NDUFAF2 – Leigh syndrome

NDUFAF2 is associated with autosomal recessive Leigh syndrome, characterized by early-onset neurodegeneration with predominant brainstem involvement. Biallelic loss-of-function variants have been reported in 15 unrelated probands (PMID:20571988; PMID:38419071), supporting a strong gene–disease association.

The initial case described a male infant presenting with severe apnea and nystagmus, brainstem lesions without basal ganglia or thalamus involvement on MRI, and normal plasma lactate. He harbored a homozygous stop variant c.9G>A (p.Trp3Ter) and succumbed within 2 months; neuropathology confirmed Leigh disease (PMID:20571988).

In a European multicenter cohort of 130 Leigh syndrome patients, NDUFAF2 was one of 77 genes implicated; the cohort exhibited seizures in 40% (HP:0001250), failure to thrive (HP:0001508), and increased CSF lactate (HP:0002490), mirroring features in NDUFAF2-deficient individuals (PMID:24731534).

A recent case series added four new patients with homozygous partial deletions of exons 2–4 and recurrent stop or frameshift alleles (including c.9G>A (p.Trp3Ter)), plus ten previously reported cases. All presented between 5 and 18 months with growth retardation, ophthalmological impairments (nystagmus, strabismus), life-threatening apnea, progressive brainstem and later basal ganglia lesions, and early lethality (PMID:38419071).

Functional assays in NDUFAF2-deficient human neuroblastoma cells and mouse fibroblasts demonstrated intact Complex I assembly but reduced enzyme activity, elevated oxidative stress, and mitochondrial DNA deletions, indicating a chaperone-like role in folding kinetics (PMID:23702311).

Baculovirus-mediated complementation of patient fibroblasts carrying the Tyr38Ter variant restored Complex I assembly and activity, confirming causality of the NDUFAF2 truncating mutation (PMID:19384974).

Mechanistically, biallelic LoF variants impair Complex I function via defective folding rather than assembly blockade, leading to brainstem-selective neurodegeneration. No conflicting reports have been published. Key Take-home: NDUFAF2 should be included in diagnostic panels for infantile Leigh syndrome with predominant brainstem changes, even if lactate levels are normal.

References

• Neuropediatrics • 2010 • Leigh disease with brainstem involvement in complex I deficiency due to assembly factor NDUFAF2 defect. PMID:20571988
• Orphanet Journal of Rare Diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534
• Orphanet Journal of Rare Diseases • 2024 • Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality. PMID:38419071
• Neurobiology of Disease • 2013 • The mitochondrial disease associated protein Ndufaf2 is dispensable for Complex-1 assembly but critical for the regulation of oxidative stress. PMID:23702311
• Human Mutation • 2009 • Baculovirus complementation restores a novel NDUFAF2 mutation causing complex I deficiency. PMID:19384974

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