NAXE – Leigh syndrome

NAXE encodes NAD(P)HX epimerase, which is critical for mitochondrial NAD(P)H repair. Biallelic pathogenic variants in NAXE have been identified in patients with Leigh syndrome, a subacute necrotizing encephalopathy. In a multi-patient study of 64 LS families, novel NAXE variants were found in 3 probands, expanding the genetic heterogeneity of LS ([PMID:32020600]). Subsequent exome analyses in 2 sisters revealed compound heterozygous c.757G>A (p.Gly253Ser) and c.665-1G>A variants, and additional homozygous missense mutations (c.733A>C (p.Lys245Gln), c.565G>A (p.Gly189Ser), c.641T>A (p.Ile214Asn)) were reported in four further families, totaling 7 probands across 4 unrelated families with autosomal recessive inheritance and segregation ([PMID:31745726];[PMID:34120322];[PMID:35819538]).

Segregation analysis demonstrated affected siblings in two families (total 2 additional affected relatives) with co-segregation of biallelic NAXE variants ([PMID:31745726];[PMID:34120322]). The variant spectrum includes missense, splice-site, and frameshift changes, e.g., c.733A>C (p.Lys245Gln) ([PMID:32020600]) and c.665-1G>A ([PMID:31745726]). Clinical features across cases overlap classical LS symptoms – hypotonia, ataxia, seizures and brain edema on imaging.

Functional studies support a loss-of-function mechanism: fibroblasts from patients with c.665-1G>A showed markedly reduced NAXE transcript and absent protein levels, and vitamin B3/coenzyme Q supplementation led to clinical improvement in one patient ([PMID:31745726]). In silico structural modeling of p.Ile214Asn predicted destabilization of the NAD(P)HX binding site, consistent with impaired enzymatic activity ([PMID:35819538]).

No studies have disputed the NAXE–LS association. The convergence of genetic segregation, variant types, and concordant functional data meets criteria for a strong gene–disease relationship.

Key Take-home: Biallelic NAXE variants cause autosomal recessive Leigh syndrome; molecular diagnosis enables early therapeutic intervention with vitamin B3/coenzyme Q.

References

• Clinical Genetics • 2020 • Genetic heterogeneity in Leigh syndrome: Highlighting treatable and novel genetic causes. PMID:32020600
• Journal of neurology • 2020 • Novel NAXE variants as a cause for neurometabolic disorder: implications for treatment. PMID:31745726
• Acta neurologica Belgica • 2022 • A novel homozygous missense variant in the NAXE gene in an Iranian family with progressive encephalopathy with brain edema and leukoencephalopathy. PMID:34120322
• Neurogenetics • 2022 • Identification of a novel homozygous mutation in NAXE gene associated with early-onset progressive encephalopathy by whole-exome sequencing: in silico protein structure characterization, molecular docking, and dynamic simulation. PMID:35819538

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