Epidemiology

• 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).

Presentation

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

Inheritance patterns

• Autosomal recessive (I, II, III, IV, V, VII, some IX). Both parents are carriers. The chance of a sibling being affected is 1 in 4.
• X-linked (some IX, VI).

Type Ia, Von Gierke's disease

See separate article Von Gierke's Glycogen Storage Disease.

Type Ib, c, d

• 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 and oral infections are 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.

Type II, Pompe's disease (acid maltase deficiency)

See separate article Pompe's Glycogen Storage Disease.

Type III, Cori's disease

Synonyms: Forbes' disease, Forbes-Cori disease

• Affected enzyme: glycogen debranching enzyme. Deposition of abnormal glycogen structure.
• Affected tissues: liver and muscle.
• Clinical features:
  • Seizures in infancy, hypoglycaemia, poor growth, hepatomegaly, moderate progressive myopathy.^[2]
  • Symptoms can regress with age.
  • A few cases of liver cirrhosis and hepatocellular carcinoma have been reported.^[3]
• Specific biochemical features: hyperlipidaemia.
• Treatment: as with type I; also protein supplements for muscle disorder.

Type IV, Andersen's disease, amylopectinosis

• Affected enzyme: transglucosidase (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: adherence to a dietary regimen may reduce liver size, prevent hypoglycaemia and improve growth and development. Management of organ failure as required.^[4]
• Complications: include hepatocellular carcinoma, liver failure, heart failure, nerve dysfunction and ventricular arrhythmia.^[4]
• Prognosis: mostly death by age 4 due to cirrhosis and portal hypertension.

Type V, McArdle's disease

See separate article McArdle's Glycogen Storage Disease.

Type VI, Hers' disease

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

• Affected enzyme: liver phosphorylase.^[5]
• Affected tissues: liver; there is a rare cardiac form.
• Clinical features:
  • The most common variant is X-linked and therefore usually affects only males.
  • Hepatomegaly, hypoglycaemia, growth retardation, hyperlipidaemia.
• Specific biochemical features: mild ketosis, hyperlipidaemia.
• Treatment: cardiac transplantation for the rare cardiac form. May need frequent feeding to avoid hypoglycaemia.
• Prognosis: usually, a normal life span.

Type VII, Tarui's disease

See separate article Phosphofructokinase Deficiency.

Type IX

• Affected enzyme: hepatic phosphorylase kinase.^[6]
• Affected tissues: liver.
• Clinical features:: divided into types IXa and IXb; both are relatively benign. Clinical symptoms in IXa include hepatomegaly, growth retardation, hyperlipidaemia and fasting ketosis. The clinical and biochemical abnormalities gradually disappear by adulthood.^[6]

Type XI, Fanconi-Bickel syndrome^[7]

• Affected enzyme: glucose transporter 2 (GLUT2).
• Clinical features: hepatomegaly, glucose and galactose intolerance, fasting hypoglycaemia, proximal tubular nephropathy and severe short stature. Symptoms persist into adulthood.
• Treatment: there is no specific therapy available. Symptomatic treatment to provide stable glucose homeostasis and compensate for renal losses of various solutes.^[8]

Type 0, Lewis' disease

Glycogen-storage disease type 0 is a rare form, representing less than 1% of all cases.^[9]

• 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. Postprandial 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 therefore may be confused with diabetes mellitus.
• Treatment: adequate diet and avoidance of fasting hypoglycaemia.^[9]
• Prognosis: normal growth and intellectual development if diagnosed early and episodes of hypoglycaemia are prevented.^[9]

Investigations

• Blood tests:
  • Blood glucose: hypoglycaemia is likely.
  • LFTs: monitoring for hepatic failure.
  • Anion gap calculation: if glucose is low, this may indicate lactic acidaemia.
  • Urate: there may be high urate levels and even associated gout.
  • Renal function tests.
  • Creatine kinase.
  • FBC: there may be anaemia, neutropenia.
  • Coagulation studies: increased bleeding tendency may occur.
  • Lipids: hyperlipidaemia occurs in some types of GSD.
• Urine tests: myoglobinuria after exercise - found in 50% of people with McArdle's disease.
• Imaging:
  • Abdominal ultrasound scan: hepatomegaly.
  • Echocardiography: 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 are now preferred.^[10]
  • Glucagon stimulation test: in GSD there is not the normal rise in blood glucose.
  • DNA analysis from peripheral lymphocytes for McArdle's disease.^[11]

Prenatal diagnosis

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

Differential diagnoses

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