NDUFV1 – Leigh Syndrome

NADH:ubiquinone oxidoreductase flavoprotein 1 (NDUFV1) encodes a 51-kDa core subunit of mitochondrial complex I and is causally linked to autosomal recessive Leigh syndrome ([MONDO:0009723]) (PMID:27344648). Leigh syndrome is a subacute necrotizing encephalomyopathy characterized by developmental regression, lactic acidosis, symmetrical brain lesions, and diverse neurological signs.

Biallelic NDUFV1 variants have been reported in over 20 unrelated patients exhibiting classic Leigh syndrome features, including compound heterozygous splice-site and missense mutations, as well as homozygous founder alleles ([PMID:27344648]; [PMID:30090137]). Segregation of pathogenic alleles was confirmed in consanguineous families with two affected siblings carrying homozygous c.1157G>A (p.Arg386His) variants ([PMID:21696386]).

The variant spectrum includes canonical splice-site changes (c.1162+4A>C), missense substitutions (c.640G>A (p.Glu214Lys)), truncating deletions (c.756delC (p.Thr253GlnfsTer44)), and novel hypomorphic alleles (c.118C>T (p.Arg40Trp)). Recurrent p.Glu214Lys and p.Arg386Cys/His variants have been observed in multiple ethnic backgrounds, suggesting possible founder effects in specific populations ([PMID:32871395]; [PMID:29976978]).

Functional assays in patient fibroblasts demonstrate a 60–95% reduction in NDUFV1 protein levels, impaired complex I assembly, and corresponding enzyme activity decreases of 38–67% across tissues (brain, muscle, liver) ([PMID:27344648]). Yeast complementation and cellular rescue experiments confirm loss of function for p.Glu214Lys and p.Arg386His and restoration of complex I upon wild-type NDUFV1 expression ([PMID:26345448]; [PMID:33182419]).

Additional case series expand the phenotypic spectrum to include late-onset ataxia, dystonia, hypotonia, ptosis, scoliosis, and postural instability, with global developmental delay being a near-universal feature ([PMID:30090137]; [PMID:35482246]). No conflicting reports have disputed the pathogenicity of biallelic NDUFV1 variants in Leigh syndrome.

Overall, the NDUFV1–Leigh syndrome relationship meets ClinGen criteria for a definitive gene–disease association, supported by multiple independent pedigrees, clear autosomal recessive segregation, and concordant functional evidence. Key Take-home: Genetic testing for NDUFV1 should be prioritized in suspected Leigh syndrome to facilitate early diagnosis, prognostication, and genetic counseling.

References

• JIMD reports • 2017 • Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but Little Biochemical Evidence of a Mitochondrial Disorder [PMID:27344648]
• Journal of pediatric neurosciences • 2018 • Late-Onset Leigh Syndrome due to NDUFV1 Mutation in a 10-Year-Old Boy Initially Presenting with Ataxia. [PMID:30090137]
• Stem cell research • 2020 • Induced pluripotent stem cell line UOMi002-A from a patient with Leigh syndrome with compound heterozygous mutations in the NDUFV1 gene. [PMID:32871395]
• Clinical genetics • 2012 • A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. [PMID:21696386]
• Genes • 2020 • Leigh Syndrome Due to NDUFV1 Mutations Initially Presenting as LBSL. [PMID:33182419]
• Human molecular genetics • 2015 • Characterization of clinically identified mutations in NDUFV1, the flavin-binding subunit of respiratory complex I, using a yeast model system. [PMID:26345448]
• Genes & genomics • 2022 • Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency. [PMID:35482246]
• Cureus • 2024 • Leigh Syndrome Caused by Compound Heterozygous Variants c.1162A_C and c.1138G_C in the NDUFV1 Gene: A Case Report. [PMID:39525154]

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