Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma

Abstract

We have previously reported that pathogenic variants in a key metabolite repair enzyme NAXD cause a lethal neurodegenerative condition triggered by episodes of fever in young children. However, the clinical and genetic spectrum of NAXD deficiency is broadening as our understanding of the disease expands and as more cases are identified. Here, we report the oldest known individual succumbing to NAXD-related neurometabolic crisis, at 32 years of age. The clinical deterioration and demise of this individual were likely triggered by mild head trauma. This patient had a novel homozygous NAXD variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of NAXD transcripts, leaving only trace levels of canonically spliced NAXD mRNA, and protein levels below the detection threshold by proteomic analysis. Accumulation of damaged NADH, the substrate of NAXD, could be detected in the fibroblasts of the patient. In agreement with prior anecdotal reports in paediatric patients, niacin-based treatment also partly alleviated some clinical symptoms in this adult patient. The present study extends our understanding of NAXD deficiency by uncovering shared mitochondrial proteomic signatures between the adult and our previously reported paediatric NAXD cases, with reduced levels of respiratory complexes I and IV as well as the mitoribosome, and the upregulation of mitochondrial apoptotic pathways. Importantly, we highlight that head trauma in adults, in addition to paediatric fever or illness, may precipitate neurometabolic crises associated with pathogenic NAXD variants.

Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

“…Niacin was used in previously reported patients as a therapeutic option that might ameliorate the PEBEL-1 and PEBEL-2 symptoms (Table 1). [2][3][4]9,[11][12][13]15 Our patient received the largest niacin dose reported for PEBEL-1 treatment up to 600 mg per day. [2][3][4]9,[11][12][13]15 There was clear transient improvement in the encephalopathic state and neurological symptoms with each dose increment.…”

“…[2][3][4]9,[11][12][13]15 Our patient received the largest niacin dose reported for PEBEL-1 treatment up to 600 mg per day. [2][3][4]9,[11][12][13]15 There was clear transient improvement in the encephalopathic state and neurological symptoms with each dose increment. Despite the fact that he decompensated shortly after each dose increment, transient improvement was clearly evident.…”

“…A total of 19 articles were found concerning PEBEL-1 and PEBEL-2 describing a total of 45 patients. 2,[11][12][13][14][15][16][17][18][19] 32 patients were found to have PEBEL-1 and 13 patients were found to have PEBEL-2. Eight patients were treated…”

“…with niacin from the two groups. [2][3][4]8,[11][12][13] Among those, five had PEBEL-1 and three had PEBEL-2 (Table 1).…”

“…10 Therefore, niacin administration has been shown to pause clinical deterioration of patients with PEBEL-1 and PEBEL-2 and provide protection against the fatal outcome of these disorders. [2][3][4]8,11,12 In fact, no patient treated with niacin has succumbed to death as anticipated by the natural history of the disease. The longest follow-up period described so far is 7 years.…”