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Glycogen Storage Disorders

Glycogen is a branched-chain polymer of glucose and serves as a dynamic but limited reservoir of glucose,
mainly in liver, skeletal muscle, heart, and sometimes the central nervous system and the kidneys. [1] There are a
number of different enzymes involved in glycogen synthesis, utilisation and breakdown within the body. Glycogen
storage disorders (GSDs) are a group of inherited inborn errors of metabolism caused by deficiency or
dysfunction of these enzymes. [2]
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. [3]

Epidemiology
The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births. [4]
Type I is the most common (25% of all GSDs).

Presentation
Suspect in infants and children with growth restriction, 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, VI, VII, some IX, Xl, 0). Both parents are carriers. The chance of a
sibling being affected is 1 in 4.
X-linked (some IX).

Type Ia: Von Gierke's disease

See the separate article on Von Gierke's Glycogen Storage Disease.

Type Ib [5]
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.

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

See the separate article on Pompe's Glycogen Storage Disease. A recent advance appears to be enzymatic
replacement therapy (ERT) in glycogenosis type II in both infantile, juvenile and adult form.

Type III: Cori's disease [6]

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.
Symptoms can regress with age.
A few cases of liver cirrhosis and hepatocellular carcinoma have been reported. [7]

Specific biochemical features: hyperlipidaemia.

Treatment: as with type I; also protein supplements for muscle disorder.

Type IV: Andersen's disease (amylopectinosis) [8]

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.
Complications: include hepatocellular carcinoma, liver failure, heart failure, nerve dysfunction and
ventricular arrhythmia.
Prognosis: mostly death by age 4, due to cirrhosis and portal hypertension.

Type V: McArdle's disease

See the separate article on McArdle's Glycogen Storage Disease.

Type VI: Hers' disease [9]

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; there is a rare cardiac form.
Clinical features:
The most common variant is X-linked and therefore usually affects only males.
Hepatomegaly, hypoglycaemia, growth restriction, 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 lifespan.

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Type VII: Tarui's disease

See the separate article on Phosphofructokinase Deficiency.

Type IX [10]
Affected enzyme: hepatic phosphorylase kinase. [11]
Affected tissues: liver.
Clinical features:: divided into types IXa and IXb; both are relatively benign. Clinical symptoms in IXa
include hepatomegaly, growth restriction, hyperlipidaemia and fasting ketosis. The clinical and
biochemical abnormalities gradually disappear by adulthood. [11]

Type XI: Fanconi-Bickel syndrome [12]

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.

Type 0 [13] [14]

GSD type 0 is a rare form, representing less than 1% of all cases.

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 restriction 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.

Prognosis: normal growth and intellectual development if diagnosed early and episodes of
hypoglycaemia are prevented.

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 (rarely) 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.

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Biopsy of liver, muscle or other tissues gives definitive diagnosis. However, biopsy has now largely
been replaced by by genetic testing.
Direct biochemical assay of tissues for glycogen and fat content and enzyme analysis.
Other tests:
Glucagon stimulation test: in GSD there is not the normal rise in blood glucose.
DNA analysis from peripheral lymphocytes for McArdle's disease.

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

Differential diagnoses [15]

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

Further reading & references

Association for Glycogen Storage Disease UK
1. Hicks J, Wartchow E, Mierau G; Glycogen storage diseases: a brief review and update on clinical features, genetic
abnormalities, pathologic features, and treatment. Ultrastruct Pathol. 2011 Oct;35(5):183-96. doi:
10.3109/01913123.2011.601404.
2. DiMauro S, Spiegel R; Progress and problems in muscle glycogenoses. Acta Myol. 2011 Oct;30(2):96-102.
3. Oldfors A, DiMauro S; New insights in the field of muscle glycogenoses. Curr Opin Neurol. 2013 Oct;26(5):544-53. doi:
10.1097/WCO.0b013e328364dbdc.
4. Ozen H; Glycogen storage diseases: New perspectives. World J Gastroenterol. 2007 May 14;13(18):2541-53.
5. Glycogen Storage Disease Ib, GSD1B; Online Mendelian Inheritance in Man (OMIM)
6. Glycogen Storage Disease III, GSD3; Online Mendelian Inheritance in Man (OMIM)
7. 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.
8. Glycogen Storage Disease IV, GSD4; Online Mendelian Inheritance in Man (OMIM)
9. Glycogen Storage Disease VI, GSD6; Online Mendelian Inheritance in Man (OMIM)
10. Tsilianidis LA, Fiske LM, Siegel S, et al; Aggressive therapy improves cirrhosis in glycogen storage disease type IX. Mol
Genet Metab. 2013 Jun;109(2):179-82. doi: 10.1016/j.ymgme.2013.03.009. Epub 2013 Mar 21.
11. Glycogen storage disease IX; Online Mendelian Inheritance in Man (OMIM)
12. Glycogen Storage Disease XI, Fanconi-Bickel syndrome; Online Mendelian Inheritance in Man (OMIM
13. Glycogen Storage Disease 0, Liver; Online Mendelian Inheritance in Man (OMIM)
14. Glycogen Storage Disease 0, Muscle; Online Mendelian Inheritance in Man (OMIM)
15. Berardo A, DiMauro S, Hirano M; Adiagnostic algorithm for metabolic myopathies. Curr Neurol Neurosci Rep. 2010
Mar;10(2):118-26. doi: 10.1007/s11910-010-0096-4.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical
conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its
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Original Author:
Dr Michelle Wright

Current Version:
Dr Colin Tidy

Peer Reviewer:
Dr Adrian Bonsall

Document ID:
2202 (v24)

Last Checked:
21/08/2014

Next Review:
20/08/2019

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