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 caused by deficiency or dysfunction of these enzymes.

• Glycogen synthesis errors result in decreased production of 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 GSD classification is based on the enzyme deficiency and the affected tissue.

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 syndrome⁷

• 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's muscular dystrophy) and secondary disorders of muscle, including polymyositis.

Document references

1. Ozen H; Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007 May 14;13(18):2541-53. [abstract]
2. Anderson WE; Glycogen Storage Disease, Type III, Medscape, Jan 2010
3. Demo E, Frush D, Gottfried M, et al; Glycogen storage disease type III-hepatocellular carcinoma a long-term complication? J Hepatol. 2007 Mar;46(3):492-8. Epub 2006 Nov 9. [abstract]
4. Anderson WE; Glycogen Storage Disease, Type IV, Medscape, Nov 2009
5. Anderson WE; Glycogen Storage Disease, Type VI, Medscape, Jan 2010
6. Glycogen storage disease IX, Online Mendelian Inheritance in Man (OMIM)
7. Santer R, Schneppenheim R, Suter D, et al; Fanconi-Bickel syndrome--the original patient and his natural history, historical Eur J Pediatr. 1998 Oct;157(10):783-97. [abstract]
8. Santer R, Steinmann B, Schaub J; Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport. Curr Mol Med. 2002 Mar;2(2):213-27. [abstract]
9. Ierardi-Curto I; Glycogen-Storage Disease Type 0, Medscape, Jun 2010
10. Kazemi-Esfarjani P, Skomorowska E, Jensen TD, et al; A nonischemic forearm exercise test for McArdle disease. Ann Neurol. 2002 Aug;52(2):153-9. [abstract]
11. Tsujino S, Shanske S, DiMauro S; Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). N Engl J Med. 1993 Jul 22;329(4):241-5. [abstract]

Internet and further reading

• Association for Glycogen Storage Disease UK
• Stojanov L et al; Glycogen Storage Diseases Types I-VII, Medscape, Mar 2009