Cerebral Microangiopathy in Leukoencephalopathy With Cerebral Calcifications and Cysts: A Pathological Description

Abstract

Leukoencephalopathy with calcifications and cysts (LCC) is a neurological syndrome recently associated with pathogenic variants in SNORD118. We report autopsy neuropathological findings from an individual with genetically confirmed LCC. Histologic studies included staining of formalin-fixed paraffin-embedded tissue sections by hematoxylin and eosin, elastic van Gieson, and luxol fast blue. Immunohistochemistry stains against glial fibrillary acidic protein, proteolipid protein, phosphorylated neurofilament, CD31, alpha-interferon, LN3, and inflammatory markers were performed. Gross examination revealed dark tan/gray appearing white matter with widespread calcifications. Microscopy revealed a diffuse destructive process due to a vasculopathy with secondary ischemic lesions and mineralization. The vasculopathy involved clustered small vessels, resembling vascular malformations, and sporadic lymphocytic infiltration of vessel walls. The white matter was also diffusely abnormal, with concurrent loss of myelin and axons, tissue rarefaction with multifocal cystic degeneration, and the presence of foamy macrophages, secondary calcifications, and astrogliosis. The midbrain, pons, and cerebellum were diffusely involved. It is not understood why variants in SNORD118 result in a disorder that predominantly causes neurological disease and significantly disrupts the cerebral vasculature. Clinical and radiological benefit was recently reported in an LCC patient treated with Bevacizumab; it is important that these patients are rapidly diagnosed and trial of this treatment modality is considered in appropriate circumstances.

Case report: Clinical and neuroradiological longitudinal follow-up in Leukoencephalopathy with Calcifications and Cysts during treatment with bevacizumab

“…While the precise role of SNORD118 in ribosome biogenesis and maturation remains uncertain, the impact of its deficit on brain function is clear ( 4 ). From a pathological point of view, LCC is an exclusively brain microangiopathy, where cerebral small blood vessels exhibit angiomatous-like features and Rosenthal fiber deposition with perivascular mineralization and minimal inflammation ( 5 ). Macroscopically, neuroimaging studies typically reveal the pathognomonic triad of leukoencephalopathy, calcifications, and cysts.…”

Expanding the Natural History of SNORD118-Related Ribosomopathy: Hints from an Early-Diagnosed Patient with Leukoencephalopathy with Calcifications and Cysts and Overview of the Literature

“…U8 snoRNA is involved in the maturation of the 60S ribosome subunit [ 10 ]. Microangiopathic changes manifest as heightened tortuosity and calcification in small blood vessels, resulting in augmented focal edema and increased water content in the white matter [ 9 , 11 , 12 , 13 , 14 ]. Nevertheless, even though U8 snoRNA plays a pivotal role in ribosomal biology, the pathophysiological connection between a potentially global disturbance in ribosomal function and the development of cerebral microangiopathy with highly stereotyped radiological characteristics remains unclear [ 1 ].…”