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

Autori
Kremer, Laura S. ; Danhauser, Katharina ; Herebian, Diran ; Petkovic Ramadža, Danijela ; Piekutowska-Abramczuk, Dorota ; Seibt, Annette ; Müller-Felber, Wolfgang ; Haack, Tobias B. ; Płoski, Rafał ; Lohmeier, Klaus ; Schneider, Dominik ; Klee, Dirk ; Rokicki, Dariusz ; Mayatepek, Ertan ; Strom, Tim M. ; Meitinger, Thomas ; Klopstock, Thomas ; Pronicka, Ewa ; Mayr, Johannes A. ; Baric, Ivo ; Distelmaier, Felix ; Prokisch, Holger

Izvornik
The American Journal of Human Genetics (0002-9297) 99 (2016), 4; 894-902

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
NAD(P)HX ; energy metabolism ; metabolite repair ; mitochondrial

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti

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