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Original article
High predictive value of brain MRI imaging in primary mitochondrial respiratory chain deficiency
  1. Isaure de Beaurepaire1,
  2. David Grévent1,2,
  3. Marlène Rio3,
  4. Isabelle Desguerre4,
  5. Pascale de Lonlay4,
  6. Raphaël Levy1,
  7. Volodia Dangouloff-Ros1,2,
  8. Jean-Paul Bonnefont3,
  9. Giulia Barcia3,
  10. Benoit Funalot3,5,
  11. Claude Besmond2,
  12. Metodi D Metodiev2,
  13. Benedetta Ruzzenente2,
  14. Zahra Assouline2,
  15. Arnold Munnich2,3,
  16. Agnès Rötig2,
  17. Nathalie Boddaert1,2
  1. 1 Department of Pediatric Radiology, INSERM UMR 1163 and INSERM U1000, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
  2. 2 IMAGINE Institute, INSERM UMR 1163 and INSERM U1000, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
  3. 3 Department of Genetics, INSERM UMR 1163 and INSERM U1000, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
  4. 4 Department of Neurology and Metabolism, INSERM UMR 1163 and INSERM U1000, Paris Descartes University, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France
  5. 5 Department of Genetics, GHU Henri Mondor, Créteil, France
  1. Correspondence to Dr Isaure de Beaurepaire, Département de Radiopédiatrie, Hôpital Necker-Enfants Malades, Bâtiment Laennec, Paris 75015, France; isaure.debeaurepaire{at}orange.fr

Abstract

Background Because the mitochondrial respiratory chain (RC) is ubiquitous, its deficiency can theoretically give rise to any symptom in any organ or tissue at any age with any mode of inheritance, owing to the twofold genetic origin of respiratory enzyme machinery, that is, nuclear and mitochondrial. Not all respiratory enzyme deficiencies are primary and secondary or artefactual deficiency is frequently observed, leading to a number of misleading conclusions and inappropriate investigations in clinical practice. This study is aimed at investigating the potential role of brain MRI in distinguishing primary RC deficiency from phenocopies and other aetiologies.

Methods Starting from a large series of 189 patients (median age: 3.5 years (8 days–56 years), 58% males) showing signs of RC enzyme deficiency, for whom both brain MRIs and disease-causing mutations were available, we retrospectively studied the positive predictive value (PPV) and the positive likelihood ratio (LR+) of brain MRI imaging and its ability to discriminate between two groups: primary deficiency of the mitochondrial RC machinery and phenocopies.

Results Detection of (1) brainstem hyperintensity with basal ganglia involvement (P≤0.001) and (2) lactate peak with either brainstem or basal ganglia hyperintensity was highly suggestive of primary RC deficiency (P≤0.01). Fourteen items had a PPV>95% and LR+ was greater than 9 for seven signs. Biallelic SLC19A3 mutations represented the main differential diagnosis. Non-significant differences between the two groups were found for cortical/subcortical atrophy, leucoencephalopathy and involvement of caudate nuclei, spinothalamic tract and corpus callosum.

Conclusion Based on these results and owing to invasiveness of skeletal muscle biopsies and cost of high-throughput DNA sequencing, we suggest giving consideration to brain MRI imaging as a diagnostic marker and an informative investigation to be performed in patients showing signs of RC enzyme deficiency.

  • mitochondrial
  • metabolic
  • respiratory chain deficiency
  • OXPHOS
  • MRI
  • brain
  • mitochondrial DNA
  • SLC19A3

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Footnotes

  • Contributors Conception and design of the study: IdB, MR, ID, PdL, J-PB, GB, BF, CB, MDM, BR, ZA, AM, AR, NB. Acquisition and analysis of data: IdB, DG, MR, RL, VD-R, AM, AR, NB. Drafting a significant portion of the manuscript or figures: IdB, DG, MR, ID, PdL, RL, VD-R, J-PB, GB, BF, CB, MDM, BR, ZA, AM, AR, NB.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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