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Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I

William J Zinnanti1*, Jelena Lazovic2, Cathy Housman3, David A Antonetti4, David M Koeller5, James R Connor6 and Lawrence Steinman1

Author Affiliations

1 Department of Neurology and Neurological Science, Stanford University, Stanford, CA 94305, USA

2 Department of Radiology, University of California, Los Angeles, CA 90095, USA

3 Department of Pathology, Penn State College of Medicine, Hershey PA, USA

4 Department of Ophthalmology and Visual Sciences, Molecular and Integrative Physiology, University of Michigan, Ann Arbor MI, USA

5 Departments of Pediatrics, and Molecular and Medical Genetics, Oregon Health & Science University, Portland OR, USA

6 Department of Neurosurgery, Penn State College of Medicine, Hershey PA, USA

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Acta Neuropathologica Communications 2014, 2:13  doi:10.1186/2051-5960-2-13

Published: 27 January 2014



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.


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.


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.

Metabolic stroke; Glutaric aciduria; Blood–brain barrier; Cerebral hemorrhage