NAXE Mutations Disrupt the Cellular NAD(P)HX Repair System and Cause a Lethal Neurometabolic Disorder of Early Childhood

Am J Hum Genet. 2016 Oct 6;99(4):894-902. doi: 10.1016/j.ajhg.2016.07.018.

Laura S Kremer ¹, Katharina Danhauser ², Diran Herebian ², Danijela Petkovic Ramadža ³, Dorota Piekutowska-Abramczuk ⁴, Annette Seibt ², Wolfgang Müller-Felber ⁵, Tobias B Haack ¹, Rafał Płoski ⁶, Klaus Lohmeier ², Dominik Schneider ⁷, Dirk Klee ⁸, Dariusz Rokicki ⁹, Ertan Mayatepek ², Tim M Strom ¹, Thomas Meitinger ¹⁰, Thomas Klopstock ¹¹, Ewa Pronicka ¹², Johannes A Mayr ¹³, Ivo Baric ¹⁴, Felix Distelmaier ¹⁵, Holger Prokisch ¹⁶

Affiliations

1 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
2 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
3 Department of Pediatrics, University Hospital Center, 10000 Zagreb, Croatia.
4 Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
5 Department of Pediatric Neurology and Developmental Medicine, Ludwig-Maximilians-University, 80337 Munich, Germany.
6 Department of Medical Genetics, Warsaw Medical University, 02-106 Warsaw, Poland.
7 Clinic of Pediatrics, 44137 Dortmund, Germany.
8 Department of Diagnostic and Interventional Radiology, University Düsseldorf, Medical Faculty, 40225 Düsseldorf, Germany.
9 Department of Pediatrics, Nutrition and Metabolic Diseases, Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
10 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.
11 Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), 80336 Munich, Germany.
12 Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland; Department of Pediatrics, Nutrition and Metabolic Diseases, Department of Medical Genetics, The Children's Memorial Health Institute, 04-730 Warsaw, Poland.
13 Department of Pediatrics, Paracelsus Medical University, 5020 Salzburg, Austria.
14 Department of Pediatrics, University Hospital Center, 10000 Zagreb, Croatia; School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
15 Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany. Electronic address: [email protected].
16 Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany. Electronic address: [email protected].

PMID: 27616477 DOI: 10.1016/j.ajhg.2016.07.018

Abstract

To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The Enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.

Keywords

NAD(P)HX; energy metabolism; metabolite repair; mitochondrial.

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