Glycogen Storage Diseases Types I-VII

Updated: Dec 01, 2022
  • Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
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Glycogen storage disease type I

Glycogen storage disease (GSD) type I, also known as von Gierke disease, is a group of inherited autosomal recessive metabolic disorders of the glucose-6- phosphatase system which helps maintain glucose homeostasis. Von Gierke described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica. [1] In 1952, Cori and Cori demonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I. [2] In 1978, Narisawa et al proposed that a transport defect of glucose-6-phosphate (G6P) into the microsomal compartment may be present in some patients with GSD type I. [3] Thus, GSD type I is divided into GSD type Ia caused by G6Pase deficiency and GSD type Ib resulting from deficiency of a specific translocase T1. These subtypes are clinically indistinguishable from one another, except for the fact that patients with GSD type Ib have altered neutrophil functions predisposing them to gram-positive bacterial infections.

Later, other translocases were discovered, adding 2 more subtypes of GSD to the disease spectrum. GSD type Ic is deficiency of translocase T2 that carries inorganic phosphates from microsomes into the cytosol and pyrophosphates from the cytosol into microsomes. GSD type Id is deficiency in a transporter that translocates free glucose molecules from microsomes into the cytosol.

For practical purposes, depending on the enzyme activity and the presence of mutations in the G6Pase and T genes, respectively, GSD type I may be subdivided into 2 major forms. GSD type Ia demonstrates deficient G6Pase activity in the fresh and frozen liver tissue. GSD type Ib demonstrates normal G6Pase activity in the frozen tissue samples and lowered activity in the fresh specimens. [4]

Glycogen storage disease type II

GSD type II, also known as alpha glucosidase deficiency (GAA, acid maltase deficiency) or Pompe disease, is a prototypic lysosomal disease. Pompe initially described the disease in 1932. Its clinical presentation clearly differs from other forms of GSD, because it is caused by the deficiency of the lysosomal enzyme, alpha-1,4-glucosidase, leading to the pathologic accumulation of normally structured glycogen within the lysosomes of most tissues, differs Three forms of the disease exist: infantile-onset, late-onset juvenile and adult onset. In the classic infantile for, the main clinical signs are cardiomyopathy and muscular hypotonia (smooth and skeletal muscle). In the juvenile and adult form, the involvement of the skeletal muscle dominates the clinical presentation. [5] The images below illustrate histologic findings of GSD type II.

Glycogen storage disease type II. Photomicrograph Glycogen storage disease type II. Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).
Glycogen storage disease type II. Photomicrograph Glycogen storage disease type II. Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).

Glycogen storage disease type III

GSD type III is also known as Forbes-Cori disease or limit dextrinosis. It is an autosomal recessive disorder in which there is an AGL gene mutations which causes deficiency in glycogen debranchinging enzyme and limited storage of dextrin. The disease presents with variable cardiac muscle, skeletal muscle and liver involvement and has different subtypes. GSD IIIa is the most common subtype, affecting about 85% of patients with this disease. GSD IIIb is less severe and less common, affecting 15% of patients with the disease. [6, 7]  In contrast to GSD type I, liver and skeletal muscles are involved in GSD type III. Glycogen deposited in these organs has an abnormal structure. Differentiating patients with GSD type III from those with GSD type I solely on the basis of physical findings is not easy. [8]

Glycogen storage disease type IV

GSD type IV, also known as amylopectinosis, Glycogen Branching enzyme deficiency (GBE) or Andersen disease, is a rare disease that leads to early death. In 1956, Andersen reported the first patient with progressive hepatosplenomegaly and accumulation of abnormal polysaccharides. The main clinical features are liver insufficiency and abnormalities of the heart and nervous system. [9]  

Glycogen storage disease type V

GSD type V, also known as McArdle disease, affects the skeletal muscles. It is an autosomal recessive disorder in which there is a deficiency of glycogen phosphorylase.McArdle reported the first patient in 1951. Initial signs of the disease usually develop in adolescents or adults. Muscle phosphorylase deficiency adversely affecting the glycolytic pathway in skeletal musculature causes GSD type V. Like other forms of GSD, McArdle disease is heterogeneous. [10, 11]

Glycogen storage disease type VI

GSD type VI, also known as Hers disease, belongs to the group of hepatic glycogenoses and represents a heterogenous disease. [12] Hepatic phosphorylase deficiency or deficiency of other enzymes that form a cascade necessary for liver phosphorylase activation cause the disease. [13] In 1959, Hers described the first patients with proven phosphorylase deficiency.

Glycogen storage disease type VII

GSD type VII, also known as Tarui disease, arises as a result of phosphofructokinase (PFK) deficiency. The enzyme is located in skeletal muscles and erythrocytes. Tarui reported the first patients in 1965. The clinical and laboratory features are similar to those of GSD type V. [14]

Medscape Reference Endocrinology articles on GSD

See the list below:



Glycogen storage disease type I

G6Pase is mainly found in the liver, kidneys and intestines to maintain glycogenolysis and gluconeogenesis. Because of insufficient G6Pase activity, G6P cannot be converted into free glucose, and instead is metabolized to lactic acid or incorporated into glycogen. The excess glycogen that is formed is stored as molecules with normal structure in the cytoplasm of hepatocytes, renal and intestinal mucosa cells. The excess storage of glycogen causes enlarged liver and kidneys, which dominate the clinical presentation of this disease. The chief biochemical alteration is non ketotic hypoglycemia, while secondary biochemical abnormalities are hyperlactatemia, metabolic acidosis, hyperlipidemia, and hyperuricemia which cause metabolic decompensation. [15]

In hypoglycemia, the deficiency of G6Pase blocks the process of glycogen degradation and gluconeogenesis in the liver, preventing the production of free glucose molecules. As a consequence, patients with GSD type I have fasting hypoglycemia. Despite the metabolic block, the endogenous glucose formation is not fully inhibited. In young patients, production of free glucose reaches half that of healthy individuals, whereas adult patients may produce as much as two thirds of the healthy amount of free glucose. Hypoglycemia inhibits insulin secretion and stimulates glucagon and cortisol release.

In hyperlactatemia and acidosis, undegraded G6P, galactose, fructose, and glycerol are metabolized via the G6P pathway to lactate, which is used in the brain as an alternative source of energy. The elevated blood lactate levels cause metabolic acidosis.

In hyperuricemia, blood uric acid levels are raised because of the increased endogenous production and reduced urinary elimination caused by competition with the elevated concentrations of lactate, which should be excreted.

In hyperlipidemia, elevated endogenous triglyceride synthesis from nicotinamide adenine dinucleotide (NADH), NAD phosphate (NADPH), acetyl-coenzyme A (CoA), glycerol, and diminished lipolysis causes hyperlipidemia. Triglycerides increase the risk of fatty liver infiltration, which contributes to the enormous amount of liver enlargement. Despite significantly elevated serum triglyceride levels in patients, vascular lesions and atherosclerosis are rare complications. The increased serum apolipoprotein E concentrations that promote the clearance of triglycerides may explain the rarity of such complications.

Glycogen storage disease type II

Alpha-1,4-glucosidase acts hydrolyzing the alpha 1,4 and 1,6 glucosidic linkages of the glycogen molecule within the lysosome, hence, causes its degradation. In the GSD II, this enzyme is deficient, leading to the progressive accumulation of glycogen in the lysosomes and cytoplasm of different tissues causing its destruction.

GSD type 2 is an autosomal recessive disorder with significant heterogeneity. Multiple mutations in the gene encoding for the enzyme (17q25.2-q25.3) have been identified. These factors contribute to the different phenotypic presentation of the disease. Some patients have a deficiency in precursor protein synthesis, while in others, because of inadequate processing, the amount of mature molecule is insufficient or the enzyme has no catalytic activity. [16] Depending on the degree of residual enzyme activity, GSD type II manifests in infantile, juvenile, or adult forms. Mutations where the enzyme activity is minimal or absent (activity < 1% of normal control) leads to severe infantile onset form, develops. In cases where the enzyme activity is reduced(activity of 2-40%) then it presents as an early non classic onset or late onset. GSD II is progressive in all ages. [17]

Glycogen storage disease type III

Deficiency of the cytosolic debrancher enzyme, a monomeric high-molecular-weight protein that consists of 2 catalytic units (amylo-1,6-glucosidase and oligo-1,4-1,4-glucanotransferase), causes GSD type III. This enzyme is located on the AGL gene on chromosome 1p21.It is inherited in an autosomal recessive fashion. Abnormal glycogen with short external branches is stored in the liver, heart, and skeletal muscle cells. [18]  The accumulated glycogen resembles the limit dextrin, which is a product of glycogen degradation by phosphorylase. Two forms of the disease exist. In GSD type IIIa, the liver, skeletal muscles, and cardiac muscle are involved. In GSD type IIIb, only the liver is involved.

Glycogen storage disease type IV

GSD IV is an autosomal recessive disorder caused by the mutation of the GBE1 gene (3p14) in which there is deficiency or reduced activity of the glycogen branching enzyme. The glycogen branching enzyme (GBE) is an enzyme that catalyze the formation of α-1,6-glycosidic bonds to the linear α-1,4-glycosidic bonds that forms the skeleton of the glycogen molecule. In case of deficiency, abnormal glycogen is formed, with long linear α-1,4 polymers and less branches. The abnormal glycogen has long branches that resemble amylopectin. The importance of the presence of polymer branches, relies in the fact that it provides multiple free ends that are easily available to the amylase to break down glucose molecules during glycogenolysis. Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system characterizes this disease. Different phenotypes have been identified, based on genetical heterogeneity: fatal perinatal neuromuscular subtype, congenital neuromuscular subtype, classic (progressive) hepatic subtype, non-progressive hepatic subtype and the childhood neuromuscular subtype. [19]  

Glycogen storage disease type V

GSD type V is an autosomal recessive disorder in which there is a deficiency of the enzyme glycogen phosphorylase. This enzyme is required in the first step of glycogen catabolism, where glycogen is released in G1P molecules. This leads to varying degrees of exercise intolerance secondary to affected muscle metabolism. [20]  During the early phase of moderate physical exertion, the principal sources of energy are glycogen and anaerobic glycolysis. [21] This phase is distinct from the resting phase when energy for the skeletal muscles is obtained through fatty acid oxidation. With further physical activity, glucose and fatty acids become irreplaceable energy sources for the skeletal muscles. However, during intense physical exertion, the skeletal muscles use energy released from endogenous glycogen (glycogenolysis by way of muscle phosphorylase), and signs of muscle fatigue occur after glycogen depletion. This effect is the reason patients with McArdle disease tolerate moderate physical activity relatively well, while intense and isometric physical exertion leads to disturbances and symptoms of the disease. The muscle glycogen concentration is increased, but its molecules are normal in structure.

Glycogen storage disease type VI

GSD type VI is an autosomal recessive disorder, caused by the deficiency of the hepatic glycogen phosphorylase, which is a rate-limiting enzyme that is necessary during glycogenolysis. It catalyzes the α1,4 glucosidic cleavage, releasing glucose 1-phosphate. Hepatic phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, and phosphorylase kinase (the cause of the GSD IX). Glucagon stimulates the chain of reactions involved in the activation of phosphorylase.

Glycogen storage disease type VII

PFK catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-biphosphate. PFK consists of 3 subunits: muscle (M), liver (L), and platelet (P). Each subunit is coded by a gene located on different chromosomes: The PFKM gene is located on chromosome 1; the PFKL gene, on chromosome 21; and the PFKP gene, on chromosome 10. The PFKL subunit is expressed in the liver and kidneys, whereas muscles contain only the M subunit. Therefore, muscles harbor only homotetramers of M subunits, and erythrocytes contain L and M subunits, which randomly tetramerize to form M4, L4, and 3 additional hybrid forms of the holoenzyme (ie, M3L, M2L2, ML3). [22]



GSD type I

GSD type Ia

G6Pase deficiency is the cause of GSD type Ia. G6Pase is an enzyme that hydrolyzes glucose-6-phosphatase into free glucose and a phosphate group.Mutations in the transmembrane helices of the protein cause the most severe deficiency of enzyme activity.

Two different G6Pase enzymes are known. Glucose-6-phosphatase-alpha (G6Pase-alpha), located in the liver, kidney, and intestine, is solely responsible for the final stages of gluconeogenesis and glycogenolysis and for releasing glucose to the blood. Glucose-6-phosphatase-beta (Glc-6-Pase-beta) is also able to hydrolyze G6P to glucose and is an integral membrane protein in the endoplasmic reticulum. It contains 9 transmembrane domains, like G6Pase-alpha, but is ubiquitously expressed, similar to G6PT, and does not participate in blood glucose homeostasis between meals.

It seems that endoplasmic reticulum G6Pase-beta and G6PT complex is necessary for endogenous production of glucose during specific stress situations in some tissue cells, such as astrocytes, peripheral neutrophils, and bone marrow myelocytes.

The G6Pase gene is located on band 17q21 as a single copy. The complementary DNA (cDNA) has been cloned, and the most frequent mutations are known,most of which of missense/nonsense mutations. [23, 24] For optimal catalytic activity, critical residues are 347-354. The gene contains 5 exons and spans approximately 12.5 kb. An analysis of the G6Pase gene in 70 unrelated patients with enzymatically confirmed diagnosis of GSD type Ia revealed that the most frequent mutations were R83C and Q347X in Caucasians, 130X and R83C in Hispanics, and R83H in Chinese.

The Q347X mutation was found only in whites, and 130X was found only in Hispanic patients. A mutational analysis in French patients has been published; this analysis reveals 14 different mutations. The most common among them, in as many as 75% of mutated alleles, were Q347X, R83C, D38V, G188R, and 158Cdel.

At present, at least 56 mutations in the G6Pase gene have been reported in patients with GSD type Ia. The mutated allele is inherited as an autosomal recessive trait. No strong evidence indicates a clear genotype-phenotype correlation, but in 2002, Matern et al [25]  reported a relationship between (1) a G188R mutation and GSD type I non–a phenotype and a homozygous G727T mutation and (2) a milder form of clinical presentation but with a higher risk for hepatocellular malignancy. On the other hand, in 2005 Melis et al [26]  did not find a correlation between individual mutations and the presence of neutropenia, bacterial infections, and systemic complications in patients with GSD type Ib.

Early prenatal genetic diagnosis of disease is possible using chorionic villi or amniocytic DNA samples instead of invasive fetal liver biopsy.

GSD type Ib

Deficiency of G6PT1 translocase causes GSD type Ib. The G6PT1 gene is expressed in liver, kidney, and hematopoietic progenitor cells, spans approximately 5 kb and contains 8 exons, and has been mapped to band 11q23. The mutated allele is inherited as an autosomal recessive trait. There is no correlation between the kind of mutation in the G6PT gene and severity of the disease. Therefore, other unknown factors are believed to be responsible for expression of different symptoms, such as neutropenia, in these patients, which dramatically influences the severity and natural course of the disease.

In 2003, Kuijpers et al found circulating neutrophils with signs of apoptosis and increased caspase activity in 5 patients with GSD type Ib. However, granulocyte colony–stimulating factor in in vitro cultures did not influence apoptosis. [27]

In 2007, Cheung et al suggested that the G6Pase-beta/G6PT complex might be functional in neutrophils and in myeloid cells. Therefore, defects in GSD-Ib might be a result of loss in activity of that complex, leading to an increasing rate of neutrophil apoptosis and impairment of hematopoiesis in the bone marrow, with neutropenia and increasing susceptibility to bacterial infections as a consequence. [28]

The G6PT1 gene is strongly expressed in liver, kidney, and hematopoietic progenitor cells, which might explain major clinical symptoms such as hepatomegaly, nephromegaly, and neutropenia in GSD type Ib.

In a 2005 multicentric study and review of the literature, Melis et al from Italy concluded that there is no correlation between individual mutations and the presence of neutropenia, bacterial infections, and systemic complications and suggested that different genes and proteins could be involved in differentiation, maturation, and apoptosis of neutrophils and the severity and frequency of infections. They also found no detectable mutations in 3 patients, indicating that the second protein may play a role in microsomal phosphate transport. [26]

GSD type Ic

Deficiency of T2 translocase causes GSD type Ic. The GSD type Ic gene is mapped to bands 11q23. The mutated allele is inherited as an autosomal recessive trait. In 1999, Janecke et al confirmed that GSD type Ic is allelic to GSD type Ib. [29]

GSD type Id

Deficiency of T3 transposes causes GSD type Id. The gene is mapped to bands 11q23-q24. The mutated allele is inherited as an autosomal recessive trait.

GSD type II

Deficiency of the acid alpha-1,4-glucosidase  (GAA) coded on bands 17q21.2-q23 causes GSD type II. The GAA gene is 20 kb in length, contains 20 exons, and codes for a 105-kd protein. The mutated allele is inherited as an autosomal recessive trait. The disease is expressed in homozygotic carriers of the mutation. Heterozygotic carriers of the mutation do not show signs of the disease. Thus far, a large number of different mutations (eg, missense, nonsense, deletion, splice site mutations) have been found, and various forms of enzyme deficiency may result from the following mutations: complete loss of the protein (infantile form), decreased enzymatic activity due to reduced affinity for substrate (juvenile and adult forms), and decreased levels of the protein with normal substrate affinity (juvenile and adult forms, IVS1-13T-->G splice site mutation common in adults). Some patients, mostly in Asian populations, are homozygous for a pseudodeficiency allele [c.1726 G>A (p. Gly576Ser)]. [30]

GSD type III

A deficiency of the debrancher enzyme causes the disease. In GSD type IIIb, the enzyme deficit is confined to the liver, whereas in GSD type IIIa, the deficit also occurs in the skeletal muscles and the myocardium. A correlation exists between the residual enzyme activity and the severity of the clinical presentation. A gene mapped to band 1p21 codes the enzyme. More than 30 different mutations have been identified in patients from many different ethnic groups. The cDNA has been cloned. The gene contains 7072 base pairs (bp), of which 4596 bp is in the coding region. Hepatic and muscular messenger RNA (mRNA) differs in the 5' region. Genetic heterogeneity is found at the mRNA level. The disease is inherited as an autosomal recessive trait. Carrier detection and prenatal diagnosis are possible by DNA mutation analysis.

GSD type IV

Amylo-1,4-1,6-transglucosidase or brancher enzyme deficiency is the cause of this disease. A gene mapped to band 3p12 codes the brancher enzyme. The full-length cDNA is approximately 3 kb. The coding sequence contains 2106 bp that encodes a protein of 702 amino acids. There is a correlation between the various gene mutations and the severity of the clinical manifestations (eg, 210-bp DNA deletion in a patient with fatal neonatal neuromuscular form, Y329S point mutation in a patient with nonprogressive hepatic form). The disease is inherited as an autosomal recessive trait. Carrier detection and prenatal diagnosis are available by DNA analysis. Further research is needed to determine whether certain mutations may be associated with particular variants of the disease.

GSD type V

Myophosphorylase (glycogen phosphorylase) deficiency causes the disease. Myophosphorylase exists in different tissue-specific isoforms (eg, muscle, liver, brain), and a separate gene codes enzyme isoforms in each tissue. The PYGM gene, located on 11q13 codes for myophosphorylase and most mutations are found between exon 1 to 17. More than 50% of the gene mutations found have been missense. [31]  The most common is C-to-T transition at codon 49 in exon 1. The most prevalent mutations in white and Japanese patients are R49X and deletion F708, respectively. Rare mutations include G-to-A transition at codon 204 in exon 5 and A-to-G transversion at codon 542 in exon 14. All other rare mutations occur in approximately fewer than 30% of patients. In 2002, Dimaur et al reported that the mutations in patients with GSD type V are spread throughout the gene and that no clear genotype-phenotype correlation exists. GSD type V is inherited as an autosomal recessive trait. [32]

GSD type VI

Hepatic phosphorylase deficiency or deficiency of other enzymes (eg, adenylate cyclase, protein kinase A, phosphorylase kinase) that form a chain of reactions necessary for the activation of phosphorylase causes GSD type VI. Heterogeneity exists in the clinical symptoms as a result of the different PYGL gene defects observed in affected individuals; they vary from hepatomegaly and subclinical hypoglycemia to severe hepatomegaly, hypoglycemia, and lactic acidosis.

The hepatic phosphorylase gene is located on bands 14q21-q22. Mutations responsible for the disease have been identified. Phosphorylase b kinase exists in an inactive form that is activated by the cyclic adenosine monophosphate (cAMP)–dependent protein kinase. The several subunits of phosphorylase kinase are coded by separate genes located on somatic chromosomes (subunits a and c) and the X chromosome (subunit b). A terminological confusion exists when classifying hepatic phosphorylase b kinase deficiencies. Some authors place all the forms under the name GSD type VI, whereas other authors label phosphorylase b kinase deficiency as GSD type IX and cAMP-dependent protein kinase deficiency as GSD type X. [12]

The X-linked form of hepatic phosphorylase kinase deficiency is the most common (75%) among patients with GSD type VI. The gene is located on the short arm of the X chromosome at band p22.

Other forms of GSD type VI are inherited as an autosomal recessive trait.

GSD type VII

PFK deficiency causes GSD type VII. The PFKM locus was assigned to band 1cen-q32 by somatic cell hybridization. The genomic organization of cDNA is known. In 1996, Howard et al, [33]  based on physical and genetic mapping, concluded that the PFKM gene is located on band 12q13.3 instead of chromosome 1, as previously believed. The different allelic variants of mutations are detected up to now. The inheritance is autosomal recessive.



United States statistics

Without systematic neonatal screening, no reliable data on the frequency of specific types of GSD exist. Based on the results of combined US and European studies, the cumulative incidence is estimated at 1 in 20,000-43,000 live births. [18]

GSD type 1 is the most common type of GSD which accounts for 24.6% of all patients with GSD. 80% of cases of GSD type 1 are classified as type 1a. 

The precise frequency of GSD type II is not known because no systematic neonatal screening programs exist; however, GSD type II may be found in 15.3% of all patients with GSD. In the United States, the incidence of all 3 forms of GSD type II, calculated on the basis of mutated gene frequencies in healthy individuals of different ethnic backgrounds, has been estimated at 1 in 40,000 live births.

Combined data from the United States and other countries suggest that GSD type III accounts for 24.2% of all patients with GSD.

Because of its rarity, the precise incidence is not known, but GSD type IV is believed to represent 3.3% of all GSD cases with an overall incidence of approximately 1:600,000-1:800,000.

GSD type V is rare. McArdle disease accounts for 2.4% of all patients with GSD.

GSD type VI is a rare condition, probably due to underdiagnosis. GSD IV and GSD IX (enzymes that regulate liver phosphorylase) accounts for 25%- 30% of all patients with GSD. Prevalence is estimated of 1:100,000. Most of these are GSD IX. The X-linked form of hepatic phosphorylase kinase deficiency is the most common among patients with GSD type VI.

GSD type VII is rare and is present in only 0.2% of all cases of GSD. GSD type VII most frequently affects Japanese persons and Jewish persons with Russian ancestry.

International statistics

Approximately 2.3 children per 100,000 births have some form of GSD in British Columbia, Canada.

In GSD type II, frequencies similar to those in the United States have been found in the Netherlands (1 in 40,000 births), as well as in Taiwan and southern China (1 in 50,000 births). In a study from Australia, birth prevalence of GSD type II, including early and late-onset phenotypes, was estimated as 1 in 146,000.

Race-, sex-, and age-related demographics


No racial or ethnic differences exist for GSD types I, II, IV, V, and VI.

Although GSD type III is distributed universally throughout the world, the highest incidence (1 in 5420 births) has been recorded in non-Ashkenazi Jews in northern Africa.

The patients most commonly reported with GSD type VII are of Japanese or Ashkenazi Jewish descent.


GSD types I-V and VII affect both sexes with equal frequency.

GSD type VI affects both sexes with equal frequency; however, in the X-linked form, most patients are males.


As with other genetically determined diseases, GSD type I develops during conception, yet the first signs of the disease may appear at birth or later. Median age of disease onset is between the 3rd and 4th month. 

In GSD type II, the age of onset depends on the clinical form of disease. The infantile form develops during the first months of life. In the juvenile form, initial clinical symptoms appear in persons aged 1-15 years. The adult form of disease appears in person aged 10-30 years and, less commonly, later.

In GSD type III, the first signs of the disease may appear shortly after birth or within several months afterwards.

In GSD type IV, patients appear healthy at birth, but they fail to thrive soon after birth, and hepatomegaly and/or splenomegaly may be observed in the next few months.

In GSD type V, the first signs of the disease usually develop in persons aged 10-20 years of age. There are case reports of the disease in babies shortly after birth, but this presentation is rare. 

In GSD type VI, the disease appears in the first months of life.

In GSD type VII, depending on the genetic variety, the disease usually develops in persons aged 10-20 years and, less frequently, earlier or later in life.



GSD type I

The prognosis is better than in the past provided that all the available dietary and medical measures are implemented.

GSD type II

Without treatment, the prognosis in the infantile form is poor.

The prognosis varies in the juvenile form.

The prognosis is relatively good in the adult form

GSD type III

The prognosis of GSD III is better than that of GSD I with many patients surviving into adulthood. GSD IIIb is a milder form of the disease, while the prognosis of GSD IIIa depends largely on the extent of cardiac involvement. 

GSD type IV

The prognosis is poor. Most children with GSD type IV die by age 2-4 years because of hepatic insufficiency.

GSD types V and VII

The prognosis varies.

GSD type VI

The course is benign.

The size of the liver decreases with age and returns to baseline at or around puberty.

All the patients attain normal height.



In GSD type I, acute hypoglycemia may be fatal. Early death is now uncommon with improving care and treatment. Late complications, such as renal failure, hypertension, or malignant alteration of hepatic adenomas, may be responsible for mortality in adolescent and adult patients. See Complications.

In GSD type II, morbidity and mortality differ among the subtypes of the disease. The infantile form has a lethal outcome caused by progressive cardiorespiratory insufficiency that usually begins by the end of the first year of life. The juvenile form has a slower course. Some patients may survive the third decade of life. Death is usually due to respiratory insufficiency, although a few cases have been described that were caused by the rupture of an intracranial aneurysm formed from glycogen accumulation in the smooth muscle cells of the arterial wall. The adult form manifests in older patients. Death due to respiratory insufficiency (sleep apnea) may occur many years after the first signs of the disease have appeared.

In GSD type III, the cirrhosis found in some patients is of a mild degree without a significant impact on the course of the disease.

In GSD type IV, the classic form, progressive liver cirrhosis rapidly leads to hepatic insufficiency so that a fatal outcome may be expected before the end of the second year of life (see Complications). Rarely, children with GSD type IV may survive longer.

In GSD type V, myoglobinuria from repeated prolonged exercise may eventually lead to renal failure and death. [20]

In GSD type VI, serious complications are unknown.

In GSD type VII, skeletal muscles and erythrocytes are affected. Rhabdomyolysis may cause acute renal failure because of myoglobinuria.



Patients with GSD can present with decreased bone mass and may ultimately suffer from fractures. Thus, in the adult population, bone density evaluation is recommended early enough so that patients can be treated adequately and in a timely manner. [34]

GSD type I

Long-term complications for GSD type 1a and 1b include the following [35]

  • Renal: Later complications of disease include renal function disturbances including nephrocalcinosis, hematuria, proteinuria and hypertension. Nephromegaly is seen secondary to glycogen deposition in the kidney. Renal insufficiency may progress to end stage renal disease, requiring dialysis and transplantation. [36]
  • Neurocognitive Deficits: Patients with GSD have normal IQ, but because of frequent hypoglycemic episodes, brain function is altered. 
  • Anemia
  • Bleeding Diathesis: Some patients may bleed easily, usually in the form of epistaxis, easy bruising, or heavy menses. Caution is to be taken during surgical procedures. This tendency is a result of altered platelet function, due to reduced or dysfunctional von Willebrand factor. 
  • Osteoporosis: Bone mineral density can be severely reduced in more than half the patients with GSD type 1 mainly because of lack of vitamin D in the diet. These patients are very susceptible to fractures secondary to osteopenia or osteoporosis
  • Pancreatitis: This is a consequence to hypertriglyceridemia
  • Hepatic Adenomas: hepatic adenomas are common findings in older adults (in 20s-30s). Complications arising from adenomas are intrahepatic hemorrhage and malignant transformation into hepatocellular carcinoma. 

In addition to the above complications, patients with GSD Ib exhibit further complications secondary to neutrophil dysfunction. This includes recurrent infections, inflammatory bowel disease/enterocolitis, thyroid autoimmunity and hypothyroidism. [15]

Early death usually caused by acute metabolic complications (eg, hypoglycemia, acidosis), bleeding in the course of various surgical procedures (in all patients with GSD type I), and infections (in patients with GSD type Ib) is now uncommon with improving care and treatment.

Late complications, such as renal failure, hypertension, or malignant alteration of hepatic adenomas, may be responsible for mortality in adolescent and adult patients.

Long-term complications encompass growth retardation, hepatic adenomas with a high rate of malignant change, xanthomas, gout, and glomerulosclerosis. Long-term complications result from metabolic disturbances, mostly hypoglycemia. Chronic metabolic lactic acidosis and changes in the proximal renal tubule cells can lead to osteopenia and rickets with severe skeletal deformities or bone fractures, particularly of the distal extremities. Such skeletal problems seriously impair the patient's mobility. Elevated uric acid excretion along with segmental glomerular sclerosis gradually causes a decrease in the glomerular function with proteinuria, hematuria, arterial hypertension, and chronic renal failure. Because of incomplete distal tubular acidosis, a number of patients develop hypercalciuria, nephrocalcinosis, and calculosis. In a 2002 report, Mundy and Lee [37]  presented the hypothesis that GSD type I and diabetes mellitus share the common mechanism for renal dysfunction. This mechanism may be due to a convergence of their metabolic sequelae in upregulation of flux through the pentose phosphate pathway that yields triose phosphate molecules, which are precursors of the lipid diacylglycerol. Diacylglycerol plays an important role in the intrarenal renin-angiotensin system via the protein kinase C pathway. Long-standing disease may be accompanied by hepatic adenomas prone to malignant alteration.

GSD type II

Aspiration pneumonia may be a complication.

In the infantile form, progressive cardiorespiratory insufficiency usually causes death by the end of the first year of life.

In the juvenile form, death is usually due to respiratory insufficiency, although a few cases have been described that were caused by the rupture of an intracranial aneurysm formed from glycogen accumulation in the smooth muscle cells of the arterial wall.

In the adult form, death due to respiratory insufficiency (eg, sleep apnea) may occur many years after the first signs of the disease have appeared.

Patients treated with enzyme replacement therapy are at risk of fractures, facial muscle weakness, dysphagia, and speech disorders. 

GSD type III

The cirrhosis found in some patients is of a mild degree and does not have a significant impact on the course of the disease. Patients can also develop hepatic adenomas which increases the risk of hepatocellular carcinoma. Muscle weakness and hypotonia is more prominent in adults with GSD IIIa, in contrast to children secondary to progression of muscle disease. Also in patients with GSD IIIa, cardiac involvement is seen in the first decade of life, usually in the form of hypertrophic cardiomyopathy and usually remains stable during the patient's life if patient is being treated appropriately. Progression to severe cardiomyopathy is less often seen but can cause severe heart failure and fatal arrhythmias (sudden death). [7]

Growth retardation may be seen in infancy and childhood, but usually reach normal levels at adolescence. Patients usually achieve normal adult height. An increased incidence of Type 2 diabetes mellitus is also being reported in patients with GSD III secondary to increased insulin resistance from constant carbohydrate enriched nutrients to induce euglycemia (same article as above).  [7]

GSD type IV

In the classic form, progressive liver cirrhosis rapidly leads to hepatic insufficiency so that a fatal outcome may be expected before the end of the second year of life. Rarely, children with GSD type IV may survive longer.

Fetal hydrops and intrauterine leg contractures may be found in more severe forms.

Liver cirrhosis is not always progressive.

Moderately severe variants exist, and affected children survive longer and with predominantly muscular lesions.

GSD type VI

Serious complications are unknown.

GSD types V and VII

Renal insufficiency caused by myoglobinuria may occur. Patients with GSD type V need to take precaution with general anesthesia as it may cause acute rhabdomyolysis and myoglobinuria resulting in possible acute renal failure. [20]


Patient Education

GSD type I

First, instruct parents, and later adult patients, concerning the measures required to control hypoglycemia and other metabolic abnormalities; such measures include proper care and nutrition.

Explain the important role played by continuous overnight feeding by means of a nasogastric tube. Teach parents to place the tube by themselves and control the entire feeding process.