Inborn errors of amino acid metabolism - from underlying pathophysiology to therapeutic advances

Abstract

Amino acids are organic molecules that serve as basic substrates for protein synthesis and have additional key roles in a diverse array of cellular functions, including cell signaling, gene expression, energy production and molecular biosynthesis. Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. Individually, these disorders are rare, but collectively, they represent an important group of potentially treatable disorders. In this Clinical Puzzle, we discuss the pathophysiology, clinical features and management of three disorders that showcase the diverse clinical presentations of disorders of amino acid metabolism: phenylketonuria, lysinuric protein intolerance and homocystinuria due to cystathionine β-synthase (CBS) deficiency. Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies aimed at improving the morbidity and mortality associated with this diverse group of disorders.

Keywords: Amino acids; Inborn errors of metabolism; Newborn screen.

Fig. 1.

Three genetic disorders of amino acid metabolism. (A) Phenylketonuria is caused by defects in phenylalanine hydroxylase (PAH) that result in the inability to metabolize phenylalanine to tyrosine, leading to toxic accumulation of phenylalanine. PAH activity depends on the cofactor tetrahydrobiopterin (BH4), meaning that certain PAH deficiencies can be ameliorated by increasing the availability of BH4. (B) The cationic amino acid (CAA) transporter complex y(+) L-type amino acid transporter 1 (y+LAT1)-4F2hc is responsible for importing ornithine, arginine and lysine and for exporting various neutral amino acids (NAAs), whereas the b^0,+ amino acid transporter (b^0,+AT) imports CAAs and exports NAAs in epithelial cells, and the CAT1 and CAT2 transporters (encoded by SLC7A1 and SLC7A2, respectively) import CAAs in non-epithelial cells. Lysinuric protein intolerance is caused by defects in the y+LAT1 subunit of y+LAT1-4F2hc, which results in insufficient CAA transport in epithelial and non-epithelial cells, leading to malabsorption and secondary defects in the urea cycle. (C) Classical homocystinuria is caused by a defect in cystathionine β-synthase (CBS), which metabolizes homocysteine to cystathione with vitamin B6 as cofactor, leading to toxic accumulation of methionine and homocysteine.