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Genotype-phenotype correlations
Original article
The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease
  1. Yi Shiau Ng1,
  2. Charlotte L Alston1,
  3. Daria Diodato2,
  4. Andrew A Morris3,
  5. Nicole Ulrick4,
  6. Stanislav Kmoch5,
  7. Josef Houštěk6,
  8. Diego Martinelli7,
  9. Alireza Haghighi8,9,
  10. Mehnaz Atiq10,
  11. Montserrat Anton Gamero11,
  12. Elena Garcia-Martinez11,
  13. Hana Kratochvílová12,
  14. Saikat Santra13,
  15. Ruth M Brown14,
  16. Garry K Brown14,
  17. Nicola Ragge15,27,
  18. Ahmad Monavari16,
  19. Karen Pysden17,
  20. Kirstine Ravn18,
  21. Jillian P Casey19,
  22. Arif Khan20,
  23. Anupam Chakrapani21,
  24. Grace Vassallo22,
  25. Cas Simons23,
  26. Karl McKeever24,
  27. Siobhan O'Sullivan24,
  28. Anne-Marie Childs17,
  29. Elsebet Østergaard18,
  30. Adeline Vanderver4,
  31. Amy Goldstein25,
  32. Julie Vogt26,
  33. Robert W Taylor1,
  34. Robert McFarland1
  1. 1Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
  2. 2Neuromuscular and Neurodegenerative Disease Unit, Children Research Hospital Bambino Gesù, Rome, Italy
  3. 3Department of Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK
  4. 4Department of Neurology, George Washington University Medical School, Children's National Health System, Washington, DC, USA
  5. 5First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, Prague, Czech Republic
  6. 6Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
  7. 7Division of Metabolism, Children Research Hospital Bambino Gesù, Rome, Italy
  8. 8Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA
  9. 9Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA
  10. 10Department of Pediatrics, Aga Khan University, Karachi, Pakistan
  11. 11Pediatric Nephrology Unit, Hospital Universitario Reina Sofia, Cordoba, Spain
  12. 12Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic
  13. 13Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK
  14. 14Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK
  15. 15Clinical Genetics Unit, West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK
  16. 16National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland
  17. 17Department of Paediatric Medicine, Leeds General Infirmary, Leeds, UK
  18. 18Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  19. 19Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland
  20. 20Leicester Children's Hospital, Leicester Royal Infirmary, Leicester, UK
  21. 21Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK
  22. 22Department of Paediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  23. 23Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia
  24. 24Department of Paediatric Medicine, The Royal Belfast Hospital for Sick Children, Belfast, UK
  25. 25Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
  26. 26Department of Medical and Molecular Genetics, Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
  27. 27Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK
  1. Correspondence to Dr Robert McFarland, Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; robert.mcfarland{at}newcastle.ac.uk

Abstract

Background Mutations in the RMND1 (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.

Methods We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with RMND1 mutations. In addition, we reviewed all the previously published cases to determine the genotype–phenotype correlates and performed survival analysis to identify prognostic factors.

Results We identified 14 new cases from 11 pedigrees that harbour recessive RMND1 mutations, including 6 novel variants: c.533C>A, p.(Thr178Lys); c.565C>T, p.(Gln189*); c.631G>A, p.(Val211Met); c.1303C>T, p.(Leu435Phe); c.830+1G>A and c.1317+1G>T. Together with all previously published cases (n=32), we show that congenital sensorineural deafness, hypotonia, developmental delay and lactic acidaemia are common clinical manifestations with disease onset under 2 years. Renal involvement is more prevalent than seizures (66% vs 44%). In addition, median survival time was longer in patients with renal involvement compared with those without renal disease (6 years vs 8 months, p=0.009). The neurological phenotype also appears milder in patients with renal involvement.

Conclusions The clinical phenotypes and prognosis associated with RMND1 mutations are more heterogeneous than that were initially described. Regular monitoring of kidney function is imperative in the clinical practice in light of nephropathy being present in over 60% of cases. Furthermore, renal replacement therapy should be considered particularly in those patients with mild neurological manifestation as shown in our study that four recipients of kidney transplant demonstrate good clinical outcome to date.

  • mitochondrial respiratory chain deficiencies
  • renal disease
  • congenital sensorineural deafness
  • prognosis
  • lactic acidosis

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: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/jmedgenet-2016-103910

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    Footnotes

    • Contributors Conception or design of the work: RWT and RMF; data acquisition, analysis and interpretation: all authors; drafting the manuscript: YSN, CLA, DD, RWT and RMF; critical review and final approval of the manuscript: all authors; RMF and RWT are listed as guarantors of the paper.

    • Funding This work was supported by the Wellcome Trust (096919Z/11/Z and 074454/Z/04/Z to RWT), the Medical Research Council (G0601943 and G0800674 to RM and RWT) and the UK NHS Specialised Services and Newcastle upon Tyne Hospitals NHS Foundation Trust supporting the ‘Rare Mitochondrial Disorders of Adults and Children’ Diagnostic Service (http://www.newcastle-mitochondria.com/). CLA is the recipient of a National Institute for Health Research (NIHR) doctoral fellowship (NIHR-HCS-D12-03-04). SK was funded by Charles University institutional programmes PRVOUK-P24/LF1/3 and by BIOCEV—Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (CZ.1.05/1.1.00/02.0109), from the European Regional Development Fund. This work was specifically supported by grants 14-36804G from the Grant Agency of the Czech Republic, LH12015 from the Ministry of Education of the Czech Republic and 15-28208A from the Ministry of Education and Ministry of Health of the Czech Republic. The genomic facility used in this work has been supported by grant OPPK.CZ.2.16/3.100/24022.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval NRES Committee East Midlands-Derby (REC 13/EM/0029), American University’s Institutional Review Board.

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