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

The clinical, biochemical and genetic features associated withRMND1-related mitochondrial disease

“…Fourteen patients from 11 families (P1–P9, P10.1, P10.2, P11.1) are new cases; their clinical details are provided in online supplementary data 1. Authors from the previously published cases5 6 8 (P11.2, P12–P18.2) also completed the case report form and provided additional data for this study (P11.2, P12–P16, online supplementary data 1). Clinical data were extracted from the literature for the remaining eight patients (P19 to P21.5) 2–4…”

“…The clinical phenotypes associated with RMND1 mutations are expanding, ranging from a fatal, infantile encephalomyopathy with lactic acidosis2 5 to a less severe phenotype characterised by developmental delay, congenital sensorineural deafness, hypotonia and renal disease 46 In this study, we identified new patients harbouring recessive mutations in RMND1 from several metabolic clinics and research centres across Europe (UK, Ireland, Italy, Denmark, Spain and Czech Republic) and the USA.…”

Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: a case report

“…RMND1 gene mutations have been linked to mitochondrial disease with varying severity and variable multisystem involvement [ 2 , 9 – 13 ]. However, all cases presented with deafness and some element of neuromuscular disease.…”

Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

“…Different studies have successfully described a molecular basis of the disease diversified phenotypic spectrum using whole exome sequencing (WES) (Taylor et al, 2014; Ng et al, 2016; Casey et al, 2016). WES analysis facilitates rapid molecular diagnosis of clinically challenging cases and their family members by providing a quick and comprehensive information about known or novel mutations in candidate genes.…”

“…It has been demonstrated that various novel and common recessive mutations in RMND1 are associated with multiple phenotypes characterized by delayed maturation of vision, developmental delay, dilated cardiomyopathy, deafness and neurological defects (Gupta et al, 2016), renal tubular acidosis type 4 presented as hyponatraemia and hyperkalaemia and cystic/hypoplastic kidneys (Ng et al, 2016). Likewise, complex clinical spectrum of patients with RMND1 mutations is emerging with infantile encephalomyopathy with lactic acidosis (Garcia-Diaz et al, 2012, Casey et al, 2016) to a less severe form of developmental delay, hypotonia, renal disease and congenital sensorineural deafness (Janer et al, 2015). Therefore, molecular screening of RMND1 gene will help identify the inheritance mode of causative genetic mutations in patients with renal and or neurological defects.…”