NDUFA3 – Leigh Syndrome

NDUFA3 encodes a core subunit of mitochondrial complex I essential for oxidative phosphorylation. A single non-consanguineous family with three affected siblings presenting early-onset abnormalities in muscle tone, delayed gross motor and language development, and basal ganglia and brainstem lesions has been reported. Genetic analysis revealed compound heterozygous NDUFA3 variants segregating with disease in all affected members (3 probands) (PMID:39661167).

Minigene splicing assays demonstrated that one of the identified variants abrogates normal transcript processing, supporting a loss-of-function mechanism consistent with mitochondrial complex I deficiency (PMID:39661167). While this report establishes a plausible link between NDUFA3 and Leigh syndrome, additional unrelated cases and in vivo models are needed to reach higher clinical validity. Key Take-home: NDUFA3 should be included in genetic testing panels for suspected Leigh syndrome with complex I deficiency.

References

• Neurogenetics • 2024 • Identification of a novel pathogenic gene, NDUFA3, in Leigh Syndrome through whole exome sequencing. PMID:39661167

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