NDUFB8 – Leigh syndrome

NDUFB8 encodes an accessory subunit of mitochondrial complex I. Biallelic variants in NDUFB8 have been identified in two unrelated individuals with infantile-onset Leigh syndrome, confirming its role in early neurodegenerative mitochondrial disease (PMID:29429571). A retrospective multicenter cohort of 130 Leigh syndrome patients revealed pathogenic mutations in 77 individuals, highlighting NDUFB8 among other nuclear-encoded complex I subunits implicated in this disorder (PMID:24731534). The convergence of independent genetic and functional data underpins the clinical validity of this gene–disease association.

Inheritance is autosomal recessive. Two probands from distinct families harbor compound heterozygous NDUFB8 variants: c.432C>G (p.Cys144Trp) and c.189del (p.Glu63fs) in one family, and c.227C>A (p.Pro76Gln) with c.184T>C (p.Tyr62His) in the other (PMID:29429571). No additional segregating affected relatives were reported. These variants include two missense changes and one frameshift, all predicted deleterious and absent from population databases.

Functional studies demonstrate loss of NDUFB8 immunoreactivity in muscle cryosections from patients with NDUFB8 mutations, using a validated quadruple immunofluorescent assay and BN-PAGE analysis (PMID:29142257). Complementation by expression of wild-type NDUFB8 in patient fibroblasts fully restored complex I enzymatic activity, confirming a direct pathogenic effect of these variants (PMID:29429571).

Clinically, affected individuals present with muscular hypotonia, failure to thrive, respiratory insufficiency, lactic acidosis, and encephalopathic features consistent with Leigh syndrome. Epileptic seizures (HP:0001250), increased CSF lactate (HP:0002490) and failure to thrive (HP:0001508) are common and correlate with disease severity and poor prognosis in large Leigh syndrome cohorts (PMID:24731534).

Mechanistically, NDUFB8 variants impair complex I assembly and activity via a loss-of-function mechanism. Restoration of NDUFB8 expression rescues mitochondrial respiratory capacity, underscoring its critical role in the oxidative phosphorylation apparatus.

Overall, two unrelated probands with biallelic NDUFB8 variants and concordant functional assays provide moderate clinical validity for the association between NDUFB8 and Leigh syndrome. Inclusion of NDUFB8 in diagnostic gene panels is recommended for early identification of complex I–related mitochondrial disorders.

References

• Orphanet Journal of Rare Diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534
• Scientific Reports • 2017 • Using a quantitative quadruple immunofluorescent assay to diagnose isolated mitochondrial Complex I deficiency. PMID:29142257
• American Journal of Human Genetics • 2018 • NDUFB8 Mutations Cause Mitochondrial Complex I Deficiency in Individuals with Leigh-like Encephalomyopathy. PMID:29429571

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