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Glycogen storage disease Made by : khloud A.elbaset Under supervision of Dr./ Galila Yakout
Glycogen :Glycogen, an important energy source, isfound in most tissues, but is especiallyabundant in liver and muscle.In the liver, glycogen serves as a glucosereserve for the maintenanceofnormoglycemia. In muscle, glycogen provides energy formuscle contraction.the need to store or releaseglucose is primarily signaledby the hormones insulin and glucagon.
There are about eleven known types of GSD,which are classified by a number, by thename of the defective enzyme, or by thename of the doctor who first described theconditionthe GSDs can be divided in three mainthose affecting liver, groups:those affecting muscle,and those which are generalized.
Note :All types of GSD cause the body to either notbe able to make enough glucose, or not beable to use glucose as a form of energy.Determining what type of GSD a person has(diagnosis) depends on an individualssymptoms. Typically a doctor will do aphysical examination and some blood andurine testing. Occasionally, a muscle and/orliver biopsy will be needed to measure theamount of a certain enzyme in that part of thebody.
A. The liver glycogenoses :The liver GSDs compriseGSD I, GSD III, GSD IV, GSD VI, the liverforms of GSD IX, andGSD 0.
Type I - Von Gierke Disease:ComprisesGSD Ia: caused by deficiency of the catalyticsubunit of glucose-6-phosphatase (G6Pase),GSD Ib: due to deficiency of the endoplasmicreticulum (ER) glucose-6-phosphate (G6P)translocase.
Symptoms :Enlarged liver and kidneysLow blood sugarHigh levels of lactate, fats, and uric acid inthe bloodImpaired growth and delayed pubertyBone thinning from osteoporosisIncreased mouth ulcers and infection
Metabolic disorder :G6Pase is unique since its catalytic site issituated inside the lumen of the ERHypoglycemia: occurs during fasting as soon asexogenous sources of glucose are exhausted,since the final steps in both glycogenolysis andgluconeogenesis are blocked.Hyperlactatemia: is a consequence of excessG6P that cannot be hydrolysed to glucose andis 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 Forbesdisease, is an autosomal recessivedisorder due to deficiency of GDE whichcauses storage of glycogen with anabnormally compact structure, known asphosphorylase limit dextrin
Symptoms :Swollen abdomen due to an enlarged liverGrowth delay during childhoodLow blood sugarElevated fat levels in bloodPossible 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 childhoodEnlarged liverProgressive cirrhosis of the liver (which maylead to liver failure)May affect muscles and heart in late-onsettype
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 glycogenphosphorylase:brain/heart, liver, and muscle, all encoded bydifferentgenes. GSD V is caused by deficient
SymptomsMuscle cramps during exerciseExtreme fatigue after exerciseBurgundy-colored urine after exercise
Glycogen Storage Disease TypeVII(Phosphofructokinase Deficiency)first described by TaruiAlthough glucose may be available as a fuelin muscles, the cells cannot metabolize it.Symptoms :Muscle cramps with exerciseAnemia
The Generalized Glycogenoses andRelated DisordersType II (Acid Maltase Deficiency)GSD II is a lysosomal storage disorder,caused by the generalized deficiency ofthe lysosomal enzyme, acid maltase or α-glucosidase.Although the defect involves a singleubiquitous enzyme, it manifests as threedifferent clinical phenotypes: Infantile,juvenile, and adult
In the infantile form, infants seem normal atbirth, but within a few months they developmuscle weakness, trouble breathing, and anenlarged heart. Cardiac failure and deathusually occur before age 2, despite medicaltreatment.The juvenile and adult forms of GSD II affectmainly the skeletal muscles in the bodyslimbs and torso. Decreased muscle strengthand weakness developed
Metabolic disorder :The enzyme defect results in the accumulationof glycogen within the lysosomes of alltissues, but particularly in muscle and heart,resulting in muscle weakness. Serum levelsof transaminases (ASAT, ALAT), CK and CK-myocardial band (in the infantile form) areelevated
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 usingrecombinant human α-glucosidase,obtained in large quantities from rabbit milkhas been used successfully;Four infants with Pompe disease weretreated with spectacular results: althoughone patient died of an intercurrent infectionat 4 years of age, all four patients showedremarkable clinical improvement in motorand cardiac function and parallelimprovement in muscle morphology.
The same therapeutic approach was appliedwith success in three children with themuscular variant Before starting enzymereplacement, all three were wheelchair-bound and two were respirator-dependent.After 3 years of treatment, their pulmonaryfunction had stabilised and their exercisetolerance had improved, and the youngestpatient resumed walking independently.
Danon DiseaseDanon Disease or GSD IIb, or pseudo-Pompe disease, is an X-linked dominantlysosomal storage disease due todeficiency of LAMP-2 (lysosomal-associated membrane protein 2). Thedisease starts after the first decade, isextremely rare and affects cardiac andskeletal muscle. Acid maltase activity isnormal, muscle biopsy shows vacuolarmyopathy with vacuoles containingglycogen and cytoplasmatic degradationproducts