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Mechanism of metabolic stroke and
spontaneous cerebral hemorrhage in organic
acidemias
William Zinnanti, MD, PhD
>80 genetic disorder
Clinic for Special Children Founded by Dr. D. Holmes Morton and Caroline Morton
Stroke – rapid onset of lasting CNS
injury typically involving ischemic or
hemorrhagic process, known vascular
territory
Metabolic stroke – rapid onset, lasting
CNS injury, typically symmetric, starts
with decompensation of underlying
metabolic condition
Metabolic Stroke
Glutaric aciduria
Isovaleric aciduria
Methylmalonic aciduria
Propionic acidurias
Clinical picture GA-1
Baric et al. 1995 Normal T2-WI
MRI at 5 month
MRI at 15 month
(Hartley et al., Pediatrics 2001
(Dave et al., Arch Neurology 1984
Questions to direct the study
What are the neuropathological changes?
What are the cerebrovascular changes
Why is the basal ganglia particularly susceptible?
Animal Model Needed
Spongiform vacuolation present in cortex by 4 weeks of age
Healthy despite exposure to starvation or infective stress
Brain glutaric acid levels 500 uM, WT mouse < 100 uM
Glutaryl-CoA dehydrogenase knockout (Gcdh-/-) mouse
(Koeller et al. 2002)
Gcdh-/- WT
Hypothesis I
Increased dietary lysine or protein may trigger
neuropathology in Gcdh-/- mice
High protein diet - 5 fold normal lysine
High lysine diet - 5 fold normal lysine
Experiment – Use weanlings (4 week old) and adult (8
week old) mice
High Lysine High Lysine High Lysine
High Protein High Protein High Protein
Gcdh-/- 8-wk Gcdh-/- 4-wk WT 4-wk
(Zinnanti et al., Brain 2006)
Protein diet exposure
[days]
Su
rviv
al
(Zinnanti et al., Brain 2006)
[days]
Su
rviv
al
Lysine diet
*
Lysine diet exposure
T2 MRI and T2 Map
0
>80
70
40
30
20
10
50
60
T2 [ms]
0
>80
70
40
30
20
10
50
60
T2 [ms]Normal diet Lysine 48h Lysine 6-days
Normal Diet High Lys 4 days High Lys 4 days
Gcdh-/- Lys 3-day Gcdh-/- Lys 3-day Gcdh-/- ND
Strauss et al. Brain 2007
A B
C D
GA1 Cortex 12h
Figure 5AB
Hetero 60h Cortex GA1 12h Cortex
A B
Figure 5CD
GA1 24h Cortex
C D
*
Zinnanti et al. Acta Neuropathologica
Communications 2014
TR=19 ms TR=100 ms
GA1 ND
Magnetic Resonance Angiography
TR=19 ms
GA1 Pro 48 hours
C A B
Het Pro 48 hours GA1 ND
GA1 Pro 36 hours GA1 Pro 72 hours
F
D E
G
GA1 ND Het Lys 72 hours
GA1 Lys 6 weeks GA1 Lys 36 hours
A B
C D
* *
**
*
Steps to Metabolic Stroke
Mitochondrial Dysfunction
Neuronal Swelling
Capillary Impingement - shunting
Blood Brain Barrier Weakness
Basal Ganglia susceptibility
Acknowledgements
Penn State
Dr. Keith Cheng
Dr. James Connor
Dr. Kathryn LaNoue
University of Michigan
Dr. Dave Antonetti
Clinic for Special Children
Dr. D. Holmes Morton
Dr. Kevin Strauss
Caltech
Dr. Scott Fraser
Dr. Russel Jacobs
Dr. Jelena Lazovic
Univ. Colorado HSC
Dr. Stephen Goodman
Dr. Mike Woontner
Stanford University
Dr. Lawrence Stienman
International Organization for Glutaric Aciduria
Maple Syrup Urine Disease Family Support Group
Keystone Innovation Zone and Ben Franklin Technology Partners
