Figure 8

Mechanism of metabolic stroke. Metabolic dysfunction associated with glutaric acid production and accumulation results in mitochondrial energy failure with secondary failure of Na/K ATPases and edema initially of neurons and neuronal projections (1). Neuronal expansion impinges on capillary blood vessels leading to ischemia, which compounds and expands regions of neuronal swelling. Compression of capillaries leads to shunting of blood to non-exchange vessels with early filling and dilation of the deep venous system (2). Lack of valves in cerebral veins allows for symmetric decreased flow from striatum and thalamus. Chronic metabolic dysfunction depletes α KG levels leading to lack of HIF1a degradation and up regulation of VEGF leading to vessel expansion and weakness including mobilization of tight-junction proteins away from blood–brain barrier (3). The combination of vessel impingement, shunting and weakened blood–brain barrier likely results in hemorrhages.