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.

1st Faculty of Medicine Institute for Inherited Metabolic Disorders Charles University Prague Prague Czech Republic

Clinical Genetics Unit West Midlands Regional Genetics Service Birmingham Women's NHS Foundation Trust Birmingham UK

Department of Clinical Genetics Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Clinical Genetics Temple Street Children's University Hospital Dublin Ireland

Department of Clinical Inherited Metabolic Disorders Birmingham Children's Hospital NHS Foundation Trust Birmingham UK

Department of Genetic Medicine Central Manchester University Hospitals NHS Foundation Trust St Mary's Hospital Manchester UK

Department of Genetics Harvard Medical School Boston Massachusetts USA

Department of Medical and Molecular Genetics Centre for Rare Diseases and Personalised Medicine School of Clinical and Experimental Medicine University of Birmingham Birmingham UK

Department of Medicine and the Howard Hughes Medical Institute Brigham and Women's Hospital Boston Massachusetts USA

Department of Metabolic Medicine Great Ormond Street Hospital NHS Foundation Trust London UK

Department of Neurology George Washington University Medical School Children's National Health System Washington DC USA

Department of Paediatric Medicine Leeds General Infirmary Leeds UK

Department of Paediatric Medicine The Royal Belfast Hospital for Sick Children Belfast UK

Department of Paediatric Neurology Central Manchester University Hospitals NHS Foundation Trust Manchester UK

Department of Pediatrics Aga Khan University Karachi Pakistan

Department of Pediatrics and Adolescent Medicine 1st Faculty of Medicine Charles University Prague and General University Hospital Prague Prague Czech Republic

Division of Child Neurology Children's Hospital of Pittsburgh Pittsburgh Pennsylvania USA

Division of Metabolism Children Research Hospital Bambino Gesù Rome Italy

Faculty of Health and Life Sciences Oxford Brookes University Oxford UK

Institute for Molecular Bioscience University of Queensland St Lucia Queensland Australia

Institute of Physiology Academy of Sciences of the Czech Republic Prague Czech Republic

Leicester Children's Hospital Leicester Royal Infirmary Leicester UK

National Centre for Inherited Metabolic Disorders Temple Street Children's University Hospital Dublin Ireland

Neuromuscular and Neurodegenerative Disease Unit Children Research Hospital Bambino Gesù Rome Italy

Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust The Churchill Hospital Oxford UK

Pediatric Nephrology Unit Hospital Universitario Reina Sofia Cordoba Spain

Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne UK

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