Disorders of Phenylalanine and Tetrahydrobiopterin Metabolism

Abstract

Hyperphenylalaninemia (HPA), a disorder of phenylalanine catabolism, is caused primarily by a deficiency of the hepatic phenylalanine-4-hydroxylase (PAH) or by one of the enzymes involved in its cofactor tetrahydrobiopterin (BH4) biosynthesis (GTP cyclohydrolase I (GTPCH) and 6-pyruvoyl-tetrahydropterin synthase (PTPS)) or regeneration (dihydropteridine reductase (DHPR) and pterin carbinolamine-4a-dehydratase (PCD)) (Blau et al. 2001). BH4 is known to be the natural cofactor for PAH, all three isoforms of nitric oxide synthase (NOS), tyrosine-3-hydroxylase, as well as tryptophan-5-hydroxylase (Werner et al. 2011), the latter two being the key enzymes in the biosynthesis of the neurotransmitters dopamine and serotonin. Thus, with two exceptions (see below) any cofactor defect will result in a deficiency of biogenic amines accompanied by HPA. Because phenylalanine is a competitive inhibitor of the uptake of tyrosine and tryptophan and other LNAA across the blood-brain barrier and of the hydroxylases of tyrosine and tryptophan, depletion of catecholamines and serotonin occurs in untreated patients with PAH deficiency. Both groups of HPA (PAH and BH4 deficiency) are heterogeneous disorders varying from severe to mild and benign forms. Because of the different clinical and biochemical severities in this group of diseases, the terms “severe” or “mild” will be used based upon the type of treatment and involvement of the CNS. For the BH4 defects, symptoms may manifest during the first weeks of life, but usually are noted within the first 6 months of life. Birth is generally uneventful, except for an increased incidence of prematurity and lower birth weights in severe PTPS deficiency (Opladen et al. 2012).