Heterozygous Monocarboxylate Transporter 1 (MCT1, SLC16A1) Deficiency as a Cause of Recurrent Ketoacidosis

Abstract

We describe two half-siblings with monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency, a defect on ketone body utilization, that has only recently been identified (van Hasselt et al., N Engl J Med, 371:1900-1907, 2014) as a cause for recurrent ketoacidoses. Our index patient is a boy with non-consanguineous parents who had presented acutely with impaired consciousness and severe metabolic ketoacidosis following a 3-day history of gastroenteritis at age 5 years. A 12.5-year-old half-brother who shared the proband's mother also had a previous history of recurrent ketoacidoses. Results of mutation and enzyme activity analyses in proband samples advocated against methylacetoacetyl-coenzyme A thiolase ("beta-ketothiolase") and succinyl-coenzyme A: 3-oxoacyl coenzyme A transferase (SCOT) deficiencies. A single heterozygous c.982C>T transition in the SLC16A1 gene resulting in a stop mutation (p.Arg328Ter) was detected in both boys. It was shared by their healthy mother and by the proband's half-sister, but was absent in the proband's father. MCT1 deficiency may be more prevalent than is apparent, as clinical manifestations can occur both in individuals with bi- and monoallelic mutations. It may be an important differential diagnosis in recurrent ketoacidosis with or without hypoglycemia, particularly in the absence of any specific metabolic profiles in blood and urine. Early diagnosis may enable improved disease management. Careful identification of potential triggers of metabolic decompensations in individuals even with single heterozygous mutations in the SLC16A1 gene is indicated.

A SLC16A1 Mutation in an Infant With Ketoacidosis and Neuroimaging Assessment: Expanding the Clinical Spectrum of MCT1 Deficiency

“…Other genetic causes of recurrent ketoacidosis are SCOT deficiency and ACAT1 deficiency, both of which are involved in ketolysis (2). Interestingly, heterozygous mutation in the SLC16A1 gene can also lead to clinical symptoms of MCT1 deficiency (16). It is possible that heterozygous mutation are subjected to nonsense mediated mRNA decay (NMD), where haploinsufficiency is a predicted in vivo mechanism responsible for the phenotypes associated with heterozygous nonsense alleles (17).…”

Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease

“…Obesity, insulin resistance, diabetes Santer et al, 2000Santer et al, , 2003van den Heuvel et al, 2002;Jurczak et al, 2011;Wright et al, 2011;Powell et al, Birkenfeld et al, 2011;Bergeron et al, 2013;Pesta et al, 2015;Brachs et al, 2016; Halestrap and Meredith, 2004;Otonkoski et al, 2007;Pullen et al, 2012;Lengacher et al, 2013;van Hasselt et al, 2014;Balasubramaniam et al, 2016; Obesity Nicholls et al, 1978;Lowell et al, 1993;Kopecky et al, 1995;Kopecký et al, 1996a,b;Baumruk et al, 1999;Li et al, 2000;Palmieri, 2004;Gates et al, 2007; Obesity …”

“…Nevertheless, MCT1 is linked to metabolic traits in humans and in mice ( Table 1). In two independent studies, homozygous and heterozygous SLC16A1 loss-of-function gene mutations were linked to recurrent, severe ketoacidosis in humans (van Hasselt et al, 2014;Balasubramaniam et al, 2016). Ketoacidosis is caused by excess circulating ketone bodies in the face of insulinopenia and is generally a severe complication of diabetes (Nuttall, 1965;Winegrad and Clements, 1971).…”

Ion Transporters, Channelopathies, and Glucose Disorders

“…This increased expression leads to an increased uptake of pyruvate and its metabolism in the Krebs cycle, with a subsequently increased production of ATP and insulin secretion [56]. There are three distinct clinical conditions that have been attributed to the mutation of the SLC16A1 gene: exercise-induced hyperinsulinaemic hypoglycaemia due to an activating mutation, erythrocyte lactate transporter defect, and MCT1 deficiency due to inactivating mutations (Figure 4) [56,57,58,59,60,61,62]. The latter two disorders do not primarily affect the glucose metabolism.…”