5th February 2024

Disorder of Carbohydrate and Glycogen Metabolism

Carbohydrate metabolism

Processes

Carbohydrates form a significant portion of the human diet and nutrition. This comprises three principal monosaccharides: glucose, fructose, and galactose. Glycogen is the storage form of carbohydrates in humans. 

In carbohydrate metabolism, one needs to understand:

Glycolysis

Glycolysis is a metabolic pathway catalysed by enzymes to convert glucose into pyruvate.

Gluconeogenesis

Gluconeogenesis results in the generation of glucose from non-carbohydrate sources that can be converted to pyruvate or intermediates of glycolysis. 

Glycogenolysis

This refers to the breakdown of glycogen into glucose-1-phosphate and then to glucose-6-phosphate, an intermediate in the glycolysis pathway. 

Glycogenesis

This refers to the process of synthesising glycogen. The glucose-6-phosphate (G6P) is the input substance for glycogenesis, created from glucose by glucokinase or hexokinase. 

Galactose metabolism

The main pathway is the Leloir pathway, which converts beta-D-galactose to alpha-D-galactose and using galactokinase enzyme to galactose-1-phosphate, then to UDP-glucose using galactose-1-phosphate uridylytransferase.

Image Source: Wikimedia Commons (2013). Galactose metabolic pathway, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/f/fd/Galactose_metabolic_pathway.png (Accessed: 21 December 2023).

Disorders of carbohydrate metabolism

Disorders of carbohydrate metabolism can occur in many forms, and they can be divided mainly into acquired or inherited (inborn). 

Acquired

Acquired forms of carbohydrate metabolism are more common, including diabetic ketoacidosis, hyperosmolar hyperglycaemic state and hypoglycaemia. 

Inherited

This section aims to describe common to rare inborn carbohydrate metabolism disorders. These conditions are usually present in children, and understanding the metabolic pathway affected is vital to understanding these conditions. Many of the clinical features of the inherited disorders of carbohydrate metabolism are caused by:

• Lack of glucose for body organ metabolism
• Inability to break down glucose to pyruvate
• Inability to oxidise pyruvate fully in the Krebs cycle

For the MRCP Part 1 exam, it is beneficial to know some (rare) disorders of carbohydrate metabolism (and its associated high-yield facts), which are favourites. 

Galactosaemia

Galactosaemia is a rare autosomal recessive condition due to the deficiency of galactose-1-phosphate uridylyltransferase, resulting in the accumulation of galactose-1-phosphate. This causes features such as:

• Jaundice and hepatomegaly
• Failure to thrive
• (Oil droplet) cataracts
• Hypoglycaemia after exposure to galactose
• Fanconi syndrome

Galactokinase deficiency

Galactokinase deficiency is an autosomal recessive disorder causing decreased conversion of galactose to galactose-1-phosphate. Galactokinase catalyses the first step of galactose phosphorylation in the Leloir pathway, and patients do not present with severe manifestations in early infancy. Important features include cataracts. Diet is the foundation of therapy, with the elimination of lactose and galactose sources being the definitive therapy.

References

• Dixon M, MacDonald A, Stafford J, Portnoi P. Disorders of carbohydrate metabolism. Clinical paediatric dietetics. 2014 Nov 7:526-87.
• DiMauro S, Akman O, Hays AP. Disorders of carbohydrate metabolism. Handbook of clinical neurology. 2007 Jan 1;86:167-82.
• Dickens F, Whelan WJ, Randle PJ, editors. Carbohydrate Metabolism: And Its Disorders. Elsevier; 2014 May 12.
• Werny D, Taplin C, Bennett JT, Pihoker C. Disorders of Carbohydrate Metabolism. InAvery’s Diseases of the Newborn 2018 Jan 1 (pp. 1403–1416). Elsevier.

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.

Disorders of glycosaminoglycan metabolism

Pathophysiology

Glycosaminoglycans, or mucopolysaccharides, are the degradation products of proteoglycans in the extracellular matrix and are proteolytic cleaved, giving origin to GAGs, which enter the lysosome for intracellular digestion. There are four different pathways:

• Dermatan sulfate
• Heparan sulfate
• Keratan sulfate
• Chondroitin sulfate

Mucopolysaccharidoses (MPs) are a group of inherited lysosomal storage disorders in which the abnormal accumulation of specific carbohydrate complexes can cause chronic and progressive symptoms with varying severity. Features can include organomegaly, dysostosis multiplex and characteristic abnormal facies. Definitive diagnosis is enzymatic assays of the defective enzyme in cultured fibroblasts, leucocytes, and serum or plasma. MPs are inherited in an autosomal recessive fashion, except MPS II (Hunter syndrome), which is X-linked.

Clinical summary

The table below shows details of common mucopolysaccharidoses that are favourites in the MRCP Part 1 exam:

References

Coutinho MF, Lacerda L, Alves S. Glycosaminoglycan storage disorders: a review. Biochemistry research international. 2012 Oct;2012.