GLYCOGEN STORAGE DISEASE (GSD)Saddam Ansari

Tbilisi State Medical University

4th May 2011

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.

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.

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).

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)

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.

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.

• 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.

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.

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.

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.

• 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.

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.

Continued…• Treatment: As with type I, also protein supplements for

muscle disorder.

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.

Continued…

• Treatment: Liver transplant.

• Prognosis: Mostly death by age 4 due to cirrhosis and portal hypertension.

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.

• 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.

Treatment • No specific treatment exists.

• Avoid strenuous (anaerobic or sustained) exercise, including lifting or pushing.

• A carbohydrate rich diet did benefit patients.

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.

Continued…• Treatment: Cardiac transplantation for rare cardiac form.

May need frequent feeding to avoid hypoglycaemia.

• Prognosis: Usually normal life span.

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.

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.

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.

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.

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

• Creatinine clearance

• Creatine kinase

• Full blood count

Urine tests:• Myoglobinuria after exercise found in 50% of people with

McArdle's disease.

Imaging• Abdominal ultrasound scan: hepatomegaly

• Echocardiography: to look for cardiac involvement in certain types of GSD

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.

Differential Diagnosis• In GSD affecting muscle, exclude the muscular

dystrophies (including Duchenne's) and secondary disorders of muscle including polymyositis.

Acknowledgement