Two Different Phenotypes Caused by Mutation in the EARS2 Gene in Two Siblings

Introduction: Mitochondrial aminoacyl tRNA synthetases are essential for glutamate, which is involved in mitochondrial DNA translation. EARS2 is one of the newest members of nuclear mitochondrial disorders characterized by disturbed mitochondrial translation. Pathogenic EARS2 variants have been related to a rare mitochondrial disorder known as leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). Two distinct clinical courses are described: severe and moderate. Cases: We present two cases diagnosed as LTBL, with a history of consanguinity. The older brother was 2.5 years old and admitted with developmental delay when he was 12 months old. His cranial magnetic resonance imaging revealed symmetrical T2 hyperintensities in the cerebral hemispheres, subcortical and deep white matter, corpus callosum. There was no regression in his developmental milestones. His two-month-old brother was born at term and in the second month of his life, elevated liver function tests, acidosis, hypoglycemia, increased lactate and elevated direct bilirubin occurred. Whole-exome sequencing analysis of two siblings were compound heterozygous for pathogenic variants (c.319C>T;p.Arg107Cys/ c.1005_1006del;p.Leu336Aspfs) in EARS2 gene and healthy parents were carriers for these mutations. The younger brother died when he was three months old while the older can currently walk unassisted. Conclusion: The severe form is characterized by early-onset, seizures, hypotonia, and persistently elevated lactate levels and the mild form usually manifests clinically after six months of age with irritability and psychomotor regression. We reported two siblings with varied clinical phenotypes of EARS2 mutations in the same family.
Keywords: EARS2 gene; Leukoencephalopathy