glycogen storage disease (gsd)
DESCRIPTION
glycogen storage disease ..TRANSCRIPT
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GLYCOGEN STORAGE DISEASE (GSD)Saddam Ansari
Tbilisi State Medical University
4th May 2011
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Introduction• Glycogen is a branched-chain polymer of glucose and
serves as a dynamic but limited reservoir of glucose, mainly in skeletal muscle and liver.
• There are a number of different enzymes involved in glycogen synthesis, utilization and breakdown within the body.
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Continued…• Glycogen storage disorders (GSD) are a group of
inherited inborn errors of metabolism due to deficiency or dysfunction of these enzymes.
• confined to just liver and muscle
• But some cause more generalised pathology and affect tissues such as the kidney, heart and bowel.
• The classification of glycogen storage disorders is based on the enzyme deficiency and the affected tissue.
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Epidiomology • The overall GSD incidence is estimated at 1 case per
20,000-43,000 live births.
• Type I is the most common (25% of all GSD).
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Inheritance patterns• Autosomal recessive (I, II, III, IV, V, VII, some IX).
• Both parents are carriers. • Chance of sibling being affected is 1 in 4.
• X-linked (some IX, VI)
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Types • There are eleven (11) distinct diseases that are commonly
considered to be glycogen storage diseases
• Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0.
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Type I, Von Gierke's disease
Affected enzyme: glucose-6-phosphatase
Affected tissue: Liver and kidney
Clinical features:• Large quantities of glycogen are formed and stored in
hepatocytes, renal and intestinal mucosa cells. The liver and kidneys become enlarged.
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• Abnormalities of lipids may lead to xanthoma formation.
• Uric acid is often elevated and may cause clinical gout. Galactose, fructose, and glycerol are metabolised to lactate. The elevated blood lactate levels cause metabolic acidosis.
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Treatment • Blood loss may require oral iron.
• Raised uric acid levels may require allopurinol.
• Treatment of hyperuricaemia and pyelonephritis protect renal
function.
• Diazoxide to maintain blood glucose has been disappointing.
• Liver transplantation for primary disease or for hepatocellular carcinoma seems effective.
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Type II, Pompe's disease
Cause: • The deficiency of the lysosomal enzyme alpha-1,4-
glucosidase (acid maltase) leads to the accumulation of glycogen in many tissues.
Clinical feature:• The clinical spectrum is continuous and broad, with
presentation in infants, children and adults.
• In the infantile form, accumulation of glycogen in cardiac muscle leads to cardiac failure.
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• Accumulation may also occur in the liver, which results in hepatomegaly and elevation of hepatic enzymes.
• Glycogen accumulation in muscle and peripheral nerves causes hypotonia and weakness.
• Glycogen deposition in blood vessels may result in intracranial aneurysms.
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Treatment:• Enzyme replacement therapy (Alglucosidase alfa)
• Diet therapy may provide temporary improvement but does not alter the disease course: a high-protein, low-carbohydrate diet may be beneficial.
• Physiotherapy and occupational therapy may be required.
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• Genetic counselling and prenatal diagnosis: chorionic villus sampling and amniocentesis can be used to determine enzyme activity in a fetus.
• Gene therapy remains a potentially effective treatment for the future.
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Type III, Cori disease• Affected enzyme: Glycogen debranching enzyme.
Deposition of abnormal glycogen structure.
• Affected tissues: Liver and muscle.
• Clinical features:• About 15% affect liver only. Hypoglycaemia, poor
growth, hepatomegaly, moderate progressive myopathy.• Symptoms can regress with age.• A few cases of liver cirrhosis and hepatocellular
carcinoma have been reported.
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Continued…• Treatment: As with type I, also protein supplements for
muscle disorder.
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Type IV, Andersen's disease, Amylopectinosis
• Affected enzyme: Glycogen branching enzyme. Abnormally structured glycogen forms.
• Affected tissues: Many, including liver. Rare variant affects peripheral nerves.
• Clinical features:• Hepatomegaly, failure to thrive, cirrhosis, splenomegaly,
jaundice, hypotonia, waddling gait, lumbar lordosis.
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Continued…
• Treatment: Liver transplant.
• Prognosis: Mostly death by age 4 due to cirrhosis and portal hypertension.
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Type V, McArdle's disease
Cause: Myophosphorylase deficiency
Affected tissue: Muscle
Clinical features• Clinical findings may be absent on physical examination.
Muscle strength and reflexes may be normal
• In later adult life, persistent proximal weakness and muscle wasting may be present.
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• The fatal infantile form presents with hypotonia and reduced reflexes.
• Ischaemic forearm test: traditional test but is painful and non-ischaemic exercise tests are now preferred.
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Treatment • No specific treatment exists.
• Avoid strenuous (anaerobic or sustained) exercise, including lifting or pushing.
• A carbohydrate rich diet did benefit patients.
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Type VI, Hers disease• Affected enzyme: Liver phosphorylase.
• Affected tissues: Liver, rare cardiac form.
• Clinical features:• Most common variant is X-linked therefore usually
affects only males.• Hepatomegaly, hypoglycaemia, growth retardation,
hyperlipidaemia.
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Continued…• Treatment: Cardiac transplantation for rare cardiac form.
May need frequent feeding to avoid hypoglycaemia.
• Prognosis: Usually normal life span.
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Type VII, Tarui disease
Cause: Phosphofructokinase (PFK) deficiency
Affected tissue: Muscle
Clinical features:• Exercise intolerance, muscle cramping, exertional
myopathy, compensated haemolysis and myoglobinuria.
Note : Symptoms can be similar to McArdle's Glycogen Storage Disease but more severe.
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Treatment:
No specific treatment exists.
There is evidence that a high protein diet may improve muscle function and slow progression of the disease.
Vigorous exercise should be avoided as it causes myoglobinuria.
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Type XI, Fanconi-Bickel syndrome• Affected enzyme: Glucose transporter GLUT2 [solute
carrier family 2 ,facilitated glucose transporter]
• Clinical features: Similar features to Von Gierke's disease, e.g. hypoglycaemia.
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Type 0, Lewis disease• Affected enzyme: Hepatic glycogen synthase.
• Affected tissues: Liver.
• Clinical features• Seizures can occur. • Fatigue and muscle cramps after exertion. • Mild growth retardation in some cases.
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Investigation
Blood tests:• Blood glucose: hypoglycaemia is likely
• Liver function tests: monitoring for hepatic failure
• Anion gap calculation: if glucose low, this may indicate lactic acidaemia
• Urate
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• Creatinine clearance
• Creatine kinase
• Full blood count
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Urine tests:• Myoglobinuria after exercise found in 50% of people with
McArdle's disease.
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Imaging• Abdominal ultrasound scan: hepatomegaly
• Echocardiography: to look for cardiac involvement in certain types of GSD
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Biopsy • Of liver.
• Muscle or other tissues gives definitive diagnosis.
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Pre-natal diagnosis• Genetic counseling.
• Referral to geneticist for possible prenatal investigation (amniotic fluid analysis) and diagnosis.
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Differential Diagnosis• In GSD affecting muscle, exclude the muscular
dystrophies (including Duchenne's) and secondary disorders of muscle including polymyositis.
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Acknowledgement
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