The recent description of biallelic DNAJC30 variants in Leber hereditary optic neuropathy (LHON) and Leigh syndrome challenged the longstanding assumption for LHON to be exclusively maternally inherited and broadened the genetic spectrum of Leigh syndrome, the most frequent paediatric mitochondrial disease. Herein, we characterize 28 so far unreported individuals from 26 families carrying a homozygous DNAJC30 p.Tyr51Cys founder variant, 24 manifesting with LHON, two manifesting with Leigh syndrome, and two remaining asymptomatic. This collection of unreported variant carriers confirms sex-dependent incomplete penetrance of the homozygous variant given a significant male predominance of disease and the report of asymptomatic homozygous variant carriers. The autosomal recessive LHON patients demonstrate an earlier age of disease onset and a higher rate of idebenone-treated and spontaneous recovery of vision in comparison to reported figures for maternally inherited disease. Moreover, the report of two additional patients with childhood- or adult-onset Leigh syndrome further evidences the association of DNAJC30 with Leigh syndrome, previously only reported in a single childhood-onset case.

Center for the Treatment of Pediatric Neurodegenerative Disease The University of Texas McGovern Medical School at Houston Houston USA

Centre for Inherited Metabolic Diseases Karolinska University Hospital Stockholm Sweden

Department of Audiology and Phoniatrics The Children's Memorial Health Institute Warsaw Poland

Department of Diagnostic Imaging The Children's Memorial Health Institute Warsaw Poland

Department of Medical Genetics The Children's Memorial Health Institute Warsaw Poland

Department of Neuro Ophthalmology St Erik Eye Hospital Stockholm Sweden

Department of Neurology Friedrich Baur Institute University Hospital of the Ludwig Maximilians Universität München Munich Germany

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Paediatrics Metabolic Disease Center Klinikum Reutlingen Reutlingen Germany

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Federal State Budgetary Institution of Science 'Research Institute of Eye Diseases' Moscow Russia

Genetics and Metabolic Clinic St Luke's Health System Boise USA

German Center for Neurodegenerative Diseases Munich Germany

Institute of Human Genetics School of Medicine Technische Universität München München Germany

Institute of Neurogenomics Helmholtz Zentrum München München Germany

IRCCS Istituto delle Scienze Neurologiche di Bologna Programma di Neurogentica Bologna Italy

Munich Cluster of Systems Neurology Munich Germany

Research Centre for Medical Genetics Moscow Russia

Unit of Neurology Department of Biomedical and NeuroMotor Sciences University of Bologna Italy

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