Expanding the Clinical and Magnetic Resonance Spectrum of Leukoencephalopathy with Thalamus and Brainstem Involvement and High Lactate (LTBL) in a Patient Harboring a Novel EARS2 Mutation

Abstract

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) is a novel mitochondrial disease caused by mutations in EARS2, which encodes the mitochondrial glutamyl-tRNA synthetase (mtGluRS). A distinctive brain MRI pattern is the hallmark of the disease.A 6-year-old boy presented at 3 months with feeding difficulties and muscle hypotonia. Brain MRI, at 8 months, showed hyperintensity of the deep cerebral and cerebellar white matter, thalamus, basal ganglia, brainstem, and thin corpus callosum. From the second year of life onward, the child reported global clinical improvement, parallel to partial resolution of brain MRI pattern. However, the last neuroimaging assessment revealed novel lesions within the left caudate and pallidum nuclei. DNA genomic sequencing analysis identified a novel EARS2 mutation.This case expands the clinical and neuroradiological phenotype of LTBL presenting intermediate clinical manifestations between the severe and milder forms of the disease and previously unreported brain MRI features.

Fig. 1

Brain MRI and MRS at age 8 months (a – f), 29 months (g – n), and 5 years and 10 months (o – t). Axial T2-weighted images show symmetrical T2 hyperintensity of the deep cerebral white matter, thalamus, basal ganglia, brainstem, cerebellar white matter, and dentate nuclei (a – e). MRS of the cerebral white matter shows markedly increased lactate (empty arrow, f). At age 29 months, axial T2-weightwed images show a substantial improvement of the signal abnormalities (g – m). MRS of the cerebral white matter reveals significantly reduced lactate (n). Three years later, axial T2-weighted images depict further improvement of these lesions (o – s). New signal abnormalities of the left caudate (arrow) and globus pallidus (arrowhead) are evident. MRS shows high lactate in the left caudate head (thick arrow, t)

Fig. 2

Muscle biopsy. (a) Trichrome staining showing three ragged-red fibers (arrows). (b) Combined COX–SDH staining (magnification 20×) confirms the same ragged-red fibers as COX-negative–SDH-positive fibers. (c) Combined COX–SDH staining (magnification 10×) highlighting several scattered COX-negative–SDH-positive fibers. (d) Oil red O staining showing lipid accumulation