Broad spectrum of clinical presentation in EARS2 beyond typical “leukoencephalopathy with thalamus and brain stem involvement”

Abstract

Mitochondrial diseases comprise a heterogeneous group of disorders due to dysfunction of mitochondrial respiratory chain caused by mutations in both mitochondrial and nuclear genes. EARS2 encodes mitochondrial glutamyl t-RNA synthetase responsible for attaching glutamate to its cognate mitochondrial t-RNA. Hence, EARS2 is critical for protein translation in mitochondria. Homozygous or compound heterozygous EARS2 pathogenic variants are associated with a neurological disorder characterized by leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) [1]. Patients with EARS2-related mitochondrial disease become symptomatic in infancy with characteristic MRI findings of diffuse white matter changes and symmetrical signal abnormalities in the thalamus and brain stem. Their clinical presentations fall into two groups-severe and mild. Patients in the severe group present before 6 months of age with marked neurological regression followed by clinical stagnation. Patients in the mild group present later in infancy with neurological regression, but they regain some milestones and follow a stable clinical *

Identification of a Novel Variant in EARS2 Associated with a Severe Clinical Phenotype Expands the Clinical Spectrum of LTBL

“…The occurrence and extent of recovery most likely depends on the severity of brain damage caused by the first symptomatic episode; some children with the most severe phenotype can die after the first clinical event [ 31 , 32 , 33 , 34 ]. Less common findings reported in LTBL include anemia, tubulopathy, hepatopathy, absence of the thalami, and even the absence of characteristic neuroimaging findings [ 10 , 35 , 36 , 37 ]. The clinical course of our patient does not appear to correspond to either of the two clinical courses described: she has a severe clinical presentation that initially manifested at 12 months of age, characterized by absence seizures with mild spasticity of the extremities.…”

The pathophyiological role of aminoacyl-tRNA synthetases in digestive system diseases

“…Mutations in ARSs exhibit a close relationship with some inherited diseases in humans, which makes patients more susceptible to digestive system related phenotypes such as elevated liver enzymes and hepatomegaly ( Prasun et al, 2019 ), liver steatosis ( Kuo et al, 2019 ), liver cirrhosis ( Xu et al, 2018 ), and advanced liver disease associated portal hypertension ( Peluso et al, 2021 ). MARS gene mutation has been shown to cause ILLD (Interstitial lung and liver disease), which includes several liver abnormalities such as hepatomegaly, cholestasis, hepatic steatosis, fibrosis, and iron deposition ( Abuduxikuer et al, 2018 ).…”