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