NAXD – NAD(P)HX Dehydratase Deficiency

Nicotinamide adenine dinucleotide phosphate hydrate dehydratase (NAXD) is a key enzyme in the repair of the toxic metabolite NAD(P)HX. Biallelic loss of NAXD function causes progressive encephalopathy with brain edema and/or leukoencephalopathy (PEBEL2; MONDO:0034121), often precipitated by febrile illness or other stressors. A recent infant presented after routine immunizations with encephalopathy and skin lesions in the absence of fever, expanding the clinical spectrum of NAXD deficiency (PMID:38214124).

In an initial cohort of eight unrelated individuals with PEBEL2, exome sequencing identified six truncating and six missense variants in NAXD in a homozygous or compound heterozygous state (PMID:34161859). This study added a novel homozygous missense variant c.301G>A (p.Ala101Thr) to the spectrum. A subsequent adult case harbored a homozygous splice‐region variant c.441+3A>G leading to aberrant NAXD transcripts (PMID:36834994). In total, nine independent probands have been reported with consistent autosomal recessive inheritance.

The variant spectrum in NAXD includes at least six truncating (loss‐of‐function), seven missense, and one splice‐region variant. No recurrent or founder alleles have been described to date. Representative pathogenic variants include c.301G>A (p.Ala101Thr).

Functional studies demonstrate that splice‐region and truncating variants result in markedly reduced or absent NAXD protein, accumulation of damaged NADH/NADPH species, and downstream mitochondrial proteomic alterations including reduced respiratory complex I and IV subunits. Patient fibroblasts treated with niacin partially restored NAD(P)HX repair and ameliorated biochemical defects ([PMID:36834994]).

The mechanism underpinning PEBEL2 is loss‐of‐function of NAXD leading to toxic NAD(P)HX accumulation and mitochondrial dysfunction. Concordant clinical phenotypes across unrelated families, biochemical biomarkers, and rescue by niacin support the pathogenicity of biallelic NAXD variants.

Key Take‐home: Biallelic loss‐of‐function variants in NAXD cause autosomal recessive NAD(P)HX dehydratase deficiency (PEBEL2); genetic testing enables diagnosis and niacin‐based interventions may modify disease course.

References

• European Journal of Medical Genetics • 2021 • NAD(P)HX dehydratase (NAXD) deficiency due to a novel biallelic missense variant and review of literature PMID:34161859
• International Journal of Molecular Sciences • 2023 • Severe NAD(P)HX Dehydratase (NAXD) Neurometabolic Syndrome May Present in Adulthood after Mild Head Trauma PMID:36834994
• American Journal of Medical Genetics Part A • 2024 • Progressive encephalopathy after routine 4-month immunizations in a patient with NAXD genetic variant PMID:38214124

Evidence Based Scoring (AI generated)