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, utilisation 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. The classification of glycogen storage disorders is 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 most common (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 Glycogen Storage Disease.

• Affected enzymes: Glucose-6-phosphatase translocase 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 Glycogen Storage 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.²
• 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 Glycogen Storage Disease.

In the past, Types VIII and X were considered distinct conditions but they are now classified with Type VI.

• 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.

See separate article on Phosphofructokinase Deficiency.

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

• Affected enzyme: Glucose transporter GLUT2.
• Clinical features: Similar features to Von Gierke's disease, e.g. hypoglycaemia.

• 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 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
  • 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.³
  • Glucagon stimulation test: in GSD there is not the normal rise in blood glucose.
  • DNA analysis from peripheral lymphocytes for McArdle's disease.⁴

Pre-natal diagnosis

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

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