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Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?

  • Jillian P. Casey
  • Ellen Crushell
  • Kyle Thompson
  • Eilish Twomey
  • Langping He
  • Sean Ennis
  • Roy K. Philip
  • Robert W. Taylor
  • Mary D. King
  • Sally Ann Lynch
Case Report
Part of the JIMD Reports book series (JIMD, volume 26)

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.

Keywords

Mitochondrial Disorder Respiratory Chain Complex Intractable Seizure Cranial Ultrasound Patient Fibroblast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We sincerely thank the participating family for their involvement in this study and the use of genetic samples and clinical information.

Supplementary material

419826_1_En_479_MOESM1_ESM.docx (23 kb)
(DOCX 32 kb)

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jillian P. Casey
    • 1
    • 2
  • Ellen Crushell
    • 2
    • 3
  • Kyle Thompson
    • 4
  • Eilish Twomey
    • 5
  • Langping He
    • 4
  • Sean Ennis
    • 2
  • Roy K. Philip
    • 6
  • Robert W. Taylor
    • 4
  • Mary D. King
    • 7
  • Sally Ann Lynch
    • 1
  1. 1.Genetics DepartmentTemple Street Children’s University HospitalDublin 1Ireland
  2. 2.School of Medicine and Medical SciencesUCD Academic Centre on Rare Diseases, University College DublinBelfield, Dublin 4Ireland
  3. 3.National Centre for Inherited Metabolic DisordersTemple Street Children’s University HospitalDublin 1Ireland
  4. 4.Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical SchoolNewcastle UniversityNewcastle upon TyneUK
  5. 5.Radiology DepartmentTemple Street Children’s University HospitalDublin 1Ireland
  6. 6.Division of Neonatology, Department of PaediatricsUniversity Maternity Hospital LimerickLimerickIreland
  7. 7.Department of Paediatric Neurology and Clinical NeurophysiologyTemple Street Children’s University HospitalDublin 1Ireland

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