Glycogen storage disease

Made by : khloud A.elbaset

Under supervision of

Dr./ Galila Yakout

Glycogen: Glycogen, an important energy source, is found in most tissues, but is especially abundant in liver and muscle.In the liver, glycogen serves as a glucose reserve for the maintenanceof normoglycemia. In muscle, glycogen provides energy for muscle contraction.the need to store or release glucose is primarily signaled by the hormones insulin and

glucagon .

There are about eleven known types of GSD, which are classified by a number, by the name of the defective enzyme, or by the name of the doctor who first described the condition

the GSDs can be divided in three main groups: those affecting liver ,those affecting muscle,and those which are generalized.

Note: All types of GSD cause the body to either not be able to make enough glucose, or not be able to use glucose as a form of energy. Determining what type of GSD a person has (diagnosis) depends on an individual's symptoms. Typically a doctor will do a physical examination and some blood and urine testing. Occasionally, a muscle and/or liver biopsy will be needed to measure the amount of a certain enzyme in that part of the body.

A. The liver glycogenoses :

The liver GSDs comprise GSD I, GSD III, GSD IV, GSD VI, the liver forms of GSD IX, andGSD 0.

Type I - Von Gierke Disease:Comprises GSD Ia: caused by deficiency of the catalytic subunit of glucose-6-phosphatase (G6Pase) ,

GSD Ib: due to deficiency of the endoplasmic reticulum (ER) glucose-6-phosphate (G6P) translocase.

Symptoms : Enlarged liver and kidneys Low blood sugar High levels of lactate, fats, and uric acid in the blood Impaired growth and delayed puberty Bone thinning from osteoporosis Increased mouth ulcers and infection

Metabolic disorder: G6Pase is unique since its catalytic site is situated inside the lumen of the ERHypoglycemia: occurs during fasting as soon as exogenous sources of glucose are exhausted, since the final steps in both glycogenolysis and gluconeogenesis are blocked.Hyperlactatemia: is a consequence of excess G6P that cannot be hydrolysed to glucose and is further metabolised in the glycolytic pathway, ultimately generating pyruvate and lactate.

Glycogen Storage Disease Type III(Debranching Enzyme Deficiency):

.GSD III, also known as Cori or Forbes disease, is an autosomal recessive disorder due to deficiency of GDE which causes storage of glycogen with an abnormally compact structure, known as phosphorylase limit dextrin

Symptoms: Swollen abdomen due to an enlarged liver Growth delay during childhood Low blood sugar Elevated fat levels in blood Possible muscle weakness

Glycogen Storage Disease Type IV (Branching Enzyme Deficiency):

Andersen Disease, is an autosomal recessive disorder due to a deficiency of glycogen branching enzyme (GBE). Deficiency of GBE results in the formation of an amylopectin-like compact glycogen molecule with fewer branching points and longer outer chains.  

Symptoms: Growth delay in childhood Enlarged liver Progressive cirrhosis of the liver (which may lead to liver failure) May affect muscles and heart in late-onset type

Glycogen Storage Disease Type 0( Glycogen Synthase Deficiency)GSD 0 is caused by a deficiency of

glycogen synthase (GS), a key-enzyme of glycogen synthesis. Consequently, patients with GS deficiency have decreased liver glycogen concentration, resulting in fasting hypoglycemia.  

The Muscle GlycogenosesGlycogen Storage Disease Type V(Myophosphorylase Deficiency)Under normal circumstances, muscles cells rely on

oxidation of fatty acids during rest or light activity. More demanding activity requires that they draw on their glycogen stockpile.

There are three isoforms of glycogen phosphorylase:brain/heart, liver, and muscle, all encoded by differentgenes. GSD V is caused by deficient myophosphorylaseactivity.

Symptoms Muscle cramps during exercise Extreme fatigue after exercise Burgundy-colored urine after exercise

Glycogen Storage Disease Type VII(Phosphofructokinase Deficiency)first described by TaruiAlthough glucose may be available as a fuel in muscles, the cells cannot metabolize it.Symptoms: Muscle cramps with exercise Anemia

The Generalized Glycogenoses and Related DisordersType II (Acid Maltase Deficiency)

GSD II is a lysosomal storage disorder, caused by the generalized deficiency of the lysosomal enzyme, acid maltase or α-glucosidase.Although the defect involves a single ubiquitous enzyme, it manifests as three different clinical phenotypes: Infantile, juvenile, and adult

In the infantile form, infants seem normal at birth, but within a few months they develop muscle weakness, trouble breathing, and an enlarged heart. Cardiac failure and death usually occur before age 2, despite medical treatment .

The juvenile and adult forms of GSD II affect mainly the skeletal muscles in the body's limbs and torso. Decreased muscle strength and weakness developed

Metabolic disorder : The enzyme defect results in the accumulation of glycogen within the lysosomes of all tissues, but particularly in muscle and heart, resulting in muscle weakness. Serum levels of transaminases (ASAT, ALAT), CK and CK-myocardial band (in the infantile form) are elevated

DiagnosisMuscle biopsy shows a severe

vacuolar myopathy with accumulation of both intralysosomal and free glycogen in both the infantile and childhood variants 

Treatment: Enzyme replacement therapy using recombinant human α-glucosidase, obtained in large quantities from rabbit milk has been used successfully ;

Four infants with Pompe disease were treated with spectacular results: although one patient died of an intercurrent infection at 4 years of age, all four patients showed remarkable clinical improvement in motor and cardiac function and parallel improvement in muscle morphology.

The same therapeutic approach was applied with success in three children with the muscular variant Before starting enzyme replacement, all three were wheelchair-bound and two were respirator-dependent. After 3 years of treatment, their pulmonary function had stabilised and their exercise tolerance had improved, and the youngest patient resumed walking

independently .

Danon DiseaseDanon Disease or GSD IIb, or pseudo-Pompe disease, is an X-linked dominant lysosomal storage disease due to deficiency of LAMP-2 (lysosomal-associated membrane protein 2). The disease starts after the first decade, is extremely rare and affects cardiac and skeletal muscle. Acid maltase activity is normal, muscle biopsy shows vacuolar myopathy with vacuoles containing glycogen and cytoplasmatic degradation products