Glycogen Storage Diseases: - PowerPoint Presentation

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Glycogen Storage Diseases:

ObjectivesStructure of Glycogen. Anabolism Vs Catabolism mechanisms.

Glycogen storage disorders.

Overview of Glycogen MetabolismExcess glucose stored as glycogenGlucose units joined by α

-1,4 and

α

-1,6 glycosidic bonds

Glucosyl chains are branched

Fasted state (catabolic)—glycogen breakdownFed state (anabolic)—glycogen synthesis

Anabolism – GlycogenesisGlycogen synthase

extends chains (

α

-1,4) from non-reducing ends; uses UDP-glucose as substrate

Branching enzyme (transferase function) required to form branched chains; forms

α-1,6 glycosidic

bonds; moves 7 residues

Anabolism – Glycogenesis Glycogen synthase needs to be activated for glycogenesis to occurEnzymes involved in breakdown need to be deactivated

Fed state dominated by

insulin

Protein phosphatase I

activated (also inactivates phosphorylase kinase

, as shown below)

Catabolism - GlycogenolysisGlycogen phosphorylase removes

glucosyl

unit from non-reducing end by

phosphorylysis

(releases glucose-1-phosphate)

Debranching enzyme (

transferase activity) moves 3 glucose units to another branch; hydrolyzes

α

-1,6 linkage with

glucosidase

function (same polypeptide chain for eukaryotes)

Catabolism - Glycogenolysis

GSD Type 0An inherited genetic diseaseEnzyme affected: glycogen synthaseThe body is unable to store glycogen

LIVER:

Chromosome 12

-hypoglycemia when fasting

-hyperglycemia right after meals

MUSCLE: Chromosome 19

-frequent fatigue and muscle cramps

GSD Type 1Edgar von Gierke’s Disease

Most common disease type (approximately 1 in 20,000 infants)

Characterized by:

-an abnormally large abdomen due to an accumulation of glycogen in the liver

-prominent hypoglycemia in between meals (may cause convulsions in infants)

Deficiency of the Enzyme glucose-6-phosphatase

An inherited defect in chromosome 17

The body is not able to break down glycogen into glucose

Glucagon

Cascade

Prolonged hypoglycemia can cause

GSD Type IIPompe’s disease, acid maltase deficiencyAlpha-1,4-glucosidase (lysosomal

glucosidase

; acid maltase)

Catalyzes

α-1,4- and α-1,6-glucosidic linkages (hydrolysis)

Lysosomes dispose/recycle waste products

acid alpha-

glucosidase

gene, mapped in

chromosome

17

Autosomal recessive disorder

Diagnosis

: Determining activity of acid alpha-

glucosidase

enzyme

Muscle weakness and heart problems are the most common features even though defected enzyme is present in all tissues

GSD Type III / Cori Disease Caused by mutation in gene responsible for making the glycogen debranching enzymeIt is inherited and

leads to abnormal

glycogen in the body

Divided into types

IIIa

, IIIb, IIIc

, IIId

Affects 1 in 100,000 individuals, whereas it affects 1 in 5,400 individuals of North African

Jewish

GSD Type IV / Anderson Disease Caused by mutation in gene responsible for making the glycogen branching enzyme It is inherited and

leads to

abnormal glycogen in the body

Divided into 5 subtypes, which vary in severity, signs and symptoms

Affects 1 in 600,000 to 800,000 individuals world wide

GSD Type V / McArdle diseaseCaused by mutation in gene

which is responsible for

myophosphorylase

It is inherited and

leads to inability

to break down glycogen in muscle cells

Symptoms include exercise intolerance marked by rapid fatigue and cramps in exercising musclesGenerally rare but affects 1 in 100,000

individuals

GSD Type VIHers disease, liver phosphorylase deficiency

Liver

glycogen phosphorylase

Early signs and symptoms frequently includes hepatomegaly and hypoglycemia; growth retardation, ketosis, and

hyperlipidemia.

GSD Type VIITarui disease, muscle phosphofructokinase deficiencyPhosphofructokinase (muscle)PFKM, chromosome 12Exercise intolerance (due to muscle pain, cramping, fatigue, and tenderness), myopathy, and hemolysis; myoglobinuria may develop (dark-red or red-brown urine)