NDUFA1 – Leigh syndrome

NDUFA1 (HGNC:7683) encodes the MWFE subunit of mitochondrial complex I. Leigh syndrome (MONDO:0009723) is a progressive neurodegenerative disorder of childhood. To date, two unrelated male patients hemizygous for NDUFA1 missense variants have been reported. One infant presented with atypical spinal cord involvement on MRI due to an unidentified hemizygous NDUFA1 mutation ((PMID:29506883)) and a second patient harbored c.55C>T (p.Pro19Ser), confirmed as pathogenic in cybrid assays ((PMID:25356405)). Conversely, a screen of 152 complex I–deficient patients, including Leigh syndrome cases, did not identify additional NDUFA1 mutations, indicating these alleles are rare ((PMID:11286378)). Clinical hallmarks include seizures, increased CSF lactate, and failure to thrive ((PMID:24731534)).

Functional studies demonstrate that p.Pro19Ser markedly reduces complex I activity in cybrid and patient fibroblast assays ((PMID:25356405)). An X-linked Ndufa1^S55A^ mouse model recapitulates systemic partial complex I deficiency with age-dependent neurodegeneration, supporting a loss-of-function mechanism ((PMID:28506826)). No studies to date have refuted the NDUFA1–Leigh syndrome link beyond the absence of common variants. Together, genetic and experimental data support a Limited level of clinical validity for X-linked recessive NDUFA1 deficiency in Leigh syndrome. Key take-home: hemizygous pathogenic missense variants in NDUFA1 cause partial complex I deficiency manifesting as Leigh syndrome, guiding molecular diagnosis and genetic counseling.

References

• Brain & development • 2018 • Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation. PMID:29506883
• Orphanet journal of rare diseases • 2014 • A multicenter study on Leigh syndrome: disease course and predictors of survival. PMID:24731534
• Journal of inherited metabolic disease • 2001 • Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain. PMID:11286378
• Annals of clinical and translational neurology • 2014 • New MT-ND6 and NDUFA1 mutations in mitochondrial respiratory chain disorders. PMID:25356405
• Neurochemistry international • 2017 • An X-chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases. PMID:28506826

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