NDUFA8 – Mitochondrial Complex I Deficiency

The association between NDUFA8 and mitochondrial complex I deficiency is supported by multiple independent lines of evidence. Case reports have identified patients with biallelic mutations in NDUFA8, including a case with a homozygous variant and another report of two affected siblings, establishing a strong clinical link (PMID:32385911, PMID:33153867). These reports document key clinical features such as global developmental delay, microcephaly, and seizures, all of which align with the expected phenotype of complex I deficiency. The genetic studies include supportive segregation analysis within families and recurrence of damaging variants in unrelated individuals.

Genetic evidence indicates an autosomal recessive inheritance pattern. The reported molecular abnormalities include loss‐of‐function and missense variants, with an exemplar mutation being c.139C>T (p.Arg47Cys). This variant has been identified in at least one patient where homozygosity confirmed the recessive mode (PMID:32385911). In addition, further reports, including cases from broader multi‐patient studies, reinforce the contribution of biallelic pathogenic variants in NDUFA8 to the disease phenotype (PMID:15576045).

Functional experiments have played a pivotal role in elucidating the pathogenic mechanism. Patient fibroblasts demonstrated marked reduction in NDUFA8 protein expression and complex I assembly. Importantly, rescue experiments showed that reintroduction of wild‑type NDUFA8 cDNA restored enzyme activity and oxygen consumption rates, thereby confirming the deleterious effect of the mutation on mitochondrial function (PMID:32385911). These in vitro studies, including complementation in knockout models, provide robust functional evidence that supports the gene–disease association.

There is no significant conflicting evidence detracting from this association. Although one multi‐patient study also reported mutations in other complex I subunits, the recurrence and specificity of NDUFA8 variants, in conjunction with detailed functional assays, leave little doubt regarding its role in disease pathogenesis. The convergence of genetic data and functional rescue experiments across independent studies underpins the clinico‐molecular link.

In summary, multiple independent reports have documented biallelic loss‐of‑function and missense mutations in NDUFA8 leading to profound complex I deficiency. Both segregation in familial cases and functional restoration of enzyme activity upon gene complementation substantiate a strong association between NDUFA8 and mitochondrial complex I deficiency. This integrated evidence strengthens the diagnostic utility and highlights the potential for targeted clinical management based on molecular findings.

Key Take‑home: NDUFA8 mutations are strongly linked to mitochondrial complex I deficiency, supporting their use in diagnostic decision‑making and tailored therapeutic strategies.

References

• Clinical genetics • 2020 • A homozygous variant in NDUFA8 is associated with developmental delay, microcephaly, and epilepsy due to mitochondrial complex I deficiency PMID:32385911
• Molecular genetics and metabolism • 2020 • Biallelic mutations in NDUFA8 cause complex I deficiency in two siblings with favorable clinical evolution PMID:33153867
• Biochimica et biophysica acta • 2004 • Clinical and molecular findings in children with complex I deficiency PMID:15576045
• American journal of human genetics • 2001 • Large‑scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency PMID:11349233

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