Submission Details

The relationship between NAXD and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 22, 2024. NAXD encodes NAD(P)HX dehydratase, which reconverts S-NAD(P)HX to S-NAD(P)H, preventing the accumulation of toxic metabolites.

The NAXD gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2019 (PMID: 30576410), in a cohort of children with illness-induced neurodegeneration or cardiac failure and early death. While various names have been given to the constellation of features seen in those with NAXD-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the NAXD phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework.

Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included 11 unique variants reported in eight cases from three publications (PMIDs: 30576410, 32462209, 31755961). The maximum score for case-level data was reached in this curation; however we note that, in total, there appear to be 14 affected individuals from 13 families reported in the medical literature (additional PMIDs: 33224489, 34161859, 35231119, 36834994, 38214124). Six missense, one splice, and four frameshift variants were included in this curation. Age of onset in reported individuals was typically early childhood although one case had longstanding milder features and did not have a serious event until his 30s (PMID: 36834994). Features in affected individuals include typically severe neurodegeneration and multisystem disease after illness (with periods of improvement and subsequent deterioration), cardiac involvement, skin lesions, movement disorder, gait changes, seizures, anemia, pancytopenia, ophthalmoplegia, sensorineural hearing loss, and cataracts. Most affected individuals died early in life, however some had a more stable course. Treatment with niacin has been proposed, with reported stabilization of features in at least one individual (PMID: 35231119). Muscle biopsy results were variable including low to normal respiratory chain enzyme activities. Imaging showed basal ganglia changes, temporal and frontal lobe atrophy, and cerebellar atrophy. Elevated lactate and creatine kinase levels were also seen.

This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease, functional alteration in patient cells, and rescue in patient cells (PMIDs: 33340416, 30576410, 24717771).

In summary, there is definitive evidence to support the relationship between NAXD and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 22, 2024 (SOP Version 10).