organic acidemia association - oaa home page ......spontaneous cerebral hemorrhage in organic...

Mechanism of metabolic stroke and

spontaneous cerebral hemorrhage in organic

acidemias

William Zinnanti, MD, PhD

wzinnanti@gmail.com

>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