Malfunction of aromatic amino acid hydroxylases enzymes can cause major peripheral and central biochemical disturbances. Such malfunction could be a result of genetic defects in aromatic amino acid hydroxylases enzymes, genetic defects in pterin synthesis pathways and/or low pterin levels in the brain.
PRIMARY BH4 DEFICIENCY
Tetrahydrobiopterin (BH4) deficiency is a rare disorder characterized by a shortage (deficiency) of tetrahydrobiopterin (BH4). There are approximately 100-200 patients in the US and close to 1,000 in the developed world. This condition alters the levels of phenylalanine as well as neurotransmitters. 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.
Phenylketonuria (PKU) is an inherited disorder caused by a defective Phenylalanine Hydroxylase resulting in high Phe plasma concentration and major CNS and non-CNS sequelae. Without treatment, PKU patients develop permanent intellectual disability, seizures, delayed development, behavioral problems, and possibly psychiatric disorders.
DISEASES OF THE CENTRAL NERVOUS SYSTEM
A connection between biopterin levels and CNS disorders has been reported in the literature. This may suggest an etiological role of a BH4 deficit in these disorders via dysregulation of neurotransmitters. Autism, for example, is associated with low BH4 levels and recent studies have demonstrated positive effects of tetrahydrobiopterin administration in these patients. Major depression and obsessive-compulsive disorder have been found in subjects with a biopterin deficiency disorder. Plasma deficit of biopterin is common in bipolar disease, schizophrenic and schizoaffective patients. Increasing level of brain BH4 levels may also have a positive effect in Parkinson’s disease.