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Heterogeneity of PNPT1 neuroimaging: mitochondriopathy, interferonopathy or both?
  1. Alessandra Pennisi1,2,
  2. Agnès Rötig1,2,
  3. Charles-Joris Roux3,
  4. Raphaël Lévy3,
  5. Marco Henneke4,
  6. Jutta Gärtner4,
  7. Pelin Teke Kisa5,
  8. Fatma Ceren Sarioglu6,
  9. Uluç Yiş7,
  10. Laura L Konczal8,9,
  11. Deepika D Burkardt8,9,10,
  12. Sulin Wu9,11,
  13. Pauline Gaignard12,
  14. Claude Besmond2,
  15. Laurence Hubert2,
  16. Marlène Rio1,
  17. Giulia Barcia1,
  18. Arnold Munnich1,2,
  19. Nathalie Boddaert2,3,
  20. Manuel Schiff1,2,13
  1. 1 Necker Hospital, APHP, Reference Center for Mitochondrial Diseases, Genetics Department, Institut Imagine, University of Paris, Paris, France
  2. 2 Inserm UMR_S1163, Institut Imagine, Paris, France
  3. 3 Necker Hospital, APHP, Pediatric Radiology Department, University of Paris, Paris, France
  4. 4 Department of Paediatrics and Adolescent Medicine, Germany, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany
  5. 5 Pediatric Metabolism and Nutrition, Dokuz Eylül University, Izmir, Turkey
  6. 6 Pediatric Radiology, Dokuz Eylül University, Izmir, Turkey
  7. 7 Pediatric Neurology, Dokuz Eylül University, Izmir, Turkey
  8. 8 Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
  9. 9 Department of Genetics, Case Western Reserve University, Cleveland, OH, USA
  10. 10 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  11. 11 Department of Internal Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
  12. 12 Bicêtre Hospital, APHP, Department of Biochemistry, Bicêtre, France
  13. 13 Necker Hospital, APHP, Reference Center for Inborn Errors of Metabolism, Institut Imagine, University of Paris, Paris, France
  1. Correspondence to Dr Manuel Schiff; manuel.schiff{at}


Background Biallelic variants in PNPT1 cause a mitochondrial disease of variable severity. PNPT1 (polynucleotide phosphorylase) is a mitochondrial protein involved in RNA processing where it has a dual role in the import of small RNAs into mitochondria and in preventing the formation and release of mitochondrial double-stranded RNA into the cytoplasm. This, in turn, prevents the activation of type I interferon response. Detailed neuroimaging findings in PNPT1-related disease are lacking with only a few patients reported with basal ganglia lesions (Leigh syndrome) or non-specific signs.

Objective and methods To document neuroimaging data in six patients with PNPT1 highlighting novel findings.

Results Two patients exhibited striatal lesions compatible with Leigh syndrome; one patient exhibited leukoencephalopathy and one patient had a normal brain MRI. Interestingly, two unrelated patients exhibited cystic leukoencephalopathy resembling RNASET2-deficient patients, patients with Aicardi-Goutières syndrome (AGS) or congenital CMV infection.

Conclusion We suggest that similar to RNASET2, PNPT1 be searched for in the setting of cystic leukoencephalopathy. These findings are in line with activation of type I interferon response observed in AGS, PNPT1 and RNASET2 deficiencies, suggesting a common pathophysiological pathway and linking mitochondrial diseases, interferonopathies and immune dysregulations.

  • brain diseases
  • metabolic

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  • Contributors AP and AR wrote the manuscript; C-JR and RL drafted the manuscript, performed MRI and generated the figure; MH, JG, PTK drafted the ms; FCS, UY, LK, DB, SW drafted the manuscript; PG, CB, LH performed NGS analysis; MR drafted the manuscript; GB generated the supplementary data and wrote the manuscript; AM drafted the manuscript; NB performed MRI interpretation, generated the figure and wrote the manuscript; MS wrote the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.