2. ⢠Glycogen is a branched-chain polymer of glucose and serves as a dynamic
but limited reservoir of glucose, mainly in skeletal muscle and liver.
â˘There are a number of different enzymes involved in glycogen synthesis,
utilization and breakdown within the body.
â˘Glycogen storage disorders (GSD) are a group of inherited inborn errors of
metabolism due to deficiency or dysfunction of these enzymes. But this is
limited to just liver and muscle.
â˘But some cause more generalized pathology and affect tissues such as the
kidney, heart and bowel.
â˘The classification of glycogen storage disorders is based on the enzyme
deficiency and the affected tissue.
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3. Epidemiology
â˘The overall GSD incidence is estimated at 1 case per
20,000-43,000 live births.
â˘Type I is the most common (25% of all GSD).
Inheritance patterns
â˘Autosomal recessive (I, II, III, IV, V,VII, some IX).
â Both parents are carriers.
â Chance of sibling being affected is 1 in 4.
â˘X-linked (some IX, VI)
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5. Types
â˘There are Nine (9) distinct diseases that are commonly considered to be
glycogen storage diseases
â˘Glycogen is stored in the liver and muscles and is normally broken down into
glucose when you do not eat
â˘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.
⢠Von Gierke's disease
⢠Pompe's disease
⢠Cori disease
⢠Andersen's disease,
Amylopectinosis
⢠McArdle's disease
⢠Hers disease
⢠Tarui disease
⢠Fanconi-Bickel syndrome
⢠Lewis disease
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6. Type I, Von Gierke'sdisease (Severe)
Affected enzyme: glucose-6-phosphatase deficiency
Affected tissue: Liver and kidney
Clinical features:
⢠Condition in which the body cannot break down glycogen for energy.
⢠Large quantities of glycogen are formed and stored in hepatocytes, renal and
intestinal mucosa cells. The liver and kidneys become enlarged.
⢠Abnormalities of lipids may lead to xanthoma formation.
⢠Uric acid is often elevated and may cause clinical gout. Galactose, fructose,
and glycerol are metabolized to lactate. The elevated blood lactate levels
cause metabolic acidosis.
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7. Symptoms
⢠Frequent infection.
⢠Gout
⢠Kidney failure.
⢠Liver tumors.
⢠Osteoporosis.
⢠Seizures, lethargy, confusion due to low blood sugar.
⢠Short height.
⢠Underdeveloped secondary sexual characteristics (breasts, pubic hair).
⢠Ulcers of the mouth or bowel.
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8. Treatment
⢠Blood loss may require oral iron.
⢠Raised uric acid levels may require allopurinol.
⢠Treatment of hyperuricemia and pyelonephritis protect renal function.
⢠Liver transplantation for primary disease or for hepatocellular carcinoma
seems effective
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9. 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.
⢠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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10. Pompeâs Disease
Infantile onset < 12 months Late onset > 12 months
Head lag
Enlarged tongue
Respiratory
insufficiency
Delayed motor
development
Organomegaly
Cardiomegaly/
cardiomyopathy
Morning headache
Daytime somnolence
Shortness of breath/
sleep apnea
Scapular winging
Scoliosis
Low back pain
Muscle weakness
Signs &
Symptoms
Muscle weakness
Unusual symptoms or clusters of more common symptoms
Respiratory
insufficiency
Gait abnormality
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11. Treatment
⢠Enzyme replacement therapy (AL glucosidase 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.
⢠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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12. Type III, Cori disease (mild form of type-I)
Affected enzyme: Glycogen debranching enzyme. Deposition of abnormal
glycogen structure.
Other names include Forbes disease, an American Physician who further
described the features of the disorder, or limit dextrinosis.
Affected tissues: Liver and muscle.
Clinical features:
⢠About 15% affect liver only. Hypoglycemia, 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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13. Cause and Treatment
⢠This disease principally affects the liver.
⢠It causes swelling of the liver, slowing of growth, low blood sugar levels
and, sometimes, seizures.
⢠Muscle weakness may develop later in life, and is most pronounced in
the muscles of the forearms, hands, lower legs and feet.
⢠Weakness often is accompanied by loss of muscle bulk and exercise
intolerance.
Treatment: As with type I, also protein supplements for muscle disorder.
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15. Symptoms
⢠Failure to thrive
⢠Poor infant weight gain
⢠Lack of infant muscle tone
⢠Gastro intestinal Problems
⢠Enlarged liver
Treatment: Liver transplant.
Prognosis: Mostly death by young age due to cirrhosis and portal
hypertension.
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16. Type V, McArdle's disease
Cause: Myophosphorylase deficiency
Affected tissue: Muscle (Muscle cramps)
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.
⢠The fatal infantile form presents with hypotonia and reduced reflexes.
Treatment:
⢠No specific treatment exists.
⢠Avoid strenuous (anaerobic or sustained) exercise, including lifting or pushing.
⢠A carbohydrate rich diet shows benefit in the patients.
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17. 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, hypoglycemia, growth retardation, hyperlipidemia.
Treatment:
⢠Cardiac transplantation for rare cardiac form.
⢠May need frequent feeding to avoid hypoglycemia.
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18. Type VII, Tarui disease
Cause: Phosphofructokinase (PFK) deficiency
Affected tissue: Muscle
Clinical features:
Exercise intolerance, muscle cramping, exertional myopathy, compensated
hemolysis and myoglobinuria.
Note : Symptoms can be similar to McArdle's Disease but more severe.
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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19. 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. hypoglycemia.
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20. 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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21. Investigation
Blood tests:
â Blood glucose: hypoglycemia is likely
â Liver function tests: monitoring for hepatic failure
â Anion gap calculation: if glucose low, this may indicate lactic acidemia
â Urate
â Creatinine clearance
â Creatine kinase
â Complete blood count
Urine tests:
â Myoglobinuria after exercise found in 50% of people with McArdle's disease.
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22. Investigation
Imaging:
â Abdominal ultrasound scan: hepatomegaly
â Echocardiography: to look for cardiac involvement in certain types of GSD
Urine tests:
â Myoglobinuria after exercise found in 50% of people with McArdle's disease.
Biopsy:
â Biopsy of liver, Muscle or other tissues gives definitive diagnosis.
Pre-natal Diagnosis:
â Genetic counseling.
â Referral to geneticist for possible prenatal investigation (amniotic fluid
analysis) and diagnosis.
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23. Differential Diagnosis
â In GSD affecting muscle, exclude the muscular dystrophies (including
Duchenne's) and secondary disorders of muscle including polymyositis.
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