NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses

NAXD Deficiency Associated with Perinatal Autoinflammation, Pancytopenia, Dermatitis, Colitis, and Cystic Encephalomalacia

“…Here, we report the fulminant course of NAXD deficiency in a neonate presenting with severe clinical signs of autoinflammation, necrotizing dermatitis, ulcerative colitis, pancytope-nia, and cystic encephalomalacia. Unlike previously described cases with NAXD deficiency, who presented with first symptoms between 3 months and 3 years of age, 10,11 the patient developed disease already in the third week of life. NAD(P)HX dehydratase encoded by the NAXD gene is an ubiquitously expressed integral component of the mitochondrial matrix involved in an essential metabolite repair system that removes toxic NAD(P)HX side products.…”

“…Recently, mutations in NAXE (five families) as well as NAXD (seven patients) have been associated with an earlyonset neurodegenerative disorder exacerbated by febrile illness. [8][9][10][11] Here, we reported a previously unknown homozygous stop-gain frameshift variant in NAXD in an infant who presented with a fulminant course of autoinflammation, dermatitis, colitis, and cystic encephalomalacia. pathogenesis of type 1 interferonopathies approved by the ethics committee (EK 386102017) of the Faculty of Medicine, Technische Universität Dresden.…”

NAD + homeostasis in human health and disease

“…Mutations in the NAXD gene have also been associated with accumulation of aberrant metabolites and neurological disorders. Three independent studies have demonstrated the consequences of NAXD deficiency (Van Bergen et al, 2019;Borna et al, 2020;Zhou et al, 2020), which resemble those found in patients with NAXE deficiency. These include accumulation of NADHX but unaltered NAD(P)H levels (Van Bergen et al, 2019), complex I deficiencies (Van Bergen et al, 2019;Borna et al, 2020), and reduced cytochrome c oxidase activity (Van Bergen et al, 2019).…”

“…Inherited deficiencies of NAXE or NAXD cause fever-induced, severe multisystemic disorders, including ataxia, cerebellar edema, respiratory insufficiency, and skin lesions, followed by rapid neurological deterioration and premature demise (Kremer et al, 2016;Spiegel et al, 2016;Van Bergen et al, 2019;Borna et al, 2020;Zhou et al, 2020). In two different studies with a total of eleven subjects, homozygous or compound heterozygous mutations in NAXE caused devastating neurological disorders (Kremer et al, 2016;Spiegel et al, 2016).…”

Genetic basis of mitochondrial diseases

“…Such heterogeneity hampers both their diagnosis and management, and many patients remain in a diagnostic odyssey, visiting different clinicians, repeating sometimes invasive tests, and even receiving a false or conflicting diagnosis. Besides cofactor deficiencies [4], there are still no curative treatments for mitochondrial disorders, and the treatment strategies are usually Abbreviations AD, autosomal dominant; AR, autosomal recessive; CNV, copy number variation; GWAS, genome-wide association study; LHON, Leber's hereditary optic neuropathy; lncRNA, long noncoding RNA; LRS, long-read sequencing; miRNA, microRNA; ncRNA, noncoding RNA; NGS, next-generation sequencing technologies; ORF, open reading frame; OXPHOS, oxidative phosphorylation; RNA-seq, RNA-sequencing; scRNA-seq, single-cell RNA-seq; SV, structural variant; uORF, upstream open reading frame; WES, whole exome sequencing; WGS, whole genome sequencing.…”