The neuropathologic findings in a case of progressive cavitating leukoencephalopathy due to NDUFV1 pathogenic variants

Abstract

Pathogenic variants in the NDUFV1 gene, which codes for complex I of the mitochondrial respiratory chain, have been associated with a variety of clinical phenotypes, including a progressive cavitating leukoencephalopathy. The neuropathology of NDUFV1-associated leukoencephalopathy is not well-described. We present a report of a 24-year-old female with two pathogenic variants in the NDUFV1 gene, together with antemortem skeletal muscle biopsy and postmortem neuropathologic examination. Autopsy neuropathology showed a cavitating leukoencephalopathy with extensive white matter involvement, regions of active demyelination, and sparing of the subcortical U-fibers. Muscle biopsy showed subtle but distinct histologic abnormalities by light microscopy, and ultrastructural analysis demonstrated mitochondrial abnormalities including abnormal subsarcolemmal mitochondrial accumulation, electron-dense inclusions, and enlarged mitochondria with abnormal cristae. Our report is the first comprehensive description of the neuropathology in a patient with compound heterozygous variants in the NDUFV1 gene and progressive cavitating leukoencephalopathy. This case is evidence of pathogenicity of one NDUFV1 variant (c.565 T > C, p.S189P), which has not been previously described as pathogenic. These findings, in combination with the ultrastructural abnormalities in the mitochondria by electron microscopy, support the mitochondrial nature of the pathology. Together, this case highlights the link between mitochondrial abnormalities and demyelinating processes in the central nervous system (CNS).

Neuropathological characterization of the cavitating leukoencephalopathy caused by COA8 cytochrome c oxidase deficiency: a case report

“…Notably, our patient demonstrated relative neuronal preservation near cavitated areas, consistent with these previous findings (Bindu et al, 2018;Becker et al, 2022). Furthermore, the preservation of subcortical U-fibers, a feature observed in our patient, has been documented in the pathological findings of a patient with NDUFV1 variants and in individuals with a progressive cavitating leukoencephalopathy of unknown genetic etiology (Naidu et al, 2005;Becker et al, 2022). The absence of spinal cord abnormalities in our patient distinguishes them from those with NDUFV1 variants, which involved the dorsal columns (Bindu et al, 2018;Becker et al, 2022).…”

“…The clinical, neuroimaging and neuropathological results presented in this study align with previous descriptions of patients with cavitating mitochondrial leukoencephalopathies caused by pathogenic variants encoding subunits of complex I, such as NDUFV1 and NDUFA1. Neuropathological findings in both diseases revealed extensive myelin loss, numerous lesions with sparing of the basal ganglia, thalamus, cerebellum and brainstem, and macrophage infiltration at the sites of demyelination (Bindu et al, 2018;Becker et al, 2022). Notably, our patient demonstrated relative neuronal preservation near cavitated areas, consistent with these previous findings (Bindu et al, 2018;Becker et al, 2022).…”

“…Neuropathological findings in both diseases revealed extensive myelin loss, numerous lesions with sparing of the basal ganglia, thalamus, cerebellum and brainstem, and macrophage infiltration at the sites of demyelination (Bindu et al, 2018;Becker et al, 2022). Notably, our patient demonstrated relative neuronal preservation near cavitated areas, consistent with these previous findings (Bindu et al, 2018;Becker et al, 2022). Furthermore, the preservation of subcortical U-fibers, a feature observed in our patient, has been documented in the pathological findings of a patient with NDUFV1 variants and in individuals with a progressive cavitating leukoencephalopathy of unknown genetic etiology (Naidu et al, 2005;Becker et al, 2022).…”