Disorders of branched chain amino acid metabolism

Abstract

The three essential branched-chain amino acids (BCAAs), leucine, isoleucine and valine, share the first enzymatic steps in their metabolic pathways, including a reversible transamination followed by an irreversible oxidative decarboxylation to coenzyme-A derivatives. The respective oxidative pathways subsequently diverge and at the final steps yield acetyl- and/or propionyl-CoA that enter the Krebs cycle. Many disorders in these pathways are diagnosed through expanded newborn screening by tandem mass spectrometry. Maple syrup urine disease (MSUD) is the only disorder of the group that is associated with elevated body fluid levels of the BCAAs. Due to the irreversible oxidative decarboxylation step distal enzymatic blocks in the pathways do not result in the accumulation of amino acids, but rather to CoA-activated small carboxylic acids identified by gas chromatography mass spectrometry analysis of urine and are therefore classified as organic acidurias. Disorders in these pathways can present with a neonatal onset severe-, or chronic intermittent- or progressive forms. Metabolic instability and increased morbidity and mortality are shared between inborn errors in the BCAA pathways, while treatment options remain limited, comprised mainly of dietary management and in some cases solid organ transplantation.

Keywords: Branched-chain; amino acid; isovaleric; maple syrup urine disease; methylmalonic; mitochondria; organic acidemia; propionic.

Fig.1

Biochemical pathway of branched chain amino acid metabolism. The enzymatic steps for the metabolism of leucine, isoleucine and valine are provided. Shaded boxes include the acronyms of the enzymes. Abbreviations: BCAT = branched chain amino acid aminotransferase; BCKDH: branched chain α-keto-acid dehydrogenase; IVD: isovaleryl CoA dehydrogenase; 3-MCC = 3-methylcrotonyl-CoA carboxylase; 3-MGA = 3-methylglutaconic-CoA hydratase; HMGL = 3-hydroxy-3- methylglutaryl-CoA lyase; SBCAD = methylbutyryl CoA dehydrogenase; MHBD = 2-methyl-3-hydroxyisobutyric dehydrogenase; BKT = mitochondrial acetoacetyl-CoA thiolase; IBDH = isobutyryl-CoA dehydrogenase; HIBDA: 3-hydroxyisobutyryl-CoA deacylase (hydrolase); HIBDH: 3-hydroxyisobutyrate dehydrogenase; MMSDH = methylmalonic semialdehyde dehydrogenase; PCC: propionyl-CoA carboxylase; MUT: methylmalonyl-CoA mutase; SUCLA: succinyl-CoA ligase; TCA cycle: tricarboxylic acid cycle (Krebs).

Fig.2

Leucine metabolic effects in multiple organ systems. Leucine displays a multitude of effects in various organs: enhances protein synthesis, inhibits muscle protein breakdown, stimulates insulin secretion and plays a role in central nervous system food intake regulatory circuits and feeding behavior. Leucine is transported via the large neutral amino acid transporter LAT1 at the blood–brain barrier, among other transporters, and can compete with other large neutral amino acids for uptake/transport affecting neurotransmitter biosynthesis. Lastly, leucine-derived α-ketoisocaproate is a potent inhibitor of the branched-chain ketoacid dehydrogenase-kinase resulting in activation of branched-chain ketoacid dehydrogenase and increased BCAA (valine and isoleucine) oxidation.

Fig.3

Organ pathology in methylmalonic acidemia. Liver and kidney pathology from patients with mut⁰ methylmalonic acidemia are presented. Mild steatosis (A), lipid-laden stellate cells (white arrows) (B), with abnormal mitochondrial ultrastructure on transmission electron microscopy (EM) (pale mitochondria with absent or disorganized cristae, yellow arrowheads) are observed in patient livers. Tubulointerstitial nephritis with patchy interstitial chronic inflammation and tubular dilation (A), proximal tubule vacuolization (B) (white arrows), and enlarged mitochondria with disorganized cristae (yellow arrowhead) along with large remnant vacuoles that contained amorphous membranous inclusions (black arrow) on transmission EM are present in patient kidneys. Pathology was obtained from explanted organs after a combined liver and kidney transplantation procedure. Patients were enrolled in the clinical study: NCT00078078.