Monocarboxylate Transporter 1 Deficiency and Ketone Utilization

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

doi:10.1056/NEJMoa1407778

Monocarboxylate Transporter 1 Deficiency and Ketone Utilization

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

^*Corresponding author for this work

GROW - Reproductive and Perinatal Medicine

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1900-1907
Journal	New England Journal of Medicine
Volume	371
Issue number	20
DOIs	https://doi.org/10.1056/NEJMoa1407778
Publication status	Published - 13 Nov 2014

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10.1056/NEJMoa1407778

Cite this

van Hasselt, P. M., Ferdinandusse, S., Monroe, G. R., Ruiter, J. P. N., Turkenburg, M., Geerlings, M. J., Duran, K., Harakalova, M., van der Zwaag, B., Monavari, A. A., Okur, I., Sharrard, M. J., Cleary, M., O'Connell, N., Walker, V., Rubio-Gozalbo, M. E., de Vries, M. C., Visser, G., Houwen, R. H. J., ... van Haaften, G. (2014). Monocarboxylate Transporter 1 Deficiency and Ketone Utilization. New England Journal of Medicine, 371(20), 1900-1907. https://doi.org/10.1056/NEJMoa1407778

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title = "Monocarboxylate Transporter 1 Deficiency and Ketone Utilization",

abstract = "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.",

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

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van Hasselt, PM, Ferdinandusse, S, Monroe, GR, Ruiter, JPN, Turkenburg, M, Geerlings, MJ, Duran, K, Harakalova, M, van der Zwaag, B, Monavari, AA, Okur, I, Sharrard, MJ, Cleary, M, O'Connell, N, Walker, V, Rubio-Gozalbo, ME, de Vries, MC, Visser, G, Houwen, RHJ, van der Smagt, JJ, Verhoeven-Duif, NM, Wanders, RJA & van Haaften, G 2014, 'Monocarboxylate Transporter 1 Deficiency and Ketone Utilization', New England Journal of Medicine, vol. 371, no. 20, pp. 1900-1907. https://doi.org/10.1056/NEJMoa1407778

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AU - van Hasselt, Peter M.

AU - Ferdinandusse, Sacha

AU - Monroe, Glen R.

AU - Ruiter, Jos P. N.

AU - Turkenburg, Marjolein

AU - Geerlings, Maartje J.

AU - Duran, Karen

AU - Harakalova, Magdalena

AU - van der Zwaag, Bert

AU - Monavari, Ardeshir A.

AU - Okur, Ilyas

AU - Sharrard, Mark J.

AU - Cleary, Maureen

AU - O'Connell, Nuala

AU - Walker, Valerie

AU - Rubio-Gozalbo, M. Estela

AU - de Vries, Maaike C.

AU - Visser, Gepke

AU - Houwen, Roderick H. J.

AU - van der Smagt, Jasper J.

AU - Verhoeven-Duif, Nanda M.

AU - Wanders, Ronald J. A.

AU - van Haaften, Gijs

PY - 2014/11/13

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N2 - 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.

AB - 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.

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DO - 10.1056/NEJMoa1407778

M3 - Article

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SN - 0028-4793

VL - 371

SP - 1900

EP - 1907

JO - New England Journal of Medicine

JF - New England Journal of Medicine

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