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

• Published in: International journal of molecular sciences Vol. 24; no. 4; p. 3582
• Main Authors: Van Bergen, Nicole J, Gunanayagam, Karen, Bournazos, Adam M, Walvekar, Adhish S, Warmoes, Marc O, Semcesen, Liana N, Lunke, Sebastian, Bommireddipalli, Shobhana, Sikora, Tim, Patraskaki, Myrto, Jones, Dean L, Garza, Denisse, Sebire, Dale, Gooley, Samuel, McLean, Catriona A, Naidoo, Parm, Rajasekaran, Mugil, Stroud, David A, Linster, Carole L, Wallis, Mathew, Cooper, Sandra T, Christodoulou, John
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.02.2023; MDPI
• Subjects: Adult; Adults; Amino acids; Apoptosis; Atrophy; Blood; Brain Concussion - complications; Brain Concussion - genetics; Brain Diseases, Metabolic - etiology; Brain Diseases, Metabolic - genetics; Case Report; Child; Child, Preschool; Convulsions & seizures; Dehydration; Fatty acids; febrile illness; Fever; Fibroblasts; Genomes; Head injuries; Humans; Hydro-Lyases - metabolism; Intensive care; Kinases; Magnetic resonance imaging; Metabolism; metabolite repair; Metabolites; Mitochondria; Mitochondria - metabolism; Mucositis; NAD - metabolism; NAXD deficiency; NAXE deficiency; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Nicotinamide adenine dinucleotide; oral ulcers; Ostomy; Patients; Pediatrics; Peptides; Proteins; Proteomics; Signs and symptoms; Splicing; Trauma; NAXE deficiency; metabolite repair; NAXD deficiency; skin lesions; oral ulcers; neurodegeneration; metabolism; myoclonic encephalopathy; febrile illness
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24043582

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 variant [NM_001242882.1:c.441+3A>G:p.?] that induces the mis-splicing of the majority of transcripts, leaving only trace levels of canonically spliced 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 variants.