Glycogen Storage Disease

Etiology

The etiology of GSDs is best understood by following the metabolic events leading to glycogen synthesis (glycogenesis) and degradation (glycogenolysis). Excess dietary glucose is stored in glycogen, and the synthesis of this molecule is, in part, accomplished by glycogen synthase. As indicated in Table 1, glycogen synthase has 2 distinct forms: one in the liver encoded by the GYS2 gene and another in skeletal muscle encoded by the GYS1 gene (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Table 1). Both enzyme forms work by attaching glucose monomers to growing glycogen polymers by creating α-1,4 links. As indicated in Figure 1 (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Figure 1), glycogen has α-1,4 and α-1,6 bonds between glucose units.

About 95% of glycogen linkages consist of α-1,4 bonds. Mutations in the GYS2 gene result in the absence or dysfunction of liver glycogen synthase, impairing glycogen synthesis in the liver and causing GSD type 0a. Similarly, mutations in the GYS1 gene lead to the absence or malfunction of muscle glycogen synthase, disrupting glycogen synthesis in muscles and resulting in GSD type 0b.

Glycogen synthase catalyzes the formation of α-1,4 glucose linkages in glycogen, but the glycogen branching enzyme (GBE1) is required to create the branching α-1,6 linkages. Mutations in GBE1 lead to the production of abnormally structured glycogen, known as polyglucosan bodies, which is the hallmark of GSD type IV. These polyglucosan bodies accumulate in liver and muscle cells and do not effectively undergo glycogenolysis. In muscle tissue, this accumulation causes weakness and myopathy, while in the liver, it results in hepatomegaly.

While GSD 0a and GSD 0b result from insufficient glycogen storage, most GSDs arise from defects in glycogenolysis, leading to glycogen accumulation. The initial step of glycogenolysis involves glycogen phosphorylase, which releases glucose-1-phosphate from glycogen. Mutations in the muscle-specific glycogen phosphorylase gene (PYGM) cause GSD type V, while mutations in the liver-specific glycogen phosphorylase gene (PYGL) result in GSD type VI.[4] The glucose-1-phosphate produced is subsequently converted to glucose-6-phosphate by phosphoglucomutase. In the liver, glucose-6-phosphatase, encoded by the G6PC gene, converts glucose-6-phosphate into free glucose, which is released into the bloodstream as an energy source for other tissues and organs (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Figure 2).

Notably, skeletal muscles lack glucose-6-phosphatase and cannot release glucose into the bloodstream. GSD type I arises from genetic defects in glucose-6-phosphatase metabolism. GSD type Ia, also known as von Gierke disease, is caused by mutations in the G6PC gene. In hepatocytes, glucose-6-phosphate is synthesized in the cytoplasm and transported into the lumen of the endoplasmic reticulum, where glucose-6-phosphatase converts it into glucose. The glucose is then transported back to the cytoplasm and subsequently released into the bloodstream via the hepatic GLUT2 transporter.[5]

Glucose-6-phosphate translocase 1 (G6PT1) is the transporter protein that facilitates the movement of glucose-6-phosphate between the cytoplasm and the endoplasmic reticulum. The G6PT protein consists of 3 subunits: G6PT1, G6PT2, and G6PT3 (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Figure 2). Mutations in the SLC37A4 gene, which encodes the G6PT1 protein, cause GSD type Ib (see Image. Glycogen, Free Glucose Release, and Glycogen Storage Diseases, Table 1). Fanconi-Bickel disease, a rare glycogen storage disorder, results from GLUT2 deficiency due to mutations in the SLC2A2 gene. GLUT2 deficiency impairs glucose export, increases intracellular glucose levels, and reduces glycogen degradation, leading to excessive glycogen storage and hepatomegaly.

Glycogen is a branched polymer, with glycogen phosphorylase removing glucose from α-1,4 linkages but unable to act on α-1,6 linkages at branch points. A glycogen debranching enzyme (GDE) is required to remove these branch points. In mammals, this enzyme is called "amylo-α-1,6-glucosidase, 4-α-glucanotransferase," encoded by the AGL gene. Mutations in the AGL gene cause GSD type III, resulting in either a nonfunctional GDE (GSD type IIIa or IIIb) or a GDE with reduced function (GSD type IIIc or IIId).[6]

GSD type II is unique among glycogen storage diseases, as it is also classified as a lysosomal storage disease.[7] Lysosomes are subcellular organelles responsible for recycling cellular macromolecules. Lysosomal storage diseases arise from the absence or dysfunction of a lysosomal enzyme. In GSD type II, the deficient enzyme is lysosomal acid α-glucosidase, encoded by the GAA gene. This enzyme breaks down glycogen into glucose for cellular energy. Mutations in the GAA gene lead to toxic glycogen accumulation within lysosomes.

Epidemiology

The true incidence of metabolic diseases is difficult to determine, given the lack of uniform, universal screening at birth. While GSD type IX has been found to be the most common subtype, the individual incidence of specific GSD types is further complicated due to overlapping symptoms and the lack of standardized specific testing in most areas of the world.

A study evaluating the incidence of inborn errors of metabolism in British Columbia in the 1990s reported that the incidence of these diseases was approximately 30 cases per 100,000 live births.[8] This figure represented a mix of metabolic disorders and was not restricted to GSDs. Approximately 2.3 children per 100,000 births were thought to have GSD in this study. Current literature suggests the incidence of GSDs is approximately 1 case per 20,000 to 43,000 live births, although incidence rates are found to be higher in specific population groups, such as non-Ashkenazi Jews.[9]

Pathophysiology

As mentioned, glycogen is the storage form of glucose and consists of long polymers of α-1,4-linked glucose, with branch points formed by α-1,6-linked glucose molecules. Glycogen's primary physiologic function is to provide glucose via glycogenolysis for glucose homeostasis. Liver stores are used to maintain glucose homeostasis in the serum, and muscle stores provide glucose for the muscles during periods of high demand, especially exercise, as a source of energy.

Hypoglycemia, hepatomegaly, muscle cramps, exercise intolerance, and weakness develop when these physiological functions are defective. Some disorders also affect the myocardial tissue and can lead to cardiomyopathy and cardiac conduction defects.[10] Failure to maintain glucose homeostasis triggers alternate pathways to meet metabolic demands. In GSD type 1, for example, failure of glycogenolysis in the liver results in increased lactic acid production, resulting in lactic acidosis due to the intracellular accumulation of glucose-6-phosphate, which stimulates the glycolytic pathway.

History and Physical

GSDs are a diverse set of rare inborn errors of carbohydrate metabolism that can have variable phenotypic presentations even within the same GSD type. Obtaining a family pedigree is useful in establishing the mode of inheritance. Most GSDs show an autosomal recessive inheritance, but a few, like GSD type IX, show an X-linked inheritance. Common presenting symptoms include growth retardation and poor weight gain in children, exercise intolerance, hypoglycemia, hepatomegaly, low muscle tone, acidosis, and hyperlipidemia. The most common manifestations of these disorders are hypoglycemia and exercise intolerance.

Patients with defects in hepatic glycogen metabolism typically present with fasting hypoglycemia and ketosis, with symptoms improving after glucose administration. The duration of fasting required to trigger hypoglycemia is a critical aspect of the history in patients with GSD. Hypoglycemia occurring after a short fasting period suggests glycogen storage disorders type I or III. In contrast, symptoms arising after an overnight fast indicate glycogen storage disorders type 0, VI, or IX.

All patients with GSDs should have anthropometric measurements obtained and graphed to assess their overall growth pattern. Short stature or poor linear growth and motor latency, especially in a child with hypoglycemia, warrant a GSD workup.

The inability to properly release glucose from glycogen can result in the abnormal accumulation of glycogen. In the liver, this failure results in hepatomegaly with the potential development of cirrhosis.

Defects in skeletal muscle glycogen metabolism lead to fatigue, muscle cramps, and exercise intolerance after brief periods of moderate-to-intense exercise, in contrast to defects in fatty acid metabolism, where symptoms typically appear after prolonged exercise. Individuals with skeletal muscle-associated GSDs may also present with rhabdomyolysis or myoglobinuria. In rare instances, these disorders may present as weakness instead of muscle cramps, which can progress to fixed weakness over time.[11] Patients with defects affecting cardiac muscles usually develop symptoms of cardiomyopathy, left ventricular hypertrophy, and, rarely, conduction defects.[12]

Evaluation

Laboratory Testing

Hypoglycemia should be documented by measuring serum glucose levels. In patients where hypoglycemia is suspected, a diagnostic fasting glucose test can be performed but should only be considered in a monitored inpatient setting.[13] Hepatic GSDs (type 0, III, VI, and IX) are characterized by ketosis and usually yield a β-hydroxybutyrate level greater than 2.5 mmol/L. These diseases also typically present with hypertriglyceridemia and elevated liver function tests. Patients with skeletal muscle-associated GSDs may also have elevated creatine kinase levels and urinary myoglobin levels. GSD type I is associated with elevated levels of lactic acid and acidosis.[14] 

Biopsy

Although specific genetic testing is now available for diagnosing most GSDs, histologic examination of liver or muscle biopsy is still used in specific scenarios. In GSD type 0, a liver biopsy typically shows decreased hepatic glycogen and can make a definitive diagnosis for this disease.[15] In GSD type I, a liver biopsy should reveal pale-staining, swollen hepatocytes, steatosis, and nuclear hyper-glycogenation. Fibrosis is another common finding on liver biopsy in patients with GSDs and is predominant in patients with GSD type III, IV, and VI. In GSD type III, periportal fibrosis and micronodular cirrhosis are often seen with distended hepatocytes due to excess glycogen accumulation.[16] 

Muscle biopsies typically reveal diastase-sensitive vacuoles that yield a positive staining result with periodic acid-Schiff (PAS) and acid phosphatase in GSD type IV.[17] In GSD type V, a muscle biopsy should demonstrate negative histochemical staining for phosphorylase activity. In the absence of phosphorylase activity, the specimen remains brown instead of taking up a deep blue hue. In addition, the biopsy should reveal subsarcolemmal deposits of glycogen detected by PAS staining.[18] In patients with GSD type XV, muscle biopsies often show PAS-positive inclusions that are not digested with α-amylase treatment and, on electron microscopy, may be seen as filamentous material corresponding to polyglucosan bodies.[19]

Molecular Testing

Molecular genetic testing is noninvasive and, for the most part, available for diagnosing these rare genetic disorders. In some cases, genetic tests have eliminated the need for invasive muscle and liver biopsies. The table below outlines the genetic foci of mutations for these disorders.

Table 2. Enzyme Deficiencies and Genes Involved in Various Glycogen Storage Diseases

Treatment / Management

GSDs currently have no cure, and most treatments aim to alleviate signs and symptoms. Critical goals include preventing and managing hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. Hypoglycemia may be avoided through starch consumption, with a commercially available, physically modified form now in use. In patients with GLUT2 deficiency, maintaining an antiketogenic diet leads to a significant decrease in liver size and glycogen content.[21] Hyperuricemia is managed with allopurinol, while hyperlipidemia is treated with statins. Some GSDs, such as GSD type II, can now be treated with enzyme replacement therapy (ERT) using recombinant alglucosidase alfa, which helps degrade lysosomal glycogen.[22] Ongoing research explores the potential use of ERT for other forms of GSD.

Liver transplantation should be considered for patients with certain GSDs that have progressed to hepatic malignancy or failure. While this procedure can correct hepatic failure and hypoglycemia, it does not address the cardiomyopathy associated with the GSD, which may continue to progress.

The immediate management of acute hypoglycemia involves rapid correction with oral carbohydrates or parenteral glucose. Glucagon is effective only in insulin-mediated hypoglycemia and will not help patients with hypoglycemia caused by a GSD.[23]

The following table provides a brief overview of therapeutic management for each GSD:

Table 3. Management Strategies for Glycogen Storage Diseases

Differential Diagnosis

The differential diagnosis of GSDs includes the following conditions:

• Charcot-Marie-Tooth disease
• Congenital disorders of glycosylation
• Congenital lactic acidosis
• Deficiencies of phosphofructokinase
• Disorders of uric acid metabolism
• DNA depletion syndrome
• Duchenne muscular dystrophy
• Duchenne-Becker muscular dystrophy
• Endocardial fibroelastosis
• Fatty acid oxidation disorders
• Fructose-1-phosphate aldolase deficiency
• Fructose-1,6-biphosphatase deficiency
• Galactosemia
• Hyperlipoproteinemia
• Limb-girdle muscular dystrophy
• Limb-girdle muscular dystrophy
• Lysosome-associated membrane protein 2 deficiency
• Mitochondrial DNA depletion syndromes
• Mitochondrial myopathies
• Neurovisceral sphingolipidosis
• Niemann-Pick disease
• Organic acidurias
• Organic acidurias
• Polymyositis
• Sphingomyelinase deficiency
• Spinal muscular atrophy
• Werdnig-Hoffman disease
• Zellweger syndrome

A comprehensive differential diagnosis is key to differentiating GSDs from other conditions with similar presentations. Prompt and accurate diagnosis can guide appropriate therapeutic approaches and prevent unnecessary treatments.

Prognosis

The prognosis of GSDs varies widely and depends on the enzyme defect and the type of GSD. Severe infantile forms are often associated with early mortality, while milder adult-onset cases have normal life spans. With early diagnosis and proper management, the prognosis of most GSDs remains favorable. The advent of ERT is expected to further improve outcomes in these patients.

Complications

Even with appropriate dietary modifications, GSDs are associated with a wide range of serious complications. In early childhood, individuals with GSDs are at risk of hypoglycemia-associated seizures and cardiac arrest. In patients with GSD type Ia, growth delay with short stature, osteopenia, renal dysfunction, hypertriglyceridemia, and hepatocellular carcinoma can occur. In GSD type Ib, recurrent bacterial infections secondary to neutropenia may be seen. In GSD type IV, progressive liver failure with cirrhosis can occur. Cardiomyopathy and limb-girdle dystrophy can be seen in patients with GSD type II. Hypertrophic cardiomyopathy is a classic complication of GSD type III.

Growth retardation and short status are also seen in GSD types IX (a, b, c, d) and XII, but a cognitive-developmental delay is also a feature of the latter. In GSD types V and XIII, exercise intolerance and rhabdomyolysis with an associated renal injury can occur. Rarely, end-stage renal disease requiring kidney transplantation may develop in patients with GSD type Ib.[24]