PharmD Glycogen storage disease Pathophysiology of GSD Nine types of GSD Epidemeology and inheritance patterns

1. GLYCOGEN STORAGE
DISEASE (GSD)
Mr. Jaineel Dharod (JD)
Dept. of Pharmacology

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.
•There are a number of different enzymes involved in glycogen synthesis,
utilization and breakdown within the body.
•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.
•But some cause more generalized 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.
JD’sPharmacology

3. Epidemiology
•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).
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)
JD’sPharmacology

4. JD’sPharmacology

5. Types
•There are Nine (9) distinct diseases that are commonly considered to be
glycogen storage diseases
•Glycogen is stored in the liver and muscles and is normally broken down into
glucose when you do not eat
•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
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

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
JD’sPharmacology

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.
JD’sPharmacology

10. Pompe’s 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
JD’sPharmacology

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
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

14. Type IV, Andersen's disease, Amylopectinosis
(Severe)
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.
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

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.
JD’sPharmacology

21. Investigation
Blood tests:
■ Blood glucose: hypoglycemia is likely
■ Liver function tests: monitoring for hepatic failure
■ Anion gap calculation: if glucose low, this may indicate lactic acidemia
■ Urate
■ Creatinine clearance
■ Creatine kinase
■ Complete blood count
Urine tests:
■ Myoglobinuria after exercise found in 50% of people with McArdle's disease.
JD’sPharmacology

22. Investigation
Imaging:
■ Abdominal ultrasound scan: hepatomegaly
■ Echocardiography: to look for cardiac involvement in certain types of GSD
Urine tests:
■ Myoglobinuria after exercise found in 50% of people with McArdle's disease.
Biopsy:
■ Biopsy of liver, Muscle or other tissues gives definitive diagnosis.
Pre-natal Diagnosis:
■ Genetic counseling.
■ Referral to geneticist for possible prenatal investigation (amniotic fluid
analysis) and diagnosis.
JD’sPharmacology

23. Differential Diagnosis
■ In GSD affecting muscle, exclude the muscular dystrophies (including
Duchenne's) and secondary disorders of muscle including polymyositis.
JD’sPharmacology

24. THANK YOU
JD’sPharmacology