5th February 2024

Glycogen storage disorders

Glycogen metabolism

As a revision to the previous section, glycogen is converted to glucose-6-phosphate under the regulation of debranching enzyme, hepatic glycogen phosphorylase and phosphorylase kinase. Glucose-6-phosphatase is responsible for converting glucose-6-phosphate to glucose.

Glycogen storage disorders are inherited disorders characterised by enzyme deficiencies which impair glycogen synthesis, glycogen degradation or glycolysis, leading to the deposition of an abnormal quantity or form of glycogen in the tissues. The liver and the skeletal muscles are the most commonly affected. The following are the diseases in this category that are favourites in the MRCP Part 1 exam:

• Maturity onset diabetes of the young type 2 (MODY type 2)
• Glucose-6-phosphatase deficiency (GSD type I, von Gierke’s disease) vs. G6PD deficiency
• McArdle disease

Clinical summary

Maturity onset diabetes of the young type 2 (MODY type 2) 

This autosomal dominant condition is due to glucokinase mutation, which facilitates phosphorylation of glucose to glucose-6-phosphate. Due to the loss-of-function mutations in the glucokinase molecule, it becomes less sensitive or responsive to rising glucose levels. This produces a chronic, mild increase in blood sugar and is usually asymptomatic. MODY type 2 does not cause insulin resistance. Therefore, many treatments for type 2 diabetes mellitus are not effective in this case. 

Further notes…

• Maturity onset diabetes of the young (MODY) type 1: type 2 diabetic mellitus in patients less than 25 years old, autosomal dominant with positive family history, very sensitive to sulphonylureas
• Maturity onset diabetes of the young (MODY) type 3: increase the risk of hepatocellular carcinoma, defect in HNF-1 alpha gene

Glucose-6-phosphatase deficiency

Also known as glycogen storage disease type 1, glucose-6-phosphatase deficiency impairs free glucose availability in the last step of gluconeogenesis (glucose-6-phosphate to glucose). This is also called Von Gierke disease, an autosomal recessive condition. The main diagnostic criteria are hepatomegaly, fast-induced hypoglycaemia with hyperlacticaemia and hyperlipidaemia. More commonly, patients present by six months of age with a distended abdomen. Hypoglycaemia may cause convulsions. Other biological hallmarks are hyperlipidaemia and hyperuricaemia. Hypercalciuria can also result from renal distal tubular dysfunction, contributing to renal calculi and nephrocalcinosis. Haemolytic anaemia is commonly found. The development of hepatocellular adenomas is a well-known complication.

Do not get confused with G6PD deficiency!

G6PD deficiency is an X-linked hereditary disease resulting in non-immune haemolytic anaemia and jaundice. The G6PD gene mutation results in low levels of functional glucose-6-phosphate dehydrogenase, leading to low levels of NADPH coenzyme and depletion of antioxidant known as glutathione, which is necessary to protect the haemoglobin and red cell membrane from highly reactive oxygen radicals (oxidative stress). In the presence of triggering factors (e.g., infection, fava beans, certain drugs), premature red blood cell membrane breakdown can occur.

McArdle disease

McArdle disease is an autosomal recessive inborn metabolic disorder characterised by a deficiency or complete absence of myophosphorylase enzyme. This enzyme catalyses reactions that cause the conversion of glycogen to glucose. A deficiency of this enzyme causes the accumulation of glycogen in tissues. Clinical sequelae are systemic, but the defect is sometimes limited to particular tissues. Glycolysis is only partially hindered in McArdle disease, as muscle fibres can convert glucose to G6P downstream of the metabolic block.

A muscle biopsy can be performed to support the diagnosis, with hallmark findings including glycogen deposits and the absence of the enzyme myophosphorylase. Clinical symptoms and signs include physical activity intolerance (painful muscle cramps/fatigue) and muscle pain/stiffness with improved symptoms after approximately 10 minutes of gentle aerobic activity (second-wind phenomenon). Muscle wasting may be seen. A characteristic feature of McArdle disease is the chronically elevated serum creatinine enzyme levels. 

References

• Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P. Glucose-6-phosphatase deficiency. Orphanet journal of rare diseases. 2011 Dec;6(1):1-2.
• Kanungo S, Wells K, Tribett T, El-Gharbawy A. Glycogen metabolism and storage disorders. Annals of translational medicine. 2018 Dec;6(24).
• Rubarth LB. Glucose-6-phosphatase and glucose-6-phosphate dehydrogenase deficiency: How are they different? Neonatal Network. 2012 Jan 1;31(1):45-7.