Glycogen Storage Diseases

  • Mingyi Chen
Part of the Molecular Pathology Library book series (MPLB, volume 5)


Glycogen is a branched polymer of glucose, which serves as a reservoir of glucose units. The two largest deposits in mammals are in the liver and skeletal muscle but many cells are capable of synthesizing glycogen. Its accumulation and utilization are under elaborate control by a variety of enzymes.


Lactic Acidosis Uric Acid Level Glycogen Storage Disease Autosomal Recessive Disorder Prevalent Mutation 
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Glycogen is a branched polymer of glucose, which serves as a reservoir of glucose units. The two largest deposits in mammals are in the liver and skeletal muscle but many cells are capable of synthesizing glycogen. Its accumulation and utilization are under elaborate control by a variety of enzymes.

Glycogen in the liver (and to a lesser degree in the kidneys) serves as a form of stored and rapidly accessible glucose, so that the blood glucose level can be maintained between meals. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis, and glycogen synthesis. For about 3 h after a carbohydrate-containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose-6-phosphate (G6P), and to add the G6P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6P is also shunted into production of triglycerides and exported for storage in adipose tissue as fat [1]. The glucose and glycogen metabolic pathways in liver are discussed in greater detail in chapter 8 of this textbook and also summarized in Fig. 45.1.
Fig. 45.1

Glucose metabolism in hepatocytes


Glycogen storage diseases (GSDs) are a heterogeneous group of disorders differing in clinical, biochemical, and molecular features. Defects in basic metabolizing enzymes lead to severe consequences, whereas, with some exceptions, mutations in the regulatory proteins appear to cause a more subtle phenotypic change. GSDs can be genetic or acquired, and are characterized by abnormal inherited glycogen metabolism in the liver, muscle, and brain. Genetic GSDs are caused by inborn errors of metabolism and involve genetically defective enzymes. They are mostly inherited as autosomal recessive disorders and result in defects of glycogen synthesis or catabolism. The acquired GSDs are often caused by intoxication with alkaloids.

Types of Glycogen Storage Diseases

The overall incidence of GSDs is estimated at 1 case per 20,000–43,000 live births. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. There are over 12 types (divided into types 0–XI), and they are classified based on the enzyme deficiency and the affected tissue (Table 45.1). Glucose-6-Phosphatase deficiency (Type I), Pompe’s disease (Type II), debrancher deficiency (Type III), and liver glycogen phosphorylase deficiency (Type VI) are the most common forms in children and myophosphorylase deficiency (Type V) is common in adults. GSD types VIa, VIII, IX, and X are caused by tissue-specific phosphorylase deficiency. Type XI is characterized by hepatic glycogenosis and renal Fanconi syndrome. Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs (as Type 0), because it is also a type of glycogen storage defect and can cause similar problems.
Table 45.1

Summary of the types of glycogen storage diseases

GSD type

Enzyme deficiency


GSD type I


von Gierke’s disease

GSD type II

Acid maltase

Pompe’s disease

GSD type III

Glycogen debrancher

Cori’s disease or Forbes disease

GSD type IV

Glycogen branching enzyme

Andersen’s disease

GSD type V

Muscle glycogen phosphorylase

McArdle’s disease

GSD type VI

Liver glycogen phosphorylase

Hers’ disease

GSD type VII

Muscle phosphofructokinase

Tarui’s disease

GSD type IX

Phosphorylase kinase

GSD type XI

Glucose transporter

Fanconi-Bickel disease

GSD type 0

Glycogen synthase

Clinical Features of GSDS

Type 1 GSD

Type 1 GSD (Von Gierke’s disease) is due to absence or deficiency of glucose-6-phosphatase activity in liver, kidney and intestinal mucosa with excessive accumulation of glycogen in these organs. It is an autosomal recessive disorder. Patients with type 1 GSD present in the neonatal period with hepatomegaly, hypoglycemic seizures, and lactic acidosis. They may present at 3–4 months with doll like facies due to accumulation of fat on cheeks and growth retardation. Laboratory parameters show hypoglycemia and lactic acidosis on short fast, hyperuricemia, and normal or slightly elevated liver enzymes with hyperlipidemia. Liver histology shows not only glycogen, but also presence of fat in the hepatocytes with little associated fibrosis (Fig. 45.2). Long-term complications include gout, hepatic adenomas, osteoporosis, renal disease, and short stature with most patients surviving to mid adulthood [2]. The diagnosis is suspected on clinical presentation and abnormal lactate & lipid levels. Administration of glucagons or epinephrine results in little or no rise in blood glucose. A definite diagnosis is made by determination of enzyme activity on liver biopsy or identification of mutations for G-6-P or translocase gene.
Fig. 45.2

Liver biopsy from an 18-month-old-male who had hepatomegaly for 6 months and was diagnosed with von Gierke’s disease. Deficiency of glucose-6-phosphatase results in accumulation of glycogen in hepatocytes. The hepatocytes are swollen and a mosaic histological pattern with compression of the sinusoids is seen. Microvesicular steatosis is also present


Type II GSD (Pompe’s disease) is a prototype of inborn lysosomal storage diseases and involves many organs, but primarily the muscle. It is due to acid maltase deficiency and is an autosomal recessive disorder. The c.−32–13T > G is the most frequent mutation in Caucasian populations [3]. The infantile variety presents at 0–6 months with cardiomegaly, hypotonia and hepatomegaly with death by 2 years. The juvenile form presents as myopathy and cardiomyopathy in childhood, and death by the second decade due to respiratory failure. The adult form presents between the second and seventh decade as slow progressive myopathy without cardiac involvement, but with progressive respiratory failure.


Type III GSD (debrancher deficiency, limit dextrinosis) is caused by deficiency of glycogen debranching enzyme activity as a result of which glycogen breakdown is incomplete and an abnormal glycogen with short outer branch chains accumulates. It is an autosomal recessive disorder with genetic defect on chromosome 1p21 [4]. Type IIIa involves both the liver and muscle, and IIIb solely the liver. The exon three mutations (17delAG and Q6X) are specifically associated with GSD-IIIb. The splice mutation IVS32-12A > G is found in GSD-III patients having mild clinical symptoms, while the 3965delT and 4529insA mutations are associated with a severe phenotype and early onset of clinical manifestations [5]. The disorder usually affects liver and muscle, although, in 15% of patients only the liver is involved. Patients present in childhood with hepatomegaly, hypoglycemia, hyperlipidemia and growth retardation and may be indistinguishable from type I disease. However, in Type III, blood lactate and uric acid levels are normal and liver enzymes are elevated. Liver symptoms improve with age and disappear after puberty. In patients with muscle involvement, the muscle weakness becomes predominant in adulthood leading to distal muscle wasting and ventricular hypertrophy. Liver histology is characterized by distension of hepatocytes by glycogen and presence of fibrous septa with paucity of fat. Glucagon administered 2 h after a carbohydrate meal provokes a normal rise of blood glucose, but no change after overnight fast. Definitive diagnosis requires enzyme assay in liver or muscle or both. Mutation analysis can also be done. Treatment is symptomatic with frequent feeds and uncooked cornstarch supplementation.


Type IV GSD (branching enzyme deficiency/Andersen’s disease) usually presents in the first year of life with hepatomegaly and growth retardation. L224P and Y329S are the two most common mutant alleles, and PCR-based mutation analysis is used for prenatal diagnosis of GSD type IV [6]. Patients present with failure to thrive, hypotonia, hepatosplenomegaly, progressive cirrhosis, and death by the fifth year. Liver transplant is an effective treatment modality.

Type V and VII GSD

Types V and VII involve only the muscle.

In Type V GSD (McArdle’s disease), muscle glycogenoses is caused by deficiency of muscle phosphorylase and presents in adulthood with exercise intolerance, muscle cramps, and attacks of myoglobinuria.

Type VII GSD is caused by deficiency of muscle phosphofructokinase with clinical features similar to GSD V, but is also associated with hemolytic anemia.

Type VI and IX GSD

Types VI and IX are a heterogeneous group of diseases caused by deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia.

Type VI GSD is caused by deficiency of liver phosphorylase and is a benign condition causing hepatomegaly, mild hypoglycemia, hyperlipidemia, and ketosis. There is no hyperlactic acidemia or hyperuricemia. The mainstay of treatment is high carbohydrate diet and frequent feedings.

Type IX GSD is due to phosphorylase kinase deficiency and the clinical picture depends on the organs involved. X-linked liver phosphorylase deficiency results in growth retardation and incidentally detected hepatomegaly. Hypoglycemia is mild, if present. Symptoms improve with age.

Type VIII and X GSD

Types VIII and X were considered distinct conditions in the past but are now reclassified with Type VI.

Molecular Mechanisms

Type 1 GSD, first described by Von Gierke in 1929, is the most common of the GSDs. It is a group of autosomal recessive disorders with an incidence of 1 in 100,000 [1]. In 1952, Cori and Cori showed that GSD-1 is caused by the absence of glucose-6-phosphatase (G6Pase) activity, establishing for the first time that metabolic disorders could arise from enzyme deficiencies [7]. Deficiency of G6Pase impairs the ability of the liver to produce free glucose from both glycogen and gluconeogenesis. Since these are the two principal metabolic mechanisms by which the liver supplies glucose to the rest of the body during periods of fasting, it causes severe hypoglycemia. Reduced glycogen breakdown results in increased glycogen storage in the liver and kidneys, causing their enlargement. Both organs function normally in childhood, but are susceptible to a variety of problems in the adult years. Other metabolic derangements include lactic acidosis and hyperlipidemia.

G6Pase is an enzyme located on the inner membrane of the endoplasmic reticulum (ER). It has been shown to comprise of at least five different polypeptides: a catalytic subunit, a regulatory Ca2+ binding protein, and three transport proteins (glucose-6-phosphate, phosphate/pyrophosphate, and glucose) [1]. The catalytic unit is associated with a calcium binding protein and three transport proteins (T1, T2, and T3) that facilitate movement of glucose-6-phosphate (G6P), phosphate, and glucose (respectively) into and out of the enzyme [8, 9]. A defect of these proteins could cause type I glycogenosis. The major subtypes of GSD I are designated as GSD Ia and GSD Ib, the former accounting for over 80% of diagnosed cases and the latter for less than 20%. Molecular and genetic evidence have unequivocally demonstrated that the two major GSD-1 subgroups, GSD-1a and GSD-1b, have different etiologies [8]. GSD-Ia is caused by complete absence of or markedly decreased microsomal G6Pase enzymatic activity in the liver and the kidneys. GSD-Ib has normal G6Pase activity, and is caused by a deficiency in the glucose-6-phosphate transporter (G6PT) systems that abolish or greatly reduce microsomal G6P uptake activity. Both G6Pase and G6PT are associated with the ER membrane. G6PT translocates G6P from the cytoplasm into the lumen of the ER, whereas, G6Pase hydrolyses the G6P into glucose and phosphate. Together, G6Pase and G6PT thus maintain glucose homeostasis. G6Pase is expressed primarily in gluconeogenic tissues, namely, the liver, kidney, and intestine. However G6PT, which transports G6P efficiently only in the presence of G6Pase, is expressed ubiquitously. This suggests that G6PT may play other roles in tissues that lack G6Pase [9]. Both GSD-Ia and GSD-Ib patients manifest phenotypic G6Pase deficiency, characterized by growth retardation, hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, and lactic acidemia. The current treatment is mainly a dietary therapy that includes frequent or continuous feedings of cornstarch or other carbohydrates [10]. Allopurinol may be given to lower uric acid levels. Other therapeutic measures may be needed for associated problems. GSD-Ib patients also suffer from chronic neutropenia, and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa, which is treated with granulocyte colony stimulating factor to restore myeloid function. The other two possible GSD type I variants; GSD-Ic and GSD-Id were observed in some literatures to be caused by deficiencies in pyrophosphate translocase, and glucose translocase activities, respectively. So far, the molecular basis of these disorders is not fully established [11].

GSD-I has an incidence in the American population of approximately 1 in 100,000–200,000 births [9]. In the past, GSD-1 was diagnosed primarily by clinical symptoms, supported by measurements of G6Pase activity in liver biopsy samples. Reliable carrier testing was not available. Recent advances in molecular analysis of hepatic GSDs have made rapid progress in our understanding of glycogen metabolism and we are able to reevaluate these disorders at the molecular level. With cloning of the GSD-Ia and GSDIb genes, DNA-based diagnostic tests for this disorder have been developed in many laboratories and a database of G6Pase and G6PT mutations has been established [8, 12]. The database provides the foundation for a gene-based diagnosis of carriers in at-risk families and a non-invasive prenatal screening test [8, 13, 14].

The human glucose-6-phosphatase cDNA was first cloned and characterized in 1993 [8, 9]. The G6Pase gene contains 5 exons, spans approximately 12.5 kb, and maps to chromosome 17q21. It encodes a 36-kDa glycoprotein that is anchored to the ER by nine transmembrane helices with its active site facing the lumen. To date, more than 80 separate mutations have been identified in the G6Pase gene [8]. These include missense (D38V, W77R, R83C, R83H, E110K, E110Q, A124T, V166G, P178S, G184E, G188S, G188R, L211P, G222R, W236R, P257L, G270V, R295C, and L345R), insertion/deletion (813insG822delC), nonsense (R170X and Q347X), and codon deletion (DF327) splicing mutations, which can abolish or greatly reduce G6Pase activity. Moreover, a splicing G6Pase mutation (727GÆT) was shown to cause exon-skipping. R83C and Q347X are the most prevalent mutations found in Caucasians [11]; R83C is the only prevalent mutation in the Ashkenazi Jewish population [15]; 130X and R83C are most prevalent in Hispanics; and R83H is most prevalent in Chinese [11, 16].

The G6PT gene maps to chromosome 11q23 and encodes a 37-kDa protein that is anchored to the ER by ten transmembrane helices [8]. DNA-based diagnostic tests for G6PT genes mutation seen in GSDIb have been developed. To date, more than 70 separate mutations have been identified in the G6PT gene. These include missense, nonsense, insertion/deletion, splicing, and codon-deletion mutations, which appear to be scattered throughout the coding region. Of the mutations identified to date, more than 80% are found in Caucasian patients, presumably reflecting their greater ethnic diversity [8]. Within this group, 1211delCT and G339C are the prevalent mutations, accounting for over 40% of all cases [8]. The prevalent mutation of G6PT gene in Japanese patients is W118R [17].

Once the diagnosis is suspected, the multiplicity of clinical and laboratory features usually makes for strong circumstantial evidence. If hepatomegaly, fasting hypoglycemia, and poor growth are accompanied by lactic acidosis, hyperuricemia, hypertriglyceridemia, and enlarged kidneys by ultrasound, GSD-I is the most likely diagnosis. The differential diagnoses include glycogenoses types III and VI, fructose 1,6-bisphosphatase deficiencies, and a few other conditions, but none are likely to produce all of the features of GSD-I. The diagnosis can be supported by liver biopsy with electron microscopy, and assay of glucose-6-phosphatase activity in the tissue. It is further confirmed by specific gene testing, establishing the molecular basis of this disorder. The database of the residual enzymatic activity retained by the G6Pase and G6PT ­mutations is facilitating the correlation of the disease phenotype with the patients’ genotype [8, 13].

The recent developments of genome-based studies have increased our understanding of the molecular mechanism of GSD disorders, and the progress will facilitate the development of novel therapeutic approaches for these disorders [18].


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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineLoma Linda University Medical CenterLoma LindaUSA

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