Inborn Errors of Ketone Body Metabolism and Transport

Abstract

Major progress occurred in understanding inborn errors of ketone body transport and metabolism between the International Congresses on Inborn Errors of Metabolism in Barcelona (2013) and Rio de Janeiro (2017). These conditions impair either ketogenesis (presenting as episodes of hypoketotic hypoglycemia) or ketolysis (presenting as ketoacidotic episodes); for both groups, immediate intravenous glucose administration is the most critical and (mHGGCS, HMGCS2) effective treatment measure. Ketogenesis Deficiencies: New biomarkers were described for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHGGCS, HMGCS2) deficiency. New patient series refined clinical knowledge of 3-hydroxy-3-methylglutaryl-CoA lyase (HGGCL, HMGCL) deficiency. Although affected humans have not been described, two animal model phenotypes are pertinent: zebrafish deficient in monocarboxylate transporter 7 (MCT7, slc16a6) (decreased ketone body exit from hepatocytes) or mice lacking D-3-hydroxy-n-butyrate dehydrogenase (BDH1, BDH1) (isolated hyperacetoacetatemia; fatty liver). Ketolysis Deficiencies: Monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency is a newly described defect of ketone body transport, joining deficiencies of succinyl-CoA:3-oxoacid CoA transferase (SCOT, OXCT1) and methylacetoacetyl-CoA thiolase (MAT, ACAT1). Some heterozygotes for MCT1 or SCOT deficiency develop ketoacidosis.

2-methylacetoacetyl-coenzyme A thiolase (beta-ketothiolase) deficiency: one disease - two pathways

“…The mitochondrial enzyme 2-methylacetoacetyl-coenzyme A thiolase (MAT; mitochondrial acetoacetyl-coenzyme A thiolase T2/ "beta-ketothiolase"; EC 2.3.1.9) does not only act in ketone body utilization (ketolysis) by catalyzing thiolytic cleavage of acetoacetyl-coenzyme A, but also catalyzes conversion of methylacetoacetyl-coenzyme A in isoleucine catabolism [1] (Fig. 1).…”

“…The number of individuals with confirmed MATD has been estimated to be approximately 250 world-wide [1]. In addition to earlier case reports and case series, four recent retrospective studies have investigated MATD patients of various ethnic backgrounds.…”

3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces

“…The mitochondrial enzyme 3-hydroxy-3-methylglutarylcoenzyme A lyase (HMGCL; EC 4.1.3.4) is required not only for the catabolism of the essential branched-chain amino acid leucine, but also for the synthesis of the ketone bodies acetoacetate and 3-hydroxy-n-butyrate [1]. Ketone bodies are an important source of energy for extrahepatic organs, in particular of the brain, in times of insufficient energy supply.…”

“…Confirmatory testing is available by enzyme activity assays in patient cells and by mutation analysis of the HMGCL gene. Recently, the number of individuals with confirmed HMGCLD has been estimated to be approximately 200 world-wide [1], but most information published so far is from case reports and small retrospective case series. Few studies have presented larger patient cohorts [2][3][4][5][6][7][8].…”

Recurrent ketoacidosis: Is it a ketone metabolism disorder?

“…Son yıllarda yayınlanan literatürde keton metabolizma bozukluklarında tedavide yağ kısıtlaması gerekli olmadığı da bildirilmektedir, ancak yüksek yağ (ketojenik) diyet kaçınılmalıdır (20) .…”