Article Text
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
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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.