Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I.
BACKGROUND
Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood.


RESULTS
Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin.


CONCLUSIONS
Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.
Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA. wzinnanti@gmail.com.
William J
WJ
Zinnanti
Jelena
J
Lazovic
Cathy
C
Housman
David A
DA
Antonetti
David M
DM
Koeller
James R
JR
Connor
Lawrence
L
Steinman
D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications* / Q000235:genetics / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001928:Brain Diseases, Metabolic / Q000150:complications* / Q000235:genetics / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D018810:Magnetic Resonance Angiography; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D062793:Occludin / Q000378:metabolism; D018709:Statistics, Nonparametric; D020521:Stroke / Q000209:etiology*
D005904:Glial Fibrillary Acidic Protein; D062793:Occludin; D050770:Glutaryl-CoA Dehydrogenase