Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy

Mov Disord Clin Pract. 2022 Jan 3;9(2):218-228. doi: 10.1002/mdc3.13398. eCollection 2022 Feb.


Background: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only.

Objectives: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease.

Methods: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature.

Results: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel.

Conclusions: Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.

Keywords: Leigh syndrome; NDUFA12; dystonia; optic atrophy; phenotypic heterogeneity.