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Kremer, L.S. ; Danhauser, K.* ; Herebian, D.* ; Petkovic Ramadža, D.* ; Piekutowska-Abramczuk, D.* ; Seibt, A.* ; Müller-Felber, W.* ; Haack, T.B. ; Płoski, R.* ; Lohmeier, K.* ; Schneider, D.* ; Klee, D.* ; Rokicki, D.* ; Mayatepek, E.* ; Strom, T.M. ; Meitinger, T. ; Klopstock, T.* ; Pronicka, E.* ; Mayr, J.A.* ; Baric, I.* ; Distelmaier, F.* ; Prokisch, H.

NAXE mutations disrupt the cellular NAD(P)HX repair system and cause a lethal neurometabolic disorder of early childhood.

Am. J. Hum. Genet. 99, 894-902 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nad(p)hx ; Energy Metabolism ; Metabolite Repair ; Mitochondrial; Hypertrophic Cardiomyopathy; Skin Rash; Pellagra; Aciduria; Nadph
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Journal American Journal of Human Genetics, The
Quellenangaben Volume: 99, Issue: 4, Pages: 894-902 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)