Glycogen Storage Disorders

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.

• Glycogen synthesis errors result in decreased normal glycogen ± deposition of abnormally branched glycogen chains.
• Degradation errors block formation of glucose from glycogen, leading to hypoglycaemia and pathological accumulation of glycogen in the tissues.

These metabolic errors can be confined to just liver and muscle but some cause more generalised pathology and affect tissues such as the kidney, heart and bowel.

There are over 12 types of GSD and they are classified based on the enzyme deficiency and the affected tissue.

• The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births.¹
• Type I is the commonest (25% of all GSD).

• Suspect in infants and children with growth retardation, hypoglycaemia and hepatomegaly.
• In juveniles/adults GSD tends to present with fatigue and weakness on exercising and a myositis or myopathy picture.

• 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)

See separate article on Von Gierke's disease.

• Affected enzyme: Glucose-6-phosphatase (deficiency). Glucose production from glycogenolysis and gluconeogenesis cannot happen.
• Affected tissues: Liver, kidney.
• Clinical features:
  • Hepatomegaly, hypoglycaemia, growth retardation, delayed puberty, osteoporosis, bleeding diathesis (due to acquired platelet defect), obesity.
  • Convulsions caused by lactic acidosis. Xanthomas.
  • Develop hepatic tumours (adenomas and carcinomas), renal failure and gout in 20s and 30s.
• Specific biochemical features: Low glucose, raised lactate, hyperuricaemia, hyperlipidaemia (but no increased risk of coronary heart disease).²
• Treatment:
  • Maintain normoglycaemia throughout 24 hours by IV feeding initially, followed by continuous nasogastric nocturnal feeding and daytime glucose supplements 1-2 hourly. These allow child to catch up with normal growth.
  • Later in childhood and adulthood, can treat with raw cornstarch every 4-6 hours in water as it releases calories slowly.^3,4
  • DDAVP can be used for platelet and clotting abnormalities. Liver transplant is reserved for patients where nutritional treatment has failed.
  • Gene therapy has also been trialled.⁵
• Prognosis - Can survive into adult life.

• Affected enzymes: Glucose-6-phosphatase tanslocase deficiencies.
• Clinical features:
  • As in Von Gierke's disease with variable clinical expression but also immunosuppression (altered neutrophil functions), leading to infection. Pneumonia or oral infection often seen.
  • May suffer from severe diarrhoea due to granulomatous infiltration of colonic mucosa.
• Treatment: As in Von Gierke's disease but avoid infection. May need prophylactic antibiotics.

See separate article on Pompe's disease.

• Affected enzyme: Acid alpha-glucosidase.
• Affected tissues:
  • Lysosomal storage disorder. Lysosomal accumulation of glycogen.
  • Generalised disorder but particularly affects heart, muscles, liver, nervous system and blood vessels.
• Clinical features:
  • Infantile form - normal at birth; within few months develop generalised hypotonia, macroglossia, breathing problems, cardiomegaly leading to cardiac failure and death usually before age 2.
  • 12.3% survival rate at 18 months in one study.⁶
  • Juvenile/adult form cause progressive proximal myopathy and respiratory failure due to diaphragmatic weakness.
  • Intracranial aneurysms may occur.
• Specific biochemical features: Raised creatine kinase
• Treatment:
  • May benefit from high protein, restricted carbohydrate diet.
  • Clinical trials have shown the effectiveness of enzyme replacement and National Service Framework Guidelines now suggest the use of Myozyme.⁷ There is prolonged survival, reversal of cardiomyopathy and motor gains with treatment.⁸
  • Gene therapy also holds promise.⁸

• 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.⁹
• Specific biochemical features: Hyperlipidaemia.
• Treatment: As with type I, also protein supplements for muscle disorder.

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

See separate article on McArdle's disease.

• Affected enzyme: Myophosphorylase. Unable to release glucose from glycogen in muscle.
• Affected tissues: Skeletal muscle only.
• Clinical features:
  • Presents in early adulthood/adolescence.
  • Muscle weakness and cramps after exercise; burgundy-coloured urine after exercise due to rhabdomyolysis and myoglobinuria; tiredness maximal after 10-15 mins with rapid recovery and ability to resume (second-wind phenomenon)
  • Pain can even occur on chewing, gripping, writing.
• Specific biochemical features: Raised creatine kinase, myoglobinuria, hypoglycaemia.
• Treatment:
  • Glucose or pre-exercise glucagon.¹⁰
  • It was thought strenuous exercise should be avoided but trials have shown that exercise may improve symptoms.^11,12
• Prognosis: Usually benign. Renal failure can occur due to myoglobinuria. Can get muscle wasting and weakness in later life.

• 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.
• Specific biochemical features: Mild ketosis, hyperlipidaemia.
• Treatment: Cardiac transplantation for rare cardiac form. May need frequent feeding to avoid hypoglycaemia.
• Prognosis: Usually normal life span.

• Affected enzyme: Phosphofructokinase. This is needed for the breakdown of glycogen to glucose.
• Affected tissues: Muscle, red blood cells.
• Clinical features
  • Commoner in Japanese and Russian Ashkenazis.
  • Similar presentation to Type V. Also fatal infantile variant. Chronic haemolysis (due to red cell phosphokinase deficiency) and pigment gallstones.
• Specific biochemical features: Hyperuricaemia, anaemia, raised bilirubin, raised creatine kinase.
• Treatment: No specific treatment

• Affected enzyme: Liver phosphorylase activating/deactivating cascade.
• Affected tissues: Liver, brain.
• Clinical features: Hepatomegaly. Progressive neural degeneration, death in childhood.

• Affected enzyme: Phosphorylase b kinase.
• Affected tissues: Liver.
• Clinical features: Hepatomegaly, hypoglycaemia.

• Affected enzyme: Cyclic-AMP dependent kinase.
• Clinical features: Similar to VI and IX.

• Affected enzyme: Hepatic glycogen synthase.
• Affected tissues: Liver.
• Clinical features: Fasting, ketotic hypoglycaemia when ceasing night time feeds in infants or between meals in older children. Seizures can occur. Post-prandial hyperglycaemia. Fatigue and muscle cramps after exertion. Mild growth retardation in some cases.
• Specific biochemical features:
  • Hypoglycaemia, ketosis, raised fasting lactate.
  • Glycosuria and ketonuria occur after breakfast and thus condition may be confused with diabetes mellitus.

• Blood tests:
  • Blood glucose: hypoglycaemia 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
  • Bleeding time
• 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.
  Direct biochemical assay of tissues for glycogen and fat content and enzyme analysis.
• Other Tests:
  • Forearm Exercise Test: Useful in McArdle's disease diagnosis where there is an absence of increased venous lactate in the exercising arm. Non-ischaemic tests that are less painful now preferred.¹³
  • Glucagon stimulation test: In GSD there is not the normal rise in blood glucose.
  • DNA analysis from peripheral lymphocytes for McArdle's disease.¹⁴

• In Glycogen Storage Disorders affecting muscle, exclude the muscular dystrophies (including Duchenne's) and secondary disorders of muscle including polymyositis.

• Genetic counselling
• Referral to geneticist for possible prenatal investigation (amniotic fluid analysis) and diagnosis