Pegvaliase (Palynziq®): A Comprehensive Pharmacological and Clinical Monograph for the Management of Phenylketonuria

Introduction to Phenylketonuria and the Rationale for Enzyme Substitution Therapy

The Pathophysiology of Phenylalanine Hydroxylase (PAH) Deficiency

Phenylketonuria (PKU), also known as phenylalanine hydroxylase (PAH) deficiency, is a rare, autosomal recessive inborn error of metabolism that represents one of the most common inherited disorders of amino acid metabolism.[1] The genetic defect underlying PKU results in a deficiency or absence of the hepatic enzyme phenylalanine hydroxylase, which is essential for the catalytic conversion of the essential amino acid L-phenylalanine (Phe) to L-tyrosine.[1] In the United States, the incidence of PKU is estimated to be approximately 1 in 10,000 to 15,000 live births, with a global prevalence of around 70,000 individuals in the regions where its primary therapeutic developer, BioMarin Pharmaceutical, operates.[1]

The metabolic block in the phenylalanine pathway leads to a cascade of pathophysiological consequences. Unable to be converted to tyrosine, phenylalanine accumulates in the blood and other tissues, a condition known as hyperphenylalaninemia.[1] This excess phenylalanine is shunted into alternative metabolic pathways, leading to the production of metabolites such as phenylpyruvic acid. The primary driver of pathology, however, is the high concentration of phenylalanine itself. Elevated blood Phe levels facilitate its transport across the blood-brain barrier, leading to the accumulation of neurotoxic concentrations of Phe within the central nervous system.[1] This neurotoxicity is the central mechanism responsible for the severe clinical manifestations of the disease if left untreated.

Clinical Manifestations and Long-Term Sequelae of Uncontrolled Hyperphenylalaninemia