title: The clinical, biochemical and genetic features associated withRMND1-related mitochondrial disease.
abstract: BACKGROUND
  Mutations in theRMND1(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 withRMND1mutations. 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 recessiveRMND1mutations, 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 withRMND1mutations 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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Yi Shiau
authors.initials: YS
authors.lastname: Ng
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Neuromuscular and Neurodegenerative Disease Unit, Children Research Hospital Bambino Gesù, Rome, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Diodato
authors.affiliation: Department of Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Morris
authors.affiliation: Department of Neurology, George Washington University Medical School, Children's National Health System, Washington, DC, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Ulrick
authors.affiliation: First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, Prague, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kmoch
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Houštěk
authors.affiliation: Division of Metabolism, Children Research Hospital Bambino Gesù, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Martinelli
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Alireza
authors.initials: A
authors.lastname: Haghighi
authors.affiliation: Department of Pediatrics, Aga Khan University, Karachi, Pakistan.
authors.forename: Mehnaz
authors.initials: M
authors.lastname: Atiq
authors.affiliation: Pediatric Nephrology Unit, Hospital Universitario Reina Sofia, Cordoba, Spain.
authors.forename: Montserrat Anton
authors.initials: MA
authors.lastname: Gamero
authors.affiliation: Pediatric Nephrology Unit, Hospital Universitario Reina Sofia, Cordoba, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Garcia-Martinez
authors.affiliation: Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Kratochvílová
authors.affiliation: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Brown
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: Garry K
authors.initials: GK
authors.lastname: Brown
authors.affiliation: Clinical Genetics Unit, West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.|Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ragge
authors.affiliation: National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Monavari
authors.affiliation: Department of Paediatric Medicine, Leeds General Infirmary, Leeds, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Pysden
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Ravn
authors.affiliation: Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.affiliation: Leicester Children's Hospital, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Arif
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
authors.forename: Anupam
authors.initials: A
authors.lastname: Chakrapani
authors.affiliation: Department of Paediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
authors.forename: Grace
authors.initials: G
authors.lastname: Vassallo
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Cas
authors.initials: C
authors.lastname: Simons
authors.affiliation: Department of Paediatric Medicine, The Royal Belfast Hospital for Sick Children, Belfast, UK.
authors.forename: Karl
authors.initials: K
authors.lastname: McKeever
authors.affiliation: Department of Paediatric Medicine, The Royal Belfast Hospital for Sick Children, Belfast, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: O'Sullivan
authors.affiliation: Department of Paediatric Medicine, Leeds General Infirmary, Leeds, UK.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Childs
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Elsebet
authors.initials: E
authors.lastname: Østergaard
authors.affiliation: Department of Neurology, George Washington University Medical School, Children's National Health System, Washington, DC, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.affiliation: Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Goldstein
authors.affiliation: Department of Medical and Molecular Genetics, Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Vogt
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
keywords: congenital sensorineural deafness; lactic acidosis; mitochondrial respiratory chain deficiencies; prognosis; renal disease