Infantile onset Encephalomyopathy, Heart Block, and Sensorineural Hearing Loss: RMND1-Associated Mitochondrial DiseaseFunding This study was supported by a grant from the Indian Council of Medical Research to B.P.S. (grant no.: 54/9/2012-HUM-BMS).
31 December 2019
19 April 2020
26 May 2020 (online)
Mutations in RMND1 (required for mitotic division-1) has been associated with infantile onset mitochondrial disease and combined oxidation phosphorylation deficiency. This report describes a girl child of Indian origin with RMND1-associated mitochondrial disease. This 13-month-old girl, born to consanguineous parents presented with gradual loss of acquired milestones and recurrent vomiting from 5 months of age. She experienced failure to thrive, profound hypotonia, areflexia, and sensorineural deafness. Evaluation showed elevated serum lactate and complete heart block. Audiological evaluation done at 6 and 13 months of age revealed bilateral A type tympanogram, bilateral absent stapedial reflexes, absent otoacoustic emissions (OAE), and absent brainstem auditory evoked responses suggestive of bilateral profound sensorineural hearing loss. Muscle biopsy revealed evidence of ragged red fibers, ragged blue fibers, and Cytochrome coxidase (COX) deficient fibers on histochemistry and multiple complex deficiency on spectrophotometry. Exome sequencing revealed homozygous stop-loss variation, c.1349G > C, in exon 12 of RMDN1 resulting in substitution of amino acid serine for stop codon at position 450 and subsequent elongation of the protein by 31 amino acids (p.Ter450SerextTer31) which was verified by Sanger's sequencing. This report further strengthen the phenotype genotype correlations in RMND1-associated mitochondrial disease, especially the occurrence of the reported variation in South Asian patients. In addition, familiarity with the phenotype may help the physician to do targeted metabolic testing and facilitate appropriate early interventions.
B.P.S. and A.B.T. contributed in conceptualization and designing, as well as acquisition, analysis, and interpretation of data. M.N. performed the literature search and wrote the manuscript. A.B.T., B.P.S., M.N., S.C., and S.S. performed as a clinical team involved in the evaluation, management, and follow-up of the patient. N.G. was involved in the acquisition and interpretation of histopathological data. J.N.J.P. contributed in acquisition and interpretation of respiratory chain assays. S.C. and P.G. performed interpretation of genetic data. V.P.V. contributed with acquisition and interpretation of audiological findings. All authors reviewed and approved the final manuscript.
- 1 Garcia-Diaz B, Barros MH, Sanna-Cherchi S. , et al. Infantile encephaloneuromyopathy and defective mitochondrial translation are due to a homozygous RMND1 mutation. Am J Hum Genet 2012; 91 (04) 729-736
- 2 Janer A, Antonicka H, Lalonde E. , et al. An RMND1 Mutation causes encephalopathy associated with multiple oxidative phosphorylation complex deficiencies and a mitochondrial translation defect. Am J Hum Genet 2012; 91 (04) 737-743
- 3 Ng YS, Alston CL, Diodato D. , et al. The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease. J Med Genet 2016; 53 (11) 768-775
- 4 Kirby DM, Thorburn DR, Turnbull DM, Taylor RW. Biochemical assays of respiratory chain complex activity. Methods Cell Biol 2007; 80: 93-119
- 5 Sonam K, Bindu PS, Srinivas Bharath MM. , et al. Mitochondrial oxidative phosphorylation disorders in children: phenotypic, genotypic and biochemical correlations in 85 patients from South India. Mitochondrion 2017; 32: 42-49
- 6 Janer A, van Karnebeek CD, Sasarman F. , et al. RMND1 deficiency associated with neonatal lactic acidosis, infantile onset renal failure, deafness, and multiorgan involvement. Eur J Hum Genet 2015; 23 (10) 1301-1307
- 7 Ulrick N, Goldstein A, Simons C. , et al; Care4Rare Canada Consortium. RMND1-related leukoencephalopathy with temporal lobe cysts and hearing loss-another mendelian mimicker of congenital cytomegalovirus infection. Pediatr Neurol 2017; 66: 59-62
- 8 Gupta A, Colmenero I, Ragge NK. , et al. Compound heterozygous RMND1 gene variants associated with chronic kidney disease, dilated cardiomyopathy and neurological involvement: a case report. BMC Res Notes 2016; 9: 325
- 9 Vinu N, Puri RD, Anand K, Verma IC. Expanding the phenotype of the founder south Asian mutation in the nuclear encoding mitochondrial RMND1 gene. Indian J Pediatr 2018; 85 (02) 87-92