Neuropediatrics 2017; 48(S 01): S1-S45
DOI: 10.1055/s-0037-1602906
OP – Oral Presentations
Georg Thieme Verlag KG Stuttgart · New York

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

F. Distelmaier
1  Klinik für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
,
L. Kremer
2  Helmholtz Zentrum München, München, Germany
,
K. Danhauser
1  Klinik für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
,
D. Herebian
1  Klinik für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
,
W. Müller-Felber
3  Institut für Humangenetik der TU München, München, Germany
,
T. Haack
2  Helmholtz Zentrum München, München, Germany
,
E. Mayatepek
1  Klinik für Allgemeine Pädiatrie, Neonatologie und Kinderkardiologie, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
,
T. Strom
2  Helmholtz Zentrum München, München, Germany
,
T. Meitinger
2  Helmholtz Zentrum München, München, Germany
,
T. Klopstock
4  Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, München, Germany
,
E. Pronicka
5  Friedrich-Baur-Institut, München, Germany
,
J. Mayr
6  Department of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland
,
I. Baric
7  Salzburger Landeskliniken, Universitätskliniken Salzburg, Salzburg, Austria
,
H. Prokisch
2  Helmholtz Zentrum München, München, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
26 April 2017 (online)

 

Background: 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.

Methods: We used whole-exome sequencing and metabolic profiling for identification and characterization of NAXE defects in children from four unrelated families.

Results: Exome sequencing revealed pathogenic biallelic mutations in NAXE in affected individuals 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.

Conclusion: Our results establish defects in NAXE as a cause of severe neurometabolic disorder with onset in early childhood. Moreover, we suggest that NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.