title: Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?
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.
authors.affiliation: Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland.|School of Medicine and Medical Sciences, UCD Academic Centre on Rare Diseases, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Jillian P
authors.initials: JP
authors.lastname: Casey
authors.affiliation: School of Medicine and Medical Sciences, UCD Academic Centre on Rare Diseases, University College Dublin, Belfield, Dublin 4, Ireland.|National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin 1, Ireland.
authors.forename: Ellen
authors.initials: E
authors.lastname: Crushell
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Kyle
authors.initials: K
authors.lastname: Thompson
authors.affiliation: Radiology Department, Temple Street Children's University Hospital, Dublin 1, Ireland.
authors.forename: Eilish
authors.initials: E
authors.lastname: Twomey
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Langping
authors.initials: L
authors.lastname: He
authors.affiliation: School of Medicine and Medical Sciences, UCD Academic Centre on Rare Diseases, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Division of Neonatology, Department of Paediatrics, University Maternity Hospital Limerick, Ennis Road, Limerick, Ireland.
authors.forename: Roy K
authors.initials: RK
authors.lastname: Philip
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Paediatric Neurology and Clinical Neurophysiology, Temple Street Children's University Hospital, Dublin 1, Ireland.
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.affiliation: Genetics Department, Temple Street Children's University Hospital, Dublin 1, Ireland. sally.lynch@ucd.ie.
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch