Angiopathy Hypothesis

Initially, it was hypothesized that stroke-like episodes were simply a metabolic insufficiency in a brain region that
mimicked a stroke. Over the last several years, accumulating clinical insights have suggested that abnormalities in
endothelial tis- sues may play a role in the specific pathophysiology of MELAS syndrome. Unlike other mitochondrial
cytopathies, angiopathy has been demonstrated. There is an increased number of enlarged mitochondria with
complicated cristae found in the pericytes of capillaries, endothelial cells, and smooth muscle cells of arterial pial vessels
and small intracerebral arteries [32]. Endothelial vessels that stain strongly with succinate dehydrogenase, indicative of
mitochondrial proliferation, have been reported in pathological specimens from patients with MELAS [33, 34] (Fig.
8.2c and d). This angiopathy appears to mainly affect small cerebral arteries, arterioles, and capillaries. Furthermore,
microangiopathy is seen in many patients with mtDNA disease on autopsy of the cerebellum [35].
Whether these histopathological abnormalities relate to the stroke-like episodes that typify this disease remains to
be demonstrated. Although the medical literature is somewhat conflicting, MELAS patients appear to have reduced
vasodilatory capacity, which is suggestive of small vessel dysfunction [36]. Limited evidence suggests that
supplementation with l-arginine, a precursor to nitric oxide (NO), may restore this capacity, suggesting a pathological
link with this substrate as well as potential for therapy. In 2005, Naini and colleagues proposed that dysfunction of NO
production and catabolism was a mechanism underlying the observed angiopa- thy and nonischemic stroke-like
episodes seen in MELAS [37]. In adults, entero- cytes of the small intestine are responsible for the bulk of citrulline
synthesis, an ATP-dependent process. In MELAS, reduced availability of ATP for citrulline pro- duction may lower
plasma levels, thus decreasing arginine and NO production. Amid such an environment, it is possible that cytochrome c
oxidase (COX; complex IV) activity drives a paradoxical increase in enzymatic activity. This theory is based on the
observation that in MELAS, ragged red fibers and blood vessels are typically COX positive, despite seemingly high
levels of mutation burden. MELAS patients appear to have a significant amount of residual respiratory chain activity
relative to patients with other mitochondrial diseases such as MERRF, where both ragged red fibers and vessel walls are
COX negative.