Abstract
Background: We report a consanguineous Sudanese family whose two affected sons presented with a lethal disorder characterised by severe neonatal lactic acidosis, hypertonia, microcephaly and intractable seizures. One child had additional unique features of periventricular calcification, abnormal pterins and dry thickened skin.
Methods: Exome enrichment was performed on pooled genomic libraries from the two affected children and sequenced on an Illumina HiSeq2000. After quality control and variant identification, rare homozygous variants were prioritised. Respiratory chain complex activities were measured and normalised to citrate synthase activity in cultured patient fibroblasts. RMND1 protein levels were analysed by standard Western blotting.
Results: Exome sequencing identified a previously reported homozygous missense variant in RMND1 (c.1250G>A; p.Arg417Gln), the gene associated with combined oxidation phosphorylation deficiency 11 (COXPD11), as the most likely cause of this disorder. This finding suggests the presence of a mutation hotspot at cDNA position 1250. Patient fibroblasts showed a severe decrease in mitochondrial respiratory chain complex I, III and IV activities and protein expression, albeit with normal RMND1 levels, supporting a generalised disorder of mitochondrial translation caused by loss of function.
Conclusions: The current study implicates RMND1 in the development of calcification and dermatological abnormalities, likely due to defective ATP-dependent processes in vascular smooth muscle cells and skin. Review of reported patients with RMND1 mutations shows intra-familial variability and evidence of an evolving phenotype, which may account for the clinical variability. We suggest that COXPD11 should be considered in the differential for patients with calcification and evidence of a mitochondrial disorder.
Competing interests: None declared
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Acknowledgements
We sincerely thank the participating family for their involvement in this study and the use of genetic samples and clinical information.
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Communicated by: Jaak Jaeken
Financial Support
This study was supported by a Medical Research Charities Group grant (MRCG/2013/02) from the Health Research Board (Ireland) and the Children’s Fund for Health, the Fundraising Office for Temple Street Children’s University Hospital, Dublin, Ireland. Jillian Casey is also supported by the Medical Research Charities Group grant (MRCG/2013/02). Studies undertaken in Newcastle upon Tyne are supported by a Wellcome Trust Strategic Award (096919/Z/11/Z), the MRC Centre for Neuromuscular Diseases (G0601943), the Lily Foundation and the UK NHS Highly Specialised “Rare Mitochondrial Disorders of Adults and Children” Service.
Synopsis
RMND1 mutation can cause calcification, abnormal pterins and dermatological features and should be considered in the differential for patients with mitochondrial disorders that include calcification.
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Conflict of Interest
Jillian P. Casey, Ellen Crushell, Kyle Thompson, Eilish Twomey, Langping He, Sean Ennis, Roy K. Philip, Robert W. Taylor, Mary D. King and Sally Ann Lynch declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from the patient’s parents for inclusion in the study. Additional informed consent was obtained from the parents to include identifying information in this article.
Author Contributions
JPC, SAL and EC were responsible for the study concept and design and obtained funding. EC, RKP, MDK and SAL performed clinical assessment and diagnostic investigations and were responsible for obtaining clinical samples and patient management. EC, ET and MDK reviewed and interpreted the biochemical, radiological and neurological findings, respectively. JPC analysed and interpreted the exome data and did a literature review on previous patients. EC, JPC, MDK, SE and SAL assessed the genetic findings in relation to the patient phenotype. KT, LH and RT analysed patient fibroblasts for respiratory chain defects and altered mitochondrial protein levels and interpreted their findings. JPC drafted the manuscript, and all authors were involved in critical revisions.
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Casey, J.P. et al. (2015). Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 26. JIMD Reports, vol 26. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_479
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DOI: https://doi.org/10.1007/8904_2015_479
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