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
Institute of Human Genetics, Technische Universität München, 81675 München, Germany; Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Am J Hum Genet. 2016 Oct 6;99(4):894-902. doi: 10.1016/j.ajhg.2016.07.018. Epub 2016 Sep 8.
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.
为保护细胞免受潜在有害代谢中间体的积累影响，特定的修复机制已经进化出来。APOA1BP，现更名为NAXE，编码一种对NADHX和NADPHX的细胞代谢物修复至关重要的差向异构酶。该酶催化NAD(P)HX的差向异构化，从而避免有毒代谢物的积累。NAD(P)HX修复系统的临床重要性一直未知。外显子组测序揭示了来自四个患有（亚）急性发作共济失调、小脑水肿、脊髓病和皮肤病变的家庭的儿童中NAXE存在致病性双等位基因突变。所有受影响个体的脑脊液中乳酸水平升高。疾病发作发生在生命的第二年，发热感染会引发临床症状以及病情恶化。病程进展迅速，导致所有受影响个体昏迷、全脑萎缩，最终死亡。在两个家庭的受影响个体的成纤维细胞中检测不到NAXE水平。在这些成纤维细胞中，我们测量到有毒代谢物环状NADHX的浓度高度升高，证实线粒体NAD(P)HX修复系统存在缺陷。最后，补充NAD或烟酸（维生素B3）可能对这种致命疾病具有治疗意义。
