-deficient hyperphenylalaninemia.

BH4-deficient hyperphenylalaninemia is a very rare disorder. It is more common in Saudi Arabia, Taiwan, China, and Turkey.

Genetics Home Reference: Tetrahydrobiopterin deficiency (http://ghr.nlm.nih.gov/)
The National Organization for Rare Disorders (NORD): Tetrahydrobiopterin deficiency (https://www.rarediseases.org/)

OMIM [BH4-deficient hyperphenylalaninemia A: 261640] (http://www.ncbi.nlm.nih.gov/omim)
Gene Reviews: Hyperphenylalaninemia (http://www.ncbi.nlm.nih.gov/books/NBK1116/)

• Full gene sequencing