Tetrahydrobiopterin (BH4) deficiency refers to a group of rare disorders affecting the biosynthesis or regeneration of tetrahydrobiopterin—a naturally occurring compound that serves as a crucial cofactor for several enzymes. A common feature of these disorders is elevated levels of the amino acid phenylalanine in the blood (hyperphenylalaninemia), which can be toxic if untreated. In addition to hyperphenylalaninemia, most BH4 deficiencies also result in reduced production of neurotransmitters which can lead to a range of neurological symptoms, including hypotonia (reduced muscle tone), hypersalivation, impaired coordination, abnormal involuntary movements, and delays in motor development. The severity and presentation of symptoms can vary widely, from mild to profound, even among individuals with the same condition. Early recognition and treatment are critical, as timely intervention can prevent irreversible neurological damage. BH4 deficiencies are typically caused by pathogenic variants (mutations) in genes responsible for enzymes involved in BH4 production or recycling. These genetic conditions are most often inherited in an autosomal recessive manner.
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