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INTRODUCTION

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Carbohydrate metabolism plays a vital role in cellular function by providing the energy required for most metabolic processes. The relevant biochemical pathways involved in the metabolism of these carbohydrates are shown in Fig. 412-1. Glucose is the principal substrate of energy metabolism in humans. Metabolism of glucose generates ATP through glycolysis and mitochondrial oxidative phosphorylation. The body obtains glucose through the ingestion of polysaccharides (primarily starch) and disaccharides (e.g., lactose, maltose, and sucrose). Lactose and fructose are two other monosaccharides that serve as sources of fuel for cellular metabolism; however, their role as fuel sources is much less significant than that of glucose. Lactose is derived from galactose + glucose, which is found in milk products, and is an important component of certain glycolipids, glycoproteins, and glycosaminoglycans. Fructose is found in fruits, vegetables, and honey. Sucrose (fructose + glucose) is another dietary source of fructose and is a commonly used sweetener.

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FIGURE 412-1

Metabolic pathways related to glycogen storage diseases and galactose and fructose disorders. Nonstandard abbreviations are as follows: GSa, active glycogen synthase; GSb, inactive glycogen synthase; Pa, active phosphorylase; Pb, inactive phosphorylase; PaP, phosphorylase α phosphatase; PbKa, active phosphorylase β kinase; PbKb, inactive phosphorylase β kinase; G, glycogenin, the primer protein for glycogen synthesis. (Modified from AR Beaudet, in KJ Isselbacher et al [eds]: Harrison’s Principles of Internal Medicine, 13th ed. New York, McGraw-Hill, 1994, p 1855.)

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Glycogen, the storage form of glucose in animal cells, is composed of glucose residues joined in straight chains by α1-4 linkages and branched at intervals of 4–10 residues by α1-6 linkages. Glycogen forms a treelike molecule and can have a molecular weight of many millions. Glycogen may aggregate to form structures recognizable by electron microscopy. With the exception of type 0 disease, defects in glycogen metabolism typically cause an accumulation of glycogen in the tissues—hence the designation glycogen storage diseases (GSDs). The structure of stored glycogen can be normal or abnormal in the various disorders. Defects in gluconeogenesis or glycolytic pathways including galactose and fructose metabolism usually do not result in glycogen accumulation.

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Clinical manifestations of the various disorders of carbohydrate metabolism differ markedly. The symptoms range from minimally harmful to lethal. Unlike disorders of lipid metabolism, mucopolysaccharidoses, or other storage diseases, many carbohydrate disorders have been managed with dietary therapy, yet despite these strides, long-term complications result, and there is a need for definitive therapies. Genes responsible for inherited defects of carbohydrate metabolism have been cloned, and mutations have been identified. With the use of tools such as DNA sequencing panels, whole exome sequencing, and whole genome sequencing, new disorders of glycogen storage continue to be identified and the phenotype of known disorders continues to expand, as is seen in ...

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