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

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

Francesca Magrinelli  1   2 , Elisa Cali  3 , Vinícius Lopes Braga  4 , Uluç Yis  5 , Hoda Tomoum  6 , Hanan Shamseldin  7 , Julian Raiman  8 , Christoph Kernstock  9 , Flávio Moura Rezende Filho  4 , Orlando Graziani Povoas Barsottini  4 , Robert W Taylor  10 , Elsebet Østergaard  11   12 , Abdullah Tamim  13 , Karin Schäferhoff  14 , Juliana Maria Ferraz Sallum  15 , Maha S Zaki  16 , Fernando Kok  17   18 , Kailash P Bhatia  1 , Bernd Wissinger  9 , Kate Sergeant  19 , Tobias B Haack  14   20 , Rita Horvath  21 , Semra Hiz  5 , Fowzan S Alkuraya  22   23 , Henry Houlden  3 , José Luiz Pedroso  4 , Reza Maroofian  3
Affiliations

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

Francesca Magrinelli et al. Mov Disord Clin Pract. .

Abstract

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.

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Conflict of interest statement

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.

Figures

FIG. 1
FIG. 1
Overview of NDUFA12‐associated phenotype–genotype correlations. (A) Family trees of nine new cases herein reported and their ethnicity. Arrows identify probands. Symbols filled in with black and gray indicate homozygotes for the mutant allele who are symptomatic and asymptomatic, respectively. Half‐filled symbols represent asymptomatic heterozygous carriers of the mutant allele; wt = wild type. (B) Brain MRI of Case 1 (left, T2‐FLAIR sequence) showing hyperintense signal of the bilateral lenticular nucleus, and Case 2 (middle, T2 sequence; right, T2‐FLAIR sequence). (C) Video frames of Case 2, highlighting dystonic‐pyramidal features, kyphoscoliosis, and generalized muscle atrophy, and Case 4, showing dystonic involvement of hands and trunk as well as kyphoscoliosis. (D) Case 8: (i) Color fundus oculi showing pale optic discs and decentralized excavation with narrow temporal rim on the left eye (yellow arrow); arterial tortuosity is seen in both eyes and a choroidal nevus can be found on the right eye (green arrow). (ii) Red free photos that highlight the arteriolar tortuosity (light blue arrow). (iii) Panoramic fundus oculi picture depicts no retinal abnormalities. (iv) Normal fundus oculi autofluorescence in both eyes. (E) Case 9: Optical coherence tomography (OCT) showed markedly reduced thickness of the peripapillary nerve fiber layer. (F) Schematic of the wide phenotypic spectrum associated with biallelic loss‐of‐function variants in NDUFA12, including dystonia, pyramidal signs, and optic atrophy, either isolated or in different combinations, and additional less prevalent features (yellow oval). (G) Schematic of the NDUFA12 gene with variants hitherto reported, including those reported in the present case series (highlighted in red; novel variants also underlined). The number of symptomatic subjects carrying the variant reported so far is indicated in squared brackets.
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