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Overview of inherited disorders of glucose and glycogen metabolism

Overview of inherited disorders of glucose and glycogen metabolism
Authors:
William J Craigen, MD, PhD
Basil T Darras, MD
Section Editor:
Sihoun Hahn, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jul 2022. | This topic last updated: Nov 23, 2021.

INTRODUCTION — There are a number of inborn errors of glucose and glycogen metabolism (dextrinosis and glycogenosis) that result from pathogenic variants in genes for virtually all of the proteins involved in glycogen synthesis, degradation, or regulation. Those disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). They are largely categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from in utero to adulthood.

This topic review provides a brief overview of the inherited disorders of glucose and glycogen metabolism (glycogenoses). The individual disorders are discussed separately in the appropriate topic reviews.

PHYSIOLOGY — Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is composed of long polymers of a 1-4 linked glucose, interrupted by a 1-6 linked branch point every 4 to 10 residues. Glycogen is formed during periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1).

Glycogen is most abundant in the liver and muscle and plays the following roles:

The main role of glycogen in the liver is to maintain glucose homeostasis. The liver stores glucose for release to tissues that are unable to synthesize significant amounts during fasting.

In muscle, glycogen is a source of energy for high-intensity muscle activity. Glycogen breakdown provides substrates for the generation of adenosine triphosphate (ATP).

CLINICAL AND LABORATORY FEATURES — The liver and skeletal muscle are most affected by disorders of glucose and glycogen metabolism. The physiologic importance of the defective enzyme in liver and muscle (table 1) determines the clinical manifestations of the disease. The major manifestations of disorders of glycogen metabolism affecting the liver are hypoglycemia and hepatomegaly (table 2) and, for those affecting muscle, are muscle cramps, exercise intolerance and easy fatigability, progressive weakness, and variable cardiac involvement with cardiomyopathy and conduction defects (table 3) [1]. Some forms of these disorders may have both liver and muscle findings along with less common complications of neurologic involvement and hemolysis.

Hypoglycemia — The main role of glycogen in the liver is to store glucose for release to tissues that are unable to synthesize significant amounts during fasting. Patients with a disorder of hepatic glycogen metabolism typically present with fasting hypoglycemia and ketosis with or without hepatomegaly. Their symptoms improve with eating or glucose administration. These children may have poor weight gain but are usually developmentally normal.

The diagnostic approach to hypoglycemia in infants, children, and newborns is discussed separately. (See "Approach to hypoglycemia in infants and children" and "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".)

Muscle symptoms — Glycogen is the primary source of energy for high-intensity muscle activity by providing substrates for the generation of adenosine triphosphate (ATP). Whereas defects in fatty acid metabolism cause symptoms after prolonged exercise, glycolytic defects usually present with symptoms after short periods of moderate-to-intense exercise. The major manifestations of disorders of glycogen metabolism affecting muscle fall into two main categories:

Exercise intolerance with muscle pain, cramps, rhabdomyolysis, and myoglobinuria – These symptoms are usually associated with defects of glycogenolysis or glycolysis.

Progressive weakness involving trunk and extremity muscles – This manifestation is typical of defects in lysosomal glycogenolysis (acid maltase deficiency) and also of defects in the glycogen synthesis pathway (glycogenin and brancher enzyme deficiency).

There are exceptions, however, because defects in certain glycogenolytic and glycolytic enzymes (eg, myophosphorylase, debrancher, phosphorylase kinase, phosphofructokinase) may present with weakness rather than cramps, and myoglobinuria or fixed weakness may develop later in life. Conversely, glycogen synthetase deficiency may cause exercise intolerance [2].

The diagnostic approach to a patient with a suspected metabolic myopathy is discussed separately. (See "Approach to the metabolic myopathies".)

Muscle and heart symptoms — A few glycogen storage diseases (GSDs) can affect both skeletal muscle and myocardium and therefore may result in both muscle symptoms and cardiomyopathy. The two main disorders are defects in lysosomal acid maltase and lysosome-associated membrane protein 2 but also two rarer GSDs, glycogenin I deficiency and muscle glycogen synthase deficiency [3].

CLASSIFICATION — Fifteen types of glycogen storage diseases (GSDs) have been identified (table 1). In a review of 1438 patients in a series from the United States and Europe, five GSDs accounted for 94 percent of cases: GSD I, GSD III, GSD VI, GSD IX (formerly VIII; all of which involve the liver), and GSD II, which involves skeletal muscle (table 4) [4]. Two other rare disorders of glycogen metabolism are glucose transporter 2 (GLUT2) deficiency and aldolase A deficiency. The functions of the enzymes and clinical characteristics of many of the individual disorders are discussed in detail separately.

Liver disorders — The following inherited disorders of glucose and glycogen metabolism primarily involve the liver:

Glycogen synthase-2 deficiency (GSD 0a) (see "Liver glycogen synthase deficiency (glycogen storage disease 0)")

Glucose-6-phosphatase deficiency (GSD Ia) (see "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)")

Glucose-6-phosphate transporter deficiency (GSD Ib) (see "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)")

Glycogen debrancher deficiency (GSD III) (see "Glycogen debrancher deficiency (glycogen storage disease III)")

Glycogen branching enzyme deficiency (GSD IV) (see "Glycogen branching enzyme deficiency (glycogen storage disease IV, Andersen disease)")

Liver phosphorylase deficiency (GSD VI) (see "Liver phosphorylase deficiency (glycogen storage disease VI, Hers disease)")

Phosphorylase kinase deficiency (GSD IXa1, formerly GSD VIII; GSD IXb-d) (see "Phosphorylase b kinase deficiency")

GLUT2 deficiency (see "Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency")

Skeletal muscle disorders — The following inherited disorders of glucose and glycogen metabolism primarily involve skeletal muscle:

Muscle phosphorylase deficiency (GSD V) (see "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)")

Phosphofructokinase deficiency (GSD VII) (see "Phosphofructokinase deficiency (glycogen storage disease VII, Tarui disease)")

Phosphoglycerate kinase deficiency (see "Phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency")

Phosphoglycerate mutase deficiency (GSD X) (see "Phosphoglycerate kinase deficiency and phosphoglycerate mutase deficiency")

Lactate dehydrogenase A deficiency (GSD XI) (see "Lactate dehydrogenase deficiency")

Aldolase A deficiency (GSD XII) (see "Other disorders of glycogen metabolism: GLUT2 deficiency and aldolase A deficiency")

Beta-enolase deficiency (GSD XIII)

Phosphoglucomutase-1 deficiency (GSD XIV) [5]

RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1) deficiency [2]

Skeletal and cardiac muscle disorders — The following inherited disorders involve both skeletal muscle and myocardium:

Lysosomal acid maltase deficiency (formerly GSD II) (see "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase deficiency)")

Lysosome-associated membrane protein 2 deficiency (formerly GSD IIb) (see "Lysosome-associated membrane protein 2 deficiency (glycogen storage disease IIb, Danon disease)")

Glycogenin-1 deficiency (GSD XV)

Muscle glycogen synthase deficiency (GSD 0b)

INTERNET RESOURCES — The following websites have information available for clinicians and patients:

Association for Glycogen Storage Disease

March of Dimes

Muscular Dystrophy Association

National Organization for Rare Disorders (NORD)

GeneReviews

Genetics Home Reference

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glycogen storage disease types I and II".)

SUMMARY

Glycogen is the stored form of glucose and serves as a buffer for glucose needs. It is formed in periods of dietary carbohydrate loading and broken down when glucose demand is high or dietary availability is low (figure 1). (See 'Introduction' above.)

Inherited disorders that result in abnormal storage of glycogen are known as glycogen storage diseases (GSDs). GSDs have largely been categorized by number according to the chronology of recognition of the responsible enzyme defect (table 1). The age of onset varies from birth to adulthood.

A disorder of hepatic glycogen metabolism should be considered in patients who present with fasting hypoglycemia and ketosis, with or without hepatomegaly, and whose symptoms improve with eating or glucose administration (table 2). (See 'Hypoglycemia' above.)

The major manifestations of disorders of glycogen metabolism affecting muscle are muscle pain, cramps, exercise intolerance and easy fatigability, progressive weakness, myoglobinuria, and variable degrees of cardiomyopathy. (See 'Muscle symptoms' above.)

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