Journal Article

Monocarboxylate Transporter 1 Deficiency and Ketone Utilization

Sharrard, Mark J, de Vries, Maaike C, van der Smagt, Jasper J, van Haaften, Gijs, van der Zwaag, Bert, Rubio-Gozalbo, M. Estela, Geerlings, Maartje J, Ferdinandusse, Sacha, Okur, Ilyas, Verhoeven-Duif, Nanda M, Monavari, Ardeshir A, Houwen, Roderick H.J, Duran, Karen, van Hasselt, Peter M, O’Connell, Nuala, Walker, Valerie, Turkenburg, Marjolein, Harakalova, Magdalena, Ruiter, Jos P.N, Cleary, Maureen, Monroe, Glen R, Visser, Gepke, Wanders, Ronald J.A

2014

Overview

Ketoacidosis is a potentially lethal condition caused by the imbalance between hepatic production and extrahepatic utilization of ketone bodies. We performed exome sequencing in a patient with recurrent, severe ketoacidosis and identified a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 ( SLC16A1 , also called MCT1 ). Genetic analysis in 96 patients suspected of having ketolytic defects yielded seven additional inactivating mutations in MCT1 , both homozygous and heterozygous. Mutational status was found to be correlated with ketoacidosis severity, MCT1 protein levels, and transport capacity. Thus, MCT1 deficiency is a novel cause of profound ketoacidosis; the present work suggests that MCT1-mediated ketone-body transport is needed to maintain acid–base balance. Ketoacidosis is potentially lethal. The authors of this study found a homozygous frameshift mutation in the gene encoding monocarboxylate transporter 1 ( MCT1 ) in a patient with recurrent, severe ketoacidosis and additional inactivating mutations in MCT1 in 96 other patients. Acetoacetate and 3-hydroxybutyrate are slightly acidic biomolecules that, together with acetone, are called ketone bodies and serve as the major circulating energy source during fasting. Ketone bodies are formed in the liver from the ultimate breakdown product of fatty acids — acetyl coenzyme A (CoA) — by coupling of two acetyl units in a three-step enzymatic process called ketogenesis. Ketone bodies are believed to undergo passive distribution to metabolically active tissues, where they are used as an energy source. 1 Ketoacidosis, a pathologic state, occurs when ketone formation exceeds ketone utilization. The clinical consequences of ketoacidosis are exemplified by diabetic ketoacidosis, . . .

• Publisher: Massachusetts Medical Society
• Subject: Biological and medical sciences / Biological Transport / Child / Child, Preschool / Diabetic ketoacidosis / Frameshift Mutation / General aspects / Genes / Genetic analysis / Genotype / Humans / Infant / Ketoacidosis / Ketone Bodies - metabolism / Ketones / Ketones - metabolism / Ketosis - genetics / Liver / Medical sciences / Monocarboxylic Acid Transporters - deficiency / Monocarboxylic Acid Transporters - genetics / Monocarboxylic Acid Transporters - physiology / Mutation / Organic chemicals / Polymorphism, Single Nucleotide / Protein transport / Symporters - deficiency / Symporters - genetics / Symporters - physiology