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

Abstract

BackgroundMetabolic 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.ResultsUsing 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.ConclusionTogether the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke.

Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload

“…However, it should be stressed that bioenergetics disruption is capable of inducing secondary excitotoxicity (Danbolt, 2001;Novelli et al, 1988). Therefore, it is conceivable that moderate disturbance of bioenergetics, associated with excitotoxicity (Kolker et al, 2002b;Lagranha et al, 2014;Wajner et al, 2004), oxidative stress Seminotti et al, 2012Seminotti et al, , 2013 and increased blood-brain barrier permeability (Isasi et al, 2014;Zinnanti et al, 2014) may contribute to the brain injury in GA I.…”

Pathogenesis of brain damage in glutaric acidemia type I: Lessons from the genetic mice model

“…Another study evidenced that Gcdh −/− mice fed a high protein chow have neuronal swelling and vacuole formation associated with cortical and striatal capillary occlusion and ischemia (Zinnanti et al, 2014). When these mice were fed either a normal or a high Lys diet there was an increase in VEGF content in both cerebral cortex and striatum leading to a decrease in the staining of the tight‐junction protein occludin located in the BBB, that was proposed to be associated with BBB breakdown.…”

Glutaric Acid-Mediated Apoptosis in Primary Striatal Neurons

“…But the cytotoxic effects are not necessarily restricted to neuronal mitochondrion. The kinetics of the metabolites transported through intra- and intercellular membranes and finally excreted into urine or faeces also seems to participate in the neuropathogenesis [ 20 – 22 ]. The destruction of striatal neurons is irreversible during the time window from birth to 36 months of age.…”

“…However, other experiments proved that astrocytic proliferation triggers progressive striatal degeneration in GA I [ 12 , 31 ] by interrupting the anaplerotic supply of astrocytes and then failing to maintain the energy metabolism and synthesizing the neurotransmitters of glutamate and GABA in neurons. Disturbance of cerebral hemodynamics due to destroyed integrity of endothelial barriers also contributes to brain damage [ 22 , 32 ]. In summary, synergistic effects among the metabolites [ 15 ] and all kinds of cellular dysfunctions perhaps could explain low concentrations of each and could combine to produce striatal degeneration in GA I children.…”