Glycogen Storage Disease Type III, VI and IX - basics -
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1 Glycogen Storage Disease Type III, VI and IX - basics - Wyboston Lakes Urike Steuerwald Tórshavn / Hannover usteuerwald@web.de
2 GSD III, VI and IX - Questions What goes wrong in glycogen storage disease type III, VI and IX? What are the problems of people with GSD III, VI and IX?
3 Where does energy come from? Sources? (where from) Function? (what for) sugar / carbohydrates fat Sources: bread, cereals, potatoes, rice, pasta, sugar, vegetables, fruits. Function: nutrition of brain, sugar = fast fuel Sources: oil, butter, cheese / meat / fish Function: fuel for muscle, transport of vitamins proteins Sources: milk, meat, fish (dried fish: 80%!), chicken, turkey, soy, tofu, beans, nuts Function: growth, muscles, 2 nd line energy-source for brain
4 Different sugars Short / fast or simple sugars/disaccharides: glucose (grapes) fructose (fruits) sucrose/ saccharide (cane sugar) lactose (milk) Delayed sugar: oligosaccharides (S.O.S, maltodextrin) Slow carbohydrate: glycogen (from corn, in potatoes, in carrots, in grain)
5 Glucose 5 6 C C O 4 C C 1 C C 3 2
6 Oligosaccharide / Glycogen Maltodextrin / Fantomalt (=oligosaccharide): 3-20 glycosyl-[=sugar-] residues; 1,4-bond 1-4 Structure of glycogen Straight chain of 1,4-bonds. After 12 to 16 glucosyl-residues are added, a branching enzyme transfers a block of about six residues to yield a new branch with a 1,6-bond
7 Why is sugar stored as glycogen? Sugar would be used immediately for energy production More space for storage: one item into one drawer
8 Structure of glycogen 1,6-bond 1,6-bond Up to sugar molecules in one glycogen!
9 Glycogen Glucose when blood sugar falls low, glycogen is cut into free sugar again and can be exported into the blood by the liver, not by muscles!
10 Glycogen Glucose At least are involved in the 14 different enzymes (tools/scissors) synthesis and degradation of glycogen.
11 Glycogen Glucose To cut down glycogen to sugar, different enzymes (=sissors) are necessary. In GSD III the enzyme cutting the 1,6-bonds (called the debrancher ) is defect. Debrancher Debrancher Phosphorylase Phosphorylase does not work properly in type VI (defect phosphorylase) and IX (defect activator of phosphorylase = phosphorylasekinase). Debrancher is defect in type III. Thus, in GSD III, VI and IX glycogen cannot be broken down completely to sugar/glucose.
12 Incomplete breakdown of glycogen Storage of partially broken down glycogen (limit dextrin) Also, this limit dextrin irritates (liver) cells Lack of energy / sugar during fast and exercise Therefore, other sources have to be used for survival/normal function of brain and muscles
13 GLYCOGEN All kind of carbohydrates Glucose Gluc-6-Phosphate Normal situation: all kinds of carbohydrates are broken down to simple sugars which then can be stored as glycogen (mostly in liver and muscles, but, too, in many other cells). If blood sugar is falling, glycogen is transformed back into sugar. But only the liver is able to set this sugar free into the blood. The other organs will use the sugar. Adapted from: Fernandes J. & Pikaar NA. Arch Dis Child and proposals by David Weinstein and Terry Derks
14 Impaired glycogen breakdown in GSD III, VI and IX What happens with glycogen in GSD type III, VI and IX?
15 GLYCOGEN GLYCOGEN GSD VI (Hers) / GSD IX (Phosphorylase Kinase) GSD III IIIb: only liver Glucose Gluc-6-Phosphate Buildup of glycogen is normal in GSD III, VI and IX. It s the break down that is hampered/impaired. During the time more and more glycogen is stored. Blood sugar tends to fall. Then a counter regulation is activated (see next slide): Protein can be transformed via pyruvate into glucose (some protein will be changed into acetyl-coa and ketones). At the same time fat gets mobilized from fatty tissue, is transported into the liver and transformed into ketone bodies. Thus blood sugar gets up again. And if you don t measure ketones, you might miss the fact that your blood sugar was low and that your body had to use muscle protein to provide sugar which is the first line energy source for the brain. Sugar from fruit (fructose) and milk (lactose = galactose and glucose) can be metabolized into glucose, too!
16 GLYCOGEN GLYCOGEN GSD VI (Hers) / GSD IX (Phosphorylase Kinase) GSD III Glucose Gluc-6-Phosphate Uric acid Fructose/ Galactose Lactate Pyruvat Fat Protein (Muscle) Acetyl-CoA Ketone Adapted from: Fernandes J. & Pikaar NA. Arch Dis Child and proposals by David Weinstein and Terry Derks
17 Clinical features of type III A In children In adults
18 IIIA: Symptoms in children enormously enlarged liver protruded abdomen truncal obesity and doll face hypoglycemia hyperlipidemia muscle hypotonia reduced physical endurance/stamina cardiomyopathy delayed motor development retarded growth / short stature normal mental development
19 Common complications in adults with GSD III who have not been treated optimally Cardiomyopathy Myopathy Liver Adenomas Hepatocellular carcinoma (rare) Liver cirrhosis Type 2 Diabetes Neuropathy / Brain? Adapted from a slide kindly provided by Prof. D. Weinstein Osteoporosis
20 Symptoms in adults myopathy (up to 100%): weakness and wasting mildly enlarged liver, cirrhosis (ketosis and smoking!), sometimes adenomas or even cancer cardiomyopathy (up to 50%) type 2 diabetes mellitus osteoporosis (poor calcium intake, vitamin D deficiency, lack of muscle effects, increased cortisol, high ketones) neuropathy / encephalopathy? early atherosclerosis / early coronary artery disease?
21 Symptoms in type VI and IX Type VI (Hers) Hepatomegaly Poor growth Delayed puberty Hypoglycemia (esp. in the morning with elevated ketones) hepatic adenomata, cirrhosis Type IX (PHK-def) (Phosphorylase-Kinase) Hepatomegaly Poor growth Delayed puberty Fasting ketosis Liver fibrosis/cirrhosis
22 Goals of intervention/treatment blood sugar mmol/l (75-100mg/dL) low/negative ketones (<0.2mmol/L) normal growth (nearly) normal strength and endurance normal life / good life quality
23 Treatment of GSD Type III, VI and IX Goal: Provide energy for the muscles without overstoring glucose as glycogen Minimum amount of cornstarch or carbohydrate possible to avoid hypoglycemia High protein diet with 3-4 grams/kg/day (in type VI and IX: 2-3g/kg/day) Adjust dose based upon home glucose, ketone, and urine myoglobin monitoring
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