Neuropathologic Features of Adult-Onset Progressive Leukodystrophy Due to KARS Pathogenic Variants

Abstract

Objectives To report the histopathologic features seen in congenital deafness and adult-onset leukoencephalopathy (DEAPLE) caused by biallelic pathogenic variants in KARS and expand on neuroradiologic features reported in other cases. Methods We present the clinical, neuroimaging, and histopathologic findings of a patient with adult-onset, rapidly progressive leukodystrophy. Clinical information, genetic reports, neuroimaging, and postmortem brain pathology were collected and analyzed. Results Compound heterozygous variants in KARS were found, including the previously reported (NM_001130089.1: c.683 C > T, p.P228L) pathogenic variant and a novel (NM_001130089.1: c.1609 C > T, p.R537W) variant of uncertain significance (VUS). Brain MRI revealed extensive, frontally predominant white matter abnormalities, involvement of the corticospinal tracts extending into the midbrain, and nodular contrast enhancement primarily in the bilateral occipital cortices and leptomeninges, noncontiguous with the white matter lesions. Autopsy 1 year later revealed frontally predominant atrophy of the white matter with relative preservation of the subcortical U-fibers, brainstem, and cerebellum; microcytic parenchymal degeneration and vacuolization; and numerous axonal spheroids. No inflammatory component was present in the occipital cortex or leptomeninges. Discussion Our findings confirm the previously reported features of DEAPLE and suggest the possibility of a transient neuroinflammatory component associated with areas of active disease.