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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., Competing Interests: Biological samples from pedigree C were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA) and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Biological samples from pedigree D were collected as part of the project RAC# 2121053. Francesca Magrinelli is supported by the Edmond J. Safra Foundation and by the research grant “Fondo Gianesini” in collaboration with UniCredit Foundation and University of Verona, Italy. Robert W. Taylor is supported by the Wellcome Centre for Mitochondrial Research (203,105/Z/16/Z), the MRC International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), Mitochondrial Disease Patient Cohort (UK) (G0800674), the UK NIHR Biomedical Research Centre for Aging and Age‐related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, The Lily Foundation, the Pathology Society and the UK NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children. Kailash P. Bhatia has received grant support from Wellcome/MRC, NIHR, Parkinson's UK and EU Horizon 2020. Tobias B. Haack was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—418081722, 433158657. Kate Sargeant thanks the UK NHS Specialist Commissioners, which funds the “Rare Mitochondrial Disease Service for Adults and Children” in Oxford for their support. The views expressed are those of the author(s) and not necessarily those of the NHS or the UK Department of Health and Social Care. Rita Horvath is a Wellcome Trust Investigator (109,915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1 and MR/V009346/1), the European Research Council (309548), the Newton Fund (UK/Turkey, MR/N027302/1), the Addenbrookes Charitable Trust (G100142), the Evelyn Trust, the Stoneygate Trust, the Lily Foundation and an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20,014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Henry Houlden is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). The authors declare that there are no conflicts of interest relevant to this work., (© 2021 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)