NDUFAF8 and Leigh Syndrome

NDUFAF8 encodes a mitochondrial complex I (CI) assembly factor whose deficiency leads to isolated CI dysfunction and the classical neurodegenerative presentation of Leigh syndrome. Bi-allelic pathogenic variants in NDUFAF8 have been reported in a total of four unrelated pediatric subjects, and each case exhibits hallmark symmetrical basal ganglia and brainstem lesions on neuroimaging consistent with Leigh syndrome. The inheritance is autosomal recessive with compound heterozygous or homozygous variants identified by diagnostic next-generation sequencing.

In the initial report, three unrelated children harbored bi-allelic variants including c.45_52dup (p.Phe18fs), c.165C>G (p.Phe55Leu), c.1A>G (p.Met1Val), and a recurrent deep-intronic splice variant c.195+271C>T, each yielding a CI assembly defect (PMID:31866046). A subsequent case confirmed the phenotype and premature death in a fourth patient with a similar biochemical defect (PMID:39921456).

The variant spectrum comprises two truncating alleles, one missense change, and one deep-intronic splice mutation. The recurrent c.195+271C>T splicing variant was observed in multiple subjects, underscoring the need to analyze non-coding regions when only a single variant is detected. All alleles are absent or extremely rare in population databases.

Clinically, NDUFAF8-deficient patients present in infancy with global developmental delay (HP:0001263), seizures (HP:0001250), failure to thrive (HP:0001508), and increased CSF lactate (HP:0002490), mirroring the predominant features and poor survival predictors observed in large Leigh syndrome cohorts (PMID:24731534).

Functional validation in patient fibroblasts demonstrates isolated CI deficiency and stalled assembly intermediates. Lentiviral transduction of wild-type NDUFAF8 cDNA restores both CI assembly and enzymatic activity, confirming a loss-of-function mechanism and early assembly role (PMID:31866046).

Together, genetic and experimental data provide moderate evidence that bi-allelic NDUFAF8 variants cause autosomal recessive Leigh syndrome. Inclusion of NDUFAF8 in mitochondrial and CI gene panels is recommended for accurate molecular diagnosis and genetic counseling.

References

• American journal of human genetics • 2020 • Pathogenic Bi-allelic Mutations in NDUFAF8 Cause Leigh Syndrome with an Isolated Complex I Deficiency. PMID:31866046
• American journal of medical genetics. Part A • 2025 • Mitochondrial DNA or Genomic DNA Variant(s): Utility of Exhaustive Sequencing in Leigh Syndrome. PMID:39921456
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534

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