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).

Keywords: Complex I; Demyelination; Mitochondrial leukoencephalopathy; Progressive cavitating leukoencephalopathy.

Fig. 1

Radiologic and pathologic findings at autopsy. MRI performed several weeks before death showed cystic changes (white arrow) in the periventricular white matter with associated areas of post-contrast enhancement a, c. Gross examination at autopsy showed numerous cystic lesions in the periventricular white matter b, as well as solid lesions characterized by softening and dusky discoloration (black arrow) d. Size bar in panels b and d are 2 cm

Fig. 2

Histopathologic and ultrastructural findings of skeletal muscle biopsy. Antemortem skeletal muscle biopsy showed mild variation in muscle fiber diameter by light microscopy on H&E-stained sections a Dual staining for cytochrome C oxidase (COX) and succinate dehydrogenase (SDH) showed fibers with abnormal subsarcolemmal accumulations of mitochondria and a single COX negative fiber b Modified Gomori trichrome staining demonstrated the abnormal subsarcolemmal mitochondrial accumulation without evidence of ragged red fibers c Ultrastructural examination of myofibers showed aggregates of mitochondria in the subsarcolemmal space (black arrow) d, corresponding with the subsarcolemmal pads seen by light microscopy and within the sarcomeric apparatus e. Individual mitochondria exhibited ultrastructural abnormalities, including enlargement and formation of irregular cristae f Size bars are 100 μm (panels a-c), 2 μm (panel d), 1 μm (panel e), and 400 nm (panel f)

Fig. 3

Histopathologic findings of brain at autopsy. Paraffin-embedded sections of the grossly solid lesions stained with Luxol fast blue / hematoxylin and eosin (LFB/H&E) demonstrated a central core of macrophage infiltration (black arrow), a rim of demyelinated axons (white arrow), and a clear demarcation from the myelinated white matter a LFB staining of the white matter adjacent to the cavitary lesions demonstrated conspicuous myelin preservation of the overlying subcortical U-fibers b and preservation of axons by neurofilament staining c In the areas of macrophage infiltration, there was evidence of myelin within macrophages on LFB (inset) d, preservation of axons by neurofilament staining e, and the macrophages were positive for CD163 f. Lymphocytic inflammation was scarce in the lesions, with only scattered parenchymal and perivascular CD3 + T-lymphocytes g H&E-stained sections of the spinal cord at all levels showed similar lesions with prominent involvement of the dorsal columns and sparing of corticospinal tracts h Ultrastructural analysis of cortical neurons did not identify definitive abnormal mitochondria (i). Size bars are 100 μm (panels a-g), 1 mm (panel h), and 600 nm (panel i)