Download ALD

ALD
Symptoms:
Dementia, loss of sight,
hearing, speech, and ambulation
CLINICAL PRESENTATION:
ALD is peroxisomal storage disease whereby abnormal
peroxisomes lead to the accumulation of very long chain
fatty acids (VLCFA) in tissues of the body, especially the
brain and the adrenal glands. Ultimately the myelin sheath
surrounding the nerves is destroyed causing neurologic
problems, and the adrenal gland malfunction causes
Addison’s Disease. While some VLCFA that accumulate
come from the diet, they are derived mainly from production
within the body. The accumulation of VLCFA in ALD patients
results from their impaired capacity to degrade these
substances. This reaction normally takes place in a part of
the cell, which is referred to as the peroxisome. Patients
with ALD lack one of the proteins required for the
degradation to take place. The protein that is missing or
defective is called ALDP (ALD protein). This, in turn, is due
to mutations or defects in the gene that codes for ALDP.
This gene is located on the X-chromosomes.
Lipid Structure
VLCFA: fatty acids that are 24 or 26 carbons
LCFA: Fatty acids with 20 or 22 carbons
Short FA: fatty acids with 14,16 or 18 carbons
Saturated fatty acid: saturated with hydrogen
because there are no double bands in the tail;
solid at room temp.
Unsaturated fatty acid: one or more double
bonds in fatty acid tail; liquid at room temp;
kinky shape
Heath implications
High levels of saturated fats: decreased levels
of HDL (high density lipoproteins) and
increased levels of LDL (low density
lipoproteins)
HDL “good guys” removes cholesterol
LDL “bad guys” associated with
cardiovascular disease
SO: saturated fats are associated with high
blood cholesterol and plagues on blood
vessels
Importance of Fats
Energy storage, cushions
and protects organs, insulates
Why are the VLCSFA dangerous?
Due to the properties (long and
straight) of VLCSFA, they are more
dangerous than VLCUFA, thus
facilitating the ability of VLCSFA to
interact with, insert into or solubilize
the hydrophobic myelin sheath
VLCSFA may:
1) solubilize or interact with hydrophobic
molecules of myelin sheath allowing for
local immune reaction to destroy the sheath
2) VLCSFA concentrate in neural membranes
to inhibit membrane function
Therefore:
Fatty acids with shorter chains or with double
bonds (kinky) would be less likely to insert
into or solubilize the myelin sheath.
CELLULAR ORGANELLES
• Smooth Endoplasmic Reticulum
• Mitochondria
• Peroxisome
Endoplasmic Reticulum- rough
(ribosomes) makes secretory
proteins and membrane proteins
Smooth ER synthesizes lipids,
metabolizes carbohydrates and
detoxifies drugs and poisons
Smooth ER contain enzymes
important to lipid synthesis
• Breaks down SCFA
• Triglycerides can release energy
following hydrolysis reactions
Triglyceride + H2O
Glycerol +
fatty acid molecules
Acetyl Coenzyme A
Beta Oxidation
Mitochondria
Peroxisomes
• Very abundant in liver and
kidneys
• Outer membrane contains
enzymes that catalyze the
breakdown of lipids called
VLCFA
Immediate
• Fat is digested, the glycerol is converted
to glyceraldehyde phosphate (an
intermediate of glycolysis)
Storage
• Fat stored in fatty acids and through a
metabolic sequence called Beta oxidation
breaks the fatty acids down to two-carbon
compounds which then enter Krebs Cycle as
Acetyl CoA.
-Beta oxidation occurs in the peroxisomes
for VLCSFA
BIOSYNTHESIS
ANABOLISM
Fatty acids can be synthesized from acetyl CoA
CATABOLISM
BETA OXIDATION
ALD is due to poor Beta oxidation or breakdown of VLCSFA in the peroxisome
PEROXISOME
Free
ribosomes in
cytoplasm
Acetyl CoA + VLCFA
catalysis
enzyme
Produce VLCSFA
CoA synthase
(degradative enzyme)
ALD
enzyme
Degrated fatty acid
ABC
transporter
protein
Degrated
fatty acid
Normal
ABC
transporter
protein