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

Background: Biallelic loss-of-function 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, -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 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 ( = 6), optic atrophy ( = 2), or was unremarkable ( = 1). All carried homozygous truncating variants, three of which are novel.

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