Download ALD

ALD: Adrenoleukodystrophy
Adreno =
Leuko = white (as
in white matter)
Dys = abnormal;
ill
Trophy = growth
Demyelinating
diseases
Normal vs. demyelinated axons
ALD is an
X-linked
disease
1/20,000 males affected
The ALD phenotype is variable,
even within families. The same
mutations in ALD will not always
produce similar phenotypes.
1. 48% - Childhood Cerebral
2. 26% - Adrenomyeloneuropathy
3. 10% - Addison Disease Only
4. 8% - Pre-/Asymptomatic
5. 5% - Adolescent Cerebral ALD
6. 3% - Adult Cerebral ALD
Female ALD carrier
2. Female Phenotypes
(2)
• 85-95% - Asymptomatic
• 10-15% - Adrenomyeloneuropathy
- late onset, less severe
Lipid Biology
• Hot topic
• Saturated vs. unsaturated fatty acids
• VLCSFAs: hexacosenoic acid C26:0 and
tetracosenoic acid C24:0
• One hypothesis: VLCSFAs insert into and
solubilize myelin sheath (not true for VLCFAs)
Fats
How does the body normally
oxidize fatty acids?
VLCFA breakdown in
peroxisomes ( oxidation)
Through series of chemical reactions,
fatty acids are shortened by
removing two carbons at a time.
Pathophysiology of X-ALD
• Demyelination diseases (acquired vs. genetic)
• Deficiency of long-chain fatty acyl CoA synthase, a
perioxisomal enxyme needed for the
degradation of very long chain fatty acids
(VLCFA).
• Reason: Transport across peroxisome
membrane does not work – defective
peroxisomal membrane transporter specific for
uptake of long-chain fatty acyl CoA synthase
from the cytosol.
Normal peroxisome (normal
oxidation of VLCFA's)
ALD peroxisome (no oxidation
of VLCFA's)
Treatment???
• Reduce intake of VLCSFAs  VLCSFA
 ?????
• Previous reference (1979): Intake of
unsaturated short chain oleic acid (C18)
 reduction of VLCSFA
• But why does it work???
Competitive inhibition!!
http://www.myelin.org/aboutoil.htm
Sink model animation
More potent competitive inhibitor
• After 3 month VLCSFAs are still too high
• Stronger CI needed
• Enter: Erucic acid (C22) – unsaturated
• VLCSFA down to normal levels
• “Lorenzo’s oil”: 4 parts oleic acid + 1 part
erucic acid
One Problem:
Lorenzo’s Oil may not
work
• Preventive vs.
therapeutic effects
• New therapies:
– gene therapy
– Stem cells
The End