Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 99, Issue 4, Pages 894-902Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2016.07.018
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Funding
- German Bundesministerium fur Bildung and Forschung (BMBF) through the German Network for mitochondrial disorders (mitoNET) [01GM1113A-E]
- E-Rare project GENOMIT [01GM1603]
- Juniorverbund in der Systemmedizin mitOmics [FKZ 01ZX1405C]
- Forschungskommission of the Medical Faculty of the Heinrich-Heine-University Dusseldorf
- CMHI project [S136/13]
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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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