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

William J. Zinnanti, Jelena Lazovic, Cathy Housman, David A. Antonetti, David M. Koeller, James R. Connor, Lawrence Steinman

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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. Conclusion: 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.

Original languageEnglish (US)
Article number13
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Jan 27 2014


  • Blood-brain barrier
  • Cerebral hemorrhage
  • Glutaric aciduria
  • Metabolic stroke

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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