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J Med Genet. 2016 Nov;53(11):768-775. doi: 10.1136/jmedgenet-2016-103910. Epub 2016 Jul 13.

The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease.

Author information

1
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
2
Neuromuscular and Neurodegenerative Disease Unit, Children Research Hospital Bambino Gesù, Rome, Italy.
3
Department of Genetic Medicine, Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital, Manchester, UK.
4
Department of Neurology, George Washington University Medical School, Children's National Health System, Washington, DC, USA.
5
First Faculty of Medicine, Institute for Inherited Metabolic Disorders, Charles University in Prague, Prague, Czech Republic.
6
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
7
Division of Metabolism, Children Research Hospital Bambino Gesù, Rome, Italy.
8
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
9
Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, Massachusetts, USA.
10
Department of Pediatrics, Aga Khan University, Karachi, Pakistan.
11
Pediatric Nephrology Unit, Hospital Universitario Reina Sofia, Cordoba, Spain.
12
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
13
Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital NHS Foundation Trust, Birmingham, UK.
14
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
15
Clinical Genetics Unit, West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
16
Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
17
National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin, Ireland.
18
Department of Paediatric Medicine, Leeds General Infirmary, Leeds, UK.
19
Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
20
Department of Clinical Genetics, Temple Street Children's University Hospital, Dublin, Ireland.
21
Leicester Children's Hospital, Leicester Royal Infirmary, Leicester, UK.
22
Department of Metabolic Medicine, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
23
Department of Paediatric Neurology, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
24
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
25
Department of Paediatric Medicine, The Royal Belfast Hospital for Sick Children, Belfast, UK.
26
Division of Child Neurology, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
27
Department of Medical and Molecular Genetics, Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, 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.

KEYWORDS:

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

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