NDUFA13 – Mitochondrial Complex I Deficiency, Nuclear Type 28

Biallelic variants in NDUFA13 have been associated with mitochondrial complex I deficiency, nuclear type 28, a moderate-to-severe neurodevelopmental disorder presenting in early childhood. In a cohort of 13 affected individuals from 11 unrelated families, patients exhibited oculomotor abnormalities (84%), spasticity/hypertonia (83%), hypotonia (69%), cerebellar ataxia (66%), movement disorders (58%) and seizures (46%) (PMID:39963288). Neuroimaging consistently revealed bilateral symmetric T2 hyperintense substantia nigra lesions and optic nerve atrophy.

Genetic evidence supports autosomal recessive inheritance. Four missense variants—including the recurrent c.170G>A (p.Arg57Gln)—and three ultra-rare predicted loss-of-function variants were identified in trans in all probands, with segregation confirmed in two families having multiple affected siblings (PMID:39963288).

Functional studies demonstrate that patient fibroblasts harboring NDUFA13 variants have markedly reduced complex I enzymatic activity and compensatory complex IV upregulation. Protein structural modeling indicates that missense substitutions destabilize a critical junction between the hydrophilic and membrane arms of complex I, impairing assembly and electron transfer (PMID:39963288).

GRIM-19 (NDUFA13) loss-of-function underlies disease pathogenesis via impaired complex I assembly and mitochondrial membrane potential collapse. Independent deletion and truncation analyses in cell models confirm that disruption of GRIM-19 abrogates membrane potential maintenance, sensitizing cells to apoptotic stimuli (PMID:18287540).

No conflicting reports have been documented to date, and the phenotypic and molecular findings are highly concordant across all studied families. Together, the genetic and experimental data robustly support a pathogenic role for biallelic NDUFA13 variants in mitochondrial complex I deficiency, nuclear type 28.

Key take-home: Biallelic NDUFA13 variants cause a distinct early-onset neurodevelopmental syndrome through loss of complex I function, establishing diagnostic and potential therapeutic avenues.

References

• Brain communications • 2025 • Biallelic NDUFA13 variants lead to a neurodevelopmental phenotype with gradual neurological impairment. PMID:39963288
• Molecular biology of the cell • 2008 • GRIM-19 is essential for maintenance of mitochondrial membrane potential. PMID:18287540

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