Article Text

Short report
Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation
  1. Ronen Spiegel1,2,
  2. Ann Saada3,
  3. Padraig J Flannery4,
  4. Florence Burté4,
  5. Devorah Soiferman3,
  6. Morad Khayat2,
  7. Verónica Eisner5,
  8. Eugene Vladovski6,
  9. Robert W Taylor4,
  10. Laurence A Bindoff7,
  11. Avraham Shaag3,
  12. Hanna Mandel8,
  13. Ora Schuler-Furman9,
  14. Stavit A Shalev2,
  15. Orly Elpeleg3,
  16. Patrick Yu-Wai-Man4,10
  1. 1Pediatric Department B’, Genetic Institute, Emek Medical Center, Afula, Israel
  2. 2Genetic Institute, Emek Medical Center, Rappaport School of Medicine, Technion, Haifa, Israel
  3. 3Monique and Jacques Roboh Department of Genetic Research, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
  4. 4Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK
  5. 5Department of Cellular and Molecular Biology, School of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
  6. 6Department of Pathology, Rambam Medical Center, Haifa, Israel
  7. 7Department of Clinical Medicine, University of Bergen, Bergen, Norway
  8. 8Metabolic Unit, Rambam Medical Center
  9. 9Department of Microbiology and Molecular Genetics, Hebrew University, Hadassah Medical Center, Jerusalem, Israel
  10. 10Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  1. Correspondence to Dr Ronen Spiegel, Department of Pediatrics B, Emek Medical Center, Afula 18101, Israel; spiegelr{at}, spiegel_ro{at}


Background Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.

Objective To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.

Methods We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.

Results Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients’ muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.

Conclusions We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.

  • Clinical genetics
  • Metabolic disorders
  • Neuroophthalmology
  • Neuromuscular disease

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See:

Statistics from

Supplementary materials

  • Supplementary Data

    This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.