Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Florence Habarou; Yamina Hamel; Tobias B Haack; René G Feichtinger; Elise Lebigot; Iris Marquardt; Kanetee Busiah; Cécile Laroche; Marine Madrange; Coraline Grisel; Clément Pontoizeau; Monika Eisermann; Audrey Boutron; Dominique Chrétien; Bernadette Chadefaux-Vekemans; Robert Barouki; Christine Bole-Feysot; Patrick Nitschke; Nicolas Goudin; Nathalie Boddaert; Ivan Nemazanyy; Agnès Delahodde; Stefan Kölker; Richard J Rodenburg; G Christoph Korenke; Thomas Meitinger; Tim M Strom; Holger Prokisch; Agnes Rotig; Chris Ottolenghi; Johannes A Mayr; Pascale de Lonlay

doi:10.1016/j.ajhg.2017.07.001

Biallelic Mutations in LIPT2 Cause a Mitochondrial Lipoylation Defect Associated with Severe Neonatal Encephalopathy

Am J Hum Genet. 2017 Aug 3;101(2):283-290. doi: 10.1016/j.ajhg.2017.07.001. Epub 2017 Jul 27.

Authors

Florence Habarou¹, Yamina Hamel², Tobias B Haack³, René G Feichtinger⁴, Elise Lebigot⁵, Iris Marquardt⁶, Kanetee Busiah⁷, Cécile Laroche⁸, Marine Madrange², Coraline Grisel⁷, Clément Pontoizeau¹, Monika Eisermann⁹, Audrey Boutron⁵, Dominique Chrétien¹⁰, Bernadette Chadefaux-Vekemans¹, Robert Barouki¹, Christine Bole-Feysot¹¹, Patrick Nitschke¹², Nicolas Goudin¹³, Nathalie Boddaert¹⁴, Ivan Nemazanyy¹⁵, Agnès Delahodde¹⁶, Stefan Kölker¹⁷, Richard J Rodenburg¹⁸, G Christoph Korenke⁶, Thomas Meitinger¹⁹, Tim M Strom¹⁹, Holger Prokisch¹⁹, Agnes Rotig¹⁰, Chris Ottolenghi¹, Johannes A Mayr²⁰, Pascale de Lonlay²¹

Affiliations

¹ Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; Metabolic Biochemistry, University Paris Descartes, Hospital Necker Enfants Malades, 75015 Paris, France.
² Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; UMR1163, University Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
³ Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
⁴ Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
⁵ Department of Biochemistry, Hospital Bicêtre, APHP, 94270 Le Kremlin Bicêtre, France.
⁶ Department of Neuropediatrics, Children's Hospital Klinikum Oldenburg, Oldenburg 26133, Germany.
⁷ Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France.
⁸ Neurology Unit, Limoges Hospital, 87042 Limoges, France.
⁹ Neurophysiology Unit, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; INSERM U1129, Paris, France; Paris Descartes University; CEA, Gif sur Yvette; Paris, France.
¹⁰ UMR1163, University Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
¹¹ Genomic Core Facility, Imagine Institute, UMR1163, University Paris Descartes, 24 Boulevard du Montparnasse, 75015 Paris, France; Hospital Necker Enfants Malades, APHP, 75015 Paris, France.
¹² Paris Descartes Bioinformatic Platform, University Paris Descartes, Hospital Necker Enfants Malades, 75015 Paris, France.
¹³ Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; Neurophysiology Unit, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; INSERM U1129, Paris, France; Paris Descartes University; CEA, Gif sur Yvette; Paris, France.
¹⁴ Department of Pediatric Radiology, Hospital Necker Enfants Malades, AP-HP, University René Descartes, PRES Sorbonne Paris Cité, INSERM U1000, Institut Imagine 24 Boulevard du Montparnasse, 75015 Paris, France.
¹⁵ Faculty of Medicine, Paris Descartes University, Paris 75015, France; Necker Enfants Malades Institute, INSERM U1151, Paris Descartes University, 75015 Paris, France.
¹⁶ Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, University Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France.
¹⁷ Department of General Pediatrics, Division of Pediatric Neurology and Inherited Metabolic Diseases, University Children's Hospital, 69120 Heidelberg, Germany.
¹⁸ Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Radboud UMC, Nijmegen, the Netherlands.
¹⁹ Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
²⁰ Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria. Electronic address: h.mayr@salk.at.
²¹ Reference Center of Inherited Metabolic Diseases, University Paris Descartes, Hospital Necker Enfants Malades, APHP, 75015 Paris, France; UMR1163, University Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France. Electronic address: pascale.delonlay@aphp.fr.

Abstract

Lipoate serves as a cofactor for the glycine cleavage system (GCS) and four 2-oxoacid dehydrogenases functioning in energy metabolism (α-oxoglutarate dehydrogenase [α-KGDHc] and pyruvate dehydrogenase [PDHc]), or amino acid metabolism (branched-chain oxoacid dehydrogenase, 2-oxoadipate dehydrogenase). Mitochondrial lipoate synthesis involves three enzymatic steps catalyzed sequentially by lipoyl(octanoyl) transferase 2 (LIPT2), lipoic acid synthetase (LIAS), and lipoyltransferase 1 (LIPT1). Mutations in LIAS have been associated with nonketotic hyperglycinemia-like early-onset convulsions and encephalopathy combined with a defect in mitochondrial energy metabolism. LIPT1 deficiency spares GCS deficiency and has been associated with a biochemical signature of combined 2-oxoacid dehydrogenase deficiency leading to early death or Leigh-like encephalopathy. We report on the identification of biallelic LIPT2 mutations in three affected individuals from two families with severe neonatal encephalopathy. Brain MRI showed major cortical atrophy with white matter abnormalities and cysts. Plasma glycine was mildly increased. Affected individuals' fibroblasts showed reduced oxygen consumption rates, PDHc, α-KGDHc activities, leucine catabolic flux, and decreased protein lipoylation. A normalization of lipoylation was observed after expression of wild-type LIPT2, arguing for LIPT2 requirement in intramitochondrial lipoate synthesis. Lipoic acid supplementation did not improve clinical condition nor activities of PDHc, α-KGDHc, or leucine metabolism in fibroblasts and was ineffective in yeast deleted for the orthologous LIP2.

Keywords: LIPT2; encephalopathy; hyperglycinemia; lipoic acid; metabolic flux; pyruvate dehydrogenase; α-oxoglutarate dehydrogenase.

MeSH terms

Acyltransferases / genetics*
Amino Acids / metabolism
Atrophy / pathology*
Brain / diagnostic imaging
Brain / pathology*
Brain Diseases / genetics*
Brain Diseases / pathology
Brain Mapping / methods
Cells, Cultured
Energy Metabolism / genetics
Energy Metabolism / physiology
Glycine / blood
Humans
Infant, Newborn
Lipoylation / genetics*
Magnetic Resonance Imaging
Mitochondria / genetics
Mitochondria / metabolism*
Oxygen Consumption / genetics
Protein Binding / genetics
Thioctic Acid / metabolism

Substances

Amino Acids
Thioctic Acid
Acyltransferases
lipoyltransferase II
Glycine

Grants and funding

I 2741/FWF_/Austrian Science Fund FWF/Austria