eMedicine Specialties > Dermatology > Pediatric Diseases

Glycogen Storage Diseases Types I-VII

Author: Ljubomir Stojanov, MD, PhD, Professor, University of Belgrade School of Medicine, Serbia
Coauthor(s): Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro; Milos D Pavlovic, MD, PhD, Head of Immunodermatology, Professor, Department of Dermatology and Venereology, Military Medical Academy, Belgrade, Serbia
Contributor Information and Disclosures

Updated: Mar 10, 2009

Introduction

Background

Glycogen storage disease type I

Glycogen storage disease (GSD) type I is also known as von Gierke disease or hepatorenal glycogenosis. von Gierke¹ described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica. In 1952, Cori and Cori² demonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I. In 1978, Narisawa et al³ proposed that a transport defect of glucose-6-phosphate (G6P) into the microsomal compartment may be present in some patients with GSD type I. 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. Apart from the substrate translocation defect, 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.

Glycogen storage disease type II

GSD type II, also known as acid maltase deficiency or Pompe disease, is a prototypic lysosomal disease. Its clinical presentation clearly differs from other forms of GSD. Deficiency of a lysosomal enzyme, alpha-1,4-glucosidase, causes GSD type II. Pompe initially described the disease in 1932. An essential pathologic finding is the accumulation of normally structured glycogen in most tissues. Three forms of the disease exist: infantile, juvenile, and adult. In the classic infantile form, the main clinical signs are cardiomyopathy and muscular hypotonia. In the juvenile and adult forms, the involvement of skeletal muscles dominates the clinical presentation.

Glycogen storage disease type III

GSD type III is also known as Forbes-Cori disease or limit dextrinosis. 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.

Glycogen storage disease type IV

GSD type IV, also known as amylopectinosis 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.

Glycogen storage disease type V

GSD type V, also known as McArdle disease, affects the skeletal muscles. McArdle⁴ 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.

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. Hepatic phosphorylase deficiency or deficiency of other enzymes that form a cascade necessary for liver phosphorylase activation cause the disease.⁵ 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. Tarui⁶ reported the first patients in 1965. The clinical and laboratory features are similar to those of GSD type V.

eMedicine Endocrinology articles on GSD

• Glycogen Storage Disease, Type Ia
• Glycogen Storage Disease, Type Ib
• Glycogen Storage Disease, Type II
• Glycogen Storage Disease, Type III
• Glycogen Storage Disease, Type IV
• Glycogen Storage Disease, Type V
• Glycogen Storage Disease, Type VI
• Glycogen Storage Disease, Type VII

Pathophysiology

Glycogen storage disease type I

Because of insufficient G6Pase activity, G6P cannot be converted into free glucose, but G6P is metabolized to lactic acid or incorporated into glycogen. In this way, large quantities of glycogen are formed and stored as molecules with normal structure in the cytoplasm of hepatocytes and renal and intestinal mucosa cells; therefore, enlarged liver and kidneys dominate the clinical presentation of the disease. The chief biochemical alteration is hypoglycemia, while secondary abnormalities are hyperlactatemia, metabolic acidosis, hyperlipidemia, and hyperuricemia.

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 is important for the degradation of smaller quantities of normally structured glycogen. Deficiency of the enzyme leads to progressive accumulation of glycogen in the cells of numerous tissues, mostly in lysosomes, which transform into large vacuoles. The most abundant deposits are in the cardiac and skeletal muscles, depending on the degree of residual enzyme activity. Glycogenolysis is not impaired. Acid alpha-glycosidase in its mature form has a molecular weight of 70 kd. 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.

Depending on the degree of residual enzyme activity, GSD type II manifests in infantile, juvenile, or adult forms. Heavy deposits of glycogen in the heart, liver, and tongue characterize the infantile form; as a result of the deposits, these tissues enlarge. The hypotonia and muscle weakness involve skeletal and respiratory muscles as well with progressive respiratory insufficiency. In the CNS, the disease primarily affects the nuclei of the brainstem and the cells of the ventral horn of the spinal cord. Mental functions are preserved.

In the juvenile and adult forms, skeletal muscles are the primary sites of glycogen deposition. The involvement of the cardiac muscle varies in the juvenile form, whereas the muscle is unaffected in the adult form; therefore, cardiomegaly is not a feature of the adult form.

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. Abnormal glycogen with short external branches is stored in the liver, heart, and skeletal muscle cells. 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

Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system characterizes this disease. The abnormal glycogen has long external branches that resemble amylopectin. This form of glycogen is less soluble; liver cirrhosis probably arises as a reaction to this insoluble material. In a predominantly myopathic form, light microscopy reveals polyglucosan inclusions in myofibrils; the inclusions are characteristic of brancher enzyme deficiency.

Glycogen storage disease type V

During the early phase of moderate physical exertion, the principal sources of energy are glycogen and anaerobic glycolysis. 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 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

Hepatic phosphorylase is a rate-limiting enzyme that is necessary during glycogenolysis. Hepatic phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, and phosphorylase kinase. 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).

Frequency

United States

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 20,000-25,000 live births.

Patients with GSD type I account for 24.6% of all patients with GSD.

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.

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

GSD type VI is the most common of the glycogenoses (30% of all patients). 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

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.

Mortality/Morbidity

• 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, rhabdomyolysis may lead to renal failure and death.
• 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.

Race

• 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.

Sex

• 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.

Age

• 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.
• 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.
• 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.

Clinical

History

• GSD type I
  • The earliest signs of the disease may develop shortly after birth and are caused by hypoglycemia and lactic acidosis.
  • Convulsions are a leading sign of disease.
  • Frequently, symptoms of moderate hypoglycemia, such as irritability, pallor, cyanosis, hypotonia, tremors, loss of consciousness, and apnea, are present.
  • Some children have diarrhea due to pseudocolitis.
• GSD type II
  • Symptoms of the infantile form usually begin in infants at the end of the second month of life, with profound hypotonia. Muscle weakness progresses rather rapidly, manifesting as respiratory and feeding difficulties. Spontaneous movements are scarce, and painful stimuli cause weak motor reactions. Mental functions are retained.
  • In the juvenile form, the initial clinical symptoms appear in persons aged 1-15 years. Retarded motor development, hypotonia, and muscle weakness due to slowly progressive skeletal muscle disease characterize the juvenile form. Intellectual development is normal. Atony of the anal sphincter and enlargement of the urinary bladder can be found in only a minority of children.
  • The adult form develops in persons aged 10-30 years and, less commonly, later. Its course progresses slowly. Dyspnea due to the involvement of respiratory muscles and difficulties in climbing up the stairs caused by proximal myopathy are the leading clinical manifestations. In one third of patients, the initial symptoms are somnolence, morning headaches, orthopnea, and exertional dyspnea. Weakness of the respiratory muscles, particularly the diaphragm, causes these symptoms.
• GSD type III
  • The first manifestations of the disease usually appear in infants aged 1 year, although in milder variants, the onset may be delayed.
  • Clinical symptoms of hypoglycemia are rarely encountered.
  • A common reason for patients to undergo detailed investigations is enlargement of the stomach or hepatomegaly disclosed on a routine examination.
  • Retarded growth may be a reason to examine patients.
  • When skeletal and cardiac muscles are involved, muscular weakness or hypotonia and cardiovascular abnormalities dominate the clinical presentation.
• GSD type IV
  • Children affected with GSD type IV are born without signs of the disease, although some of them may have a dysmorphic face.
  • However, in the weeks after birth, failure to thrive, hypotonia, and atrophy of the muscles are noted.
• GSD type V
  • The classic form appears in persons aged 10-20 years.
  • Patients commonly report fatigue during physical exertion, muscle cramps, and later, muscle weakness and burgundy red–colored urine.
• GSD type VI
  • Symptoms, if present, are minimal.
  • Often, patients seek help for retarded growth.
• GSD type VII
  • Similar to that of GSD type V, intolerance of physical activity, muscle cramps, and burgundy red–colored urine occur during a rhabdomyolysis episode.
  • Attacks of rhabdomyolysis may be associated with nausea and vomiting, and more often than not, a meal rich in carbohydrates is consumed beforehand.

Physical

• GSD type I
  • A leading sign of GSD type I is enlargement of the liver and kidneys. During the first weeks of life, the liver is normal size. It enlarges gradually thereafter, and in some patients, it even reaches the symphysis. Enlargement of the abdomen due to hepatomegaly can be the first sign noted by the patient's mother.
  • The patient's face is characteristically reminiscent of a doll's face (rounded cheeks due to fat deposition).

• Mental development proceeds normally.
• Growth is retarded, and children affected with GSD type I never gain the height otherwise expected from the genetically determined potential of their families. The patient's height is usually below the third percentile for their age. The onset of puberty is delayed.

• Late complications of disease are renal function disturbance (including nephrocalcinosis), renal stones, tubular defects, and hypertension, mainly in patients older than 20 years. Renal function deterioration progresses to terminal insufficiency, requiring dialysis and transplantation.
• Skin and mucous membrane changes include the following:
  • Eruptive xanthomas develop on the extensor surfaces of the extremities.
  • Tophi or gouty arthritis may occur. Uric tophi often have the same distribution as xanthomas.
  • Spider angiomas may be present.
  • Perianal and gingival abscesses of the oral mucosa and gums may be observed. Aphthous ulcers are often present in patients with GSD type Ib.
  • Perianal erythema and erosions may occur in patients with prolonged diarrhea due to pseudocolitis.
  • In a 2002 report, Visser et al⁷ presumed that the main cause of disturbed intestinal function is loss of the integrity of the mucosal barrier, which occurs as a result of inflammation, and loss of neutrophil function, which often occurs in patients with GSD lb.
• Many patients bleed easily, particularly from the nose. This tendency is a result of altered platelet function due to the platelets' lower adhesiveness. Frequent and, occasionally, prolonged epistaxis may cause sideropenic anemia. At times, the bleeding may be so severe that blood transfusions are required.
• Risk factors and adverse events are as follows:
  • Hypoglycemia and infections are frequent.
  • Assisted ventilation is often not tolerated well.
  • Foods rich in fructose, galactose, and triglycerides adversely affect the long-term complications caused by lactic acidosis, hyperuricemia, and hyperlipidemia.
• GSD type II
  • Infantile form
    • Generalized severe hypotonia is present. Despite severe hypotonia and weakness, the affected muscles are firm on palpation and, occasionally, hypertrophic. In some patients, tongue fasciculations have been observed.
    • Conspicuous cardiomegaly with cardiomyopathy and heart failure may be present.
    • Macroglossia and hepatomegaly may be noted.
    • Tendon reflexes are diminished or absent.
    • Signs of respiratory insufficiency are due to the involvement of respiratory musculature.
  • Juvenile form
    • Respiratory insufficiency and hypotonia largely of the proximal musculature are present.
    • Macroglossia, cardiomegaly, cardiomyopathy, and hepatomegaly are absent.
  • Adult form
    • Proximal muscle weakness is noted.
    • Muscle volume is decreased, and tendon reflexes are diminished.
    • The visceral organs are not affected; however, intracranial aneurysms are possible because of glycogen deposits in the smooth muscle cells of the cerebral arteries.
• GSD type III: GSD type III is a heterogeneous disease. Two subtypes exist: GSD type IIIa and GSD type IIIb. In most patients, the liver and the spleen are enlarged. In some children, growth retardation, renal tubular dysfunction, and liver cirrhosis can be observed.
  • GSD type IIIa is more common and prognostically more unfavorable than other forms. The main clinical features include the following:
    • Hepatomegaly and/or splenomegaly may be present.
    • Muscular weakness and atrophy, particularly of the girdle and limb musculature, may be observed.
    • Cardiomegaly and cardiomyopathy may occur.
    • Cardiac and skeletal muscle abnormalities possibly taking on a progressive course and possibly appearing at different ages (from early childhood to late adulthood) may be noted.
  • GSD type IIIb is less common (approximately 15%) although prognostically more favorable than other forms.
    • The liver is the only organ involved.
    • Hepatosplenomegaly is moderate.
    • Mild fibrosis and micronodular cirrhosis of the liver are rare and often clinically silent.
    • Hepatomegaly is pronounced during childhood but usually normalizes at puberty.
    • Growth is accelerated at puberty; therefore, most patients reach their expected height.
• GSD type IV
  • Hepatosplenomegaly is evident in the first months of life. Soon thereafter, signs of progressive liver cirrhosis appear resulting in hepatic insufficiency, portal hypertension, and death.
  • Besides hepatosplenomegaly, heart dilatation and neurologic deficits with muscle atrophy and diminished or absent tendon reflexes can be observed.
  • Patients with fetal hydrops, muscular degeneration, and arthrogryposis have been reported.
  • Prominent venous distention is sometimes visible on the anterior abdominal wall.
• GSD type V
  • In a milder variety, the first symptoms and signs may appear late, even in elderly patients.
  • Forms clinically expressed in the first years of life occur with muscle hypotonia and generalized muscle weakness and occasionally lead to respiratory insufficiency.
  • Rhabdomyolysis can be a cause of renal failure.
• GSD type VI
  • GSD type VI is a benign disease.
  • At times, hepatomegaly is incidentally noted during an investigation of the child's slow growth.
  • Skeletal and cardiac muscles are unaffected.
  • With age, the size of the liver decreases and normalizes at or around puberty.
• GSD type VII
  • GSD type VII is more severe than GSD type V.
  • Rhabdomyolysis with renal failure is common.
  • In some patients, erythrocyte hemolysis occurs.
  • Jaundice is apparent in severe hemolysis.
  • Two rare varieties of GSD type VII exist. One form occurs in infants with hypotonia and weakness of the extremity muscles; this form progresses in severity, with a lethal outcome in early childhood. The other form occurs in young adults or older persons; this form progresses slowly, and its clinical presentation is dominated by the weakness of the different muscle groups rather than the muscle cramps and myoglobinuria.

Causes

• GSD type I
  • GSD type Ia: Deficiency of G6Pase or hydrolase is a cause of GSD type Ia. G6Pase is an integral membrane protein. 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. 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 whites, 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 al⁸ 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 al⁹ 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 al¹⁰ 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.
    • In 2007, Cheung et al¹¹ 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.
    • 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 al⁹ 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.
  • 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 al¹² confirmed that GSD type Ic is allelic to GSD type Ib.
  • 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 coded on bands 17q21.2-q23 causes GSD type II. The 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 are compound heterozygote and may have a less severe clinical picture than those with homoallelic forms.
• 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.
• GSD type V: Myophosphorylase 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. A gene mapped to bands 11q13-qter codes muscle phosphorylase. Myophosphorylase gene mutations are identified. 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 al¹³ 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.
• 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.
  • 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,¹⁴ 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.

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