Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

Abstract

Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood–brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood–brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.

Mitochondrial Abnormality Associates with Type-Specific Neuronal Loss and Cell Morphology Changes in the Pedunculopontine Nucleus in Parkinson Disease

“…mtDNA anomalies can be effectively indicated by a dual COX/SDH histochemical assay. 83 Here, PD cases indicated COX deficiency, albeit limited, in scattered neuronal soma (Figure 9, A and C) and in neuronal projection fibers (Figure 9, B and D), but with an atypical structure, including patches of soma appearing COX-deficient in a generally COX-positive cytoplasm. It is possible that this represents mitochondrial heteroplasmy with certain mitochondria within a cell showing COX deficiency and others being normal, with entirely COXdeficient cells only appearing as such when mtDNA mutations reach critical levels.…”

Elevated cerebrospinal fluid protein in POLG‐related epilepsy: Diagnostic and prognostic implications

“…OXPHOS deficiency in central nervous system microvasculature, including vascular smooth muscle cell layer and endothelial cells, has been reported previously . Evidence of BBB dysfunction, with plasma protein extravasation, has been suggested by the findings of raised CSF protein, but has only been demonstrated on postmortem examination in a single patient with POLG disease …”

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

“…The precise mechanisms leading to vascular mineralization remain unknown, but some studies suggest that smooth muscle cell or pericyte dysfunction may lead to osteogenic differentiation of these cells into osteoclast and osteoblast cells (29,30). We have previously speculated that mitochondrial dysfunction within the smooth muscle layer could initiate smooth muscle cell transdifferentiation as a protective mechanism (31). These abnormalities are particularly interesting given the location of the lesion, which corresponds well with the watershed territory supplied by the lenticulostriate arteries and distal arteries of the middle cerebral artery (32).…”