NDUFA4 – Leigh Syndrome

Leigh syndrome is a genetically heterogeneous mitochondrial disorder characterized by neurodevelopmental regression, lactic acidosis, and characteristic brainstem and basal ganglia lesions. Biallelic loss-of-function variants in NDUFA4 have been implicated in a subset of cases, defining a recessive form of Complex IV deficiency presenting as Leigh syndrome (LS) (PMID:23746447, PMID:38674434).

Autosomal recessive inheritance is established by segregation of a homozygous splice-donor variant in a consanguineous pedigree with two affected siblings and by a homozygous 12.9 Kb deletion in an unrelated patient. To date, 3 probands across 2 independent families have been reported, with segregation in affected sib-pairs confirming biallelic involvement ([PMID:23746447], [PMID:38674434]).

The primary variant described in early-onset cases is a splice donor site mutation, c.42+1G>C, which disrupts normal mRNA processing and is observed in homozygosity in affected individuals. A separate patient harbored a homozygous genomic deletion fully encompassing NDUFA4, identified by whole-genome sequencing.

Functional assays demonstrate that NDUFA4 loss leads to undetectable protein by western blot and immunocytochemistry, significantly reduced complex IV enzymatic activity in patient fibroblasts, and altered assembly of the COX holoenzyme on blue-native gels. These concordant experimental data confirm a loss-of-function mechanism with resultant mitochondrial respiratory chain deficiency ([PMID:23746447], [PMID:38674434]).

No conflicting evidence disputing the association between NDUFA4 biallelic variants and Leigh syndrome has been reported to date.

Collectively, genetic and functional evidence support a moderate strength association between autosomal recessive NDUFA4 deficiency and Leigh syndrome. Testing for NDUFA4 variants should be considered in patients with unexplained complex IV deficiency presenting with neurodevelopmental regression and lactic acidosis. Key Take-home: Biallelic NDUFA4 loss-of-function variants cause a recessive form of Leigh syndrome via complex IV deficiency, with clear diagnostic and therapeutic implications.

References

• Genes • 2024 • Biallelic NDUFA4 Deletion Causes Mitochondrial Complex IV Deficiency in a Patient with Leigh Syndrome. PMID:38674434
• Cell reports • 2013 • NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. PMID:23746447

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