Glycogen Storage Diseases Types I-VII

Updated: Oct 05, 2016
  • Author: Ljubomir Stojanov, MD, PhD; Chief Editor: William D James, MD  more...
  • Print
Overview

Background

Glycogen storage disease type I

Glycogen storage disease (GSD) type I is also known as von Gierke disease or hepatorenal glycogenosis. von Gierke [1] described the first patient with GSD type I in 1929 under the name hepatonephromegalia glycogenica. In 1952, Cori and Cori [2] demonstrated that glucose-6-phosphatase (G6Pase) deficiency was a cause of GSD type I. In 1978, Narisawa et al [3] 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. [4]

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. [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. 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. [6]

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. [7]

Glycogen storage disease type V

GSD type V, also known as McArdle disease, affects the skeletal muscles. McArdle [8, 9] 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. [10] 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 [11] reported the first patients in 1965. The clinical and laboratory features are similar to those of GSD type V.

Medscape Reference Endocrinology articles on GSD

See the list below:

Next:

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. [12]

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. [13] 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). [14]

Previous
Next:

Epidemiology

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.

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.

Previous
Next:

Prognosis

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

The prognosis is poor in the infantile form.

The prognosis varies in the juvenile form.

The prognosis is relatively good in the adult form.

GSD type III

The prognosis of GSD type III is better than that of GSD type I.

Many patients with GSD type III survive to adulthood.

GSD type IIIb is a milder form of the disease, while in GSD type IIIa, the prognosis depends largely on the cardiac involvement.

In most patients, the prognosis is good.

Liver size and transaminases levels return to baseline.

Most patients attain normal height at puberty.

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.

Previous
Next:

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.

Previous
Next:

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.

Previous