Hypomyelinating Leukodystrophy with Spinal Cord Involvement Caused by a Novel Variant in RARS: Report of Two Unrelated Patients

Abstract

Leukodystrophies are heterogeneous group of genetic white matter disorders with a wide range of neurologic and systemic manifestations. Defects in genes encoding aminoacyl tRNA (transfer ribonucleic acid) synthetase enzymes (aaRSs) are recently identified as the etiology of some leukodystrophies. Herein, we described two unrelated children referred to Children's Medical Center, Tehran, Iran, with developmental delay, nystagmus, seizures, psuedo-bulbar palsy and dystonia. Whole exome sequencing (WES) in both patients identified a homozygous (c.2T > C) variant in exon one of RARS gene, encoding cytoplasmic arginyl-tRNA synthetase. Our finding was confirmed by segregation analysis. In silico analyses of the c.2T > C variant showed its possible pathogenic role due to the absence of the start codon. Severe hypomyelination was the common neuroimaging finding of both cases. Spinal cord involvement was found in one of our patients which was not previously reported in studies. We, therefore, showed that RARS-related hypomyelination might affect spinal cord.

Keywords

leukodystrophy - hypomyelination - children - RARS gene

^* Zahra Rezaei and Sareh Hosseinpour are equally contributed as first authors.

• References

• 1 Ashrafi MR, Rezaei Z, Heidari M. , et al. The first report of relative incidence of inherited white matter disorders in an Asian country based on an Iranian bioregistry system. J Child Neurol 2018; 33 (04) 255-259
• 2 Ashrafi MR, Tavasoli AR. Childhood leukodystrophies: a literature review of updates on new definitions, classification, diagnostic approach and management. Brain Dev 2017; 39 (05) 369-385
• 3 Wolf NI, Salomons GS, Rodenburg RJ. , et al. Mutations in RARS cause hypomyelination. Ann Neurol 2014; 76 (01) 134-139
• 4 Nafisinia M, Sobreira N, Riley L. , et al. Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. Eur J Hum Genet 2017; 25 (10) 1134-1141
• 5 Konovalova S, Tyynismaa H. Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 2013; 108 (04) 206-211
• 6 Schwenzer H, Zoll J, Florentz C, Sissler M. Pathogenic implications of human mitochondrial aminoacyl-tRNA synthetases. Top Curr Chem 2014; 344: 247-292
• 7 Diodato D, Ghezzi D, Tiranti V. The mitochondrial aminoacyl tRNA synthetases: genes and syndromes. Int J Cell Biol 2014; 2014: 787956
• 8 Wolfe CL, Warrington JA, Treadwell L, Norcum MT. A three-dimensional working model of the multienzyme complex of aminoacyl-tRNA synthetases based on electron microscopic placements of tRNA and proteins. J Biol Chem 2005; 280 (46) 38870-38878
• 9 Yao P, Fox PL. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol Med 2013; 5 (03) 332-343
• 10 Pouwels PJ, Vanderver A, Bernard G. , et al. Hypomyelinating leukodystrophies: translational research progress and prospects. Ann Neurol 2014; 76 (01) 5-19
• 11 Taft RJ, Vanderver A, Leventer RJ. , et al. Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am J Hum Genet 2013; 92 (05) 774-780
• 12 Mendes MI, Gutierrez Salazar M, Guerrero K. , et al. Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA synthetase, cause a hypomyelinating leukodystrophy. Am J Hum Genet 2018; 102 (04) 676-684
• 13 Fu Y, Kim Y, Jin KS. , et al. Structure of the ArgRS-GlnRS-AIMP1 compl ex and its implications for mammalian translation. Proc Natl Acad Sci U S A 2014; 111 (42) 15084-15089