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

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 Heath implications

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

Mitochondria Breaks down SCFA Triglycerides can release energy following hydrolysis reactions Triglyceride + H 2 O Glycerol + fatty acid molecules Beta Oxidation Acetyl Coenzyme A

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

Fatty acids can be synthesized from acetyl CoA BIOSYNTHESIS ANABOLISM CATABOLISM BETA OXIDATION

Free ribosomes in cytoplasm Produce VLCSFA CoA synthase (degradative enzyme) enzyme Acetyl CoA + VLCFA Degrated fatty acid ABC transporter protein PEROXISOME catalysis ABC transporter protein Degrated fatty acid ALD Normal ALD is due to poor Beta oxidation or breakdown of VLCSFA in the peroxisome