Glycogen Storage Disease Type III

Glycogen Storage Disease Type III

Overview

The human diet contains 3 macronutrients that can be stored by the body as energy: carbohydrates (as the natural carbohydrate polymer glycogen, in mainly the liver and muscle), protein (as muscle, the natural protein source of the body) and fat (in organs and fat tissue). There are at least 13 glycogen storage disease (GSD) subtypes, in which the energy stored as glycogen cannot be adequately produced or broken down. The liver GSD subtypes cause fasting intolerance (types 0, Ia, Ib, III, VI, IX and XI) or liver failure (type IV), with or without muscle symptoms. The fasting induced low blood glucose concentrations decrease the energy supply by the liver to organs like the brain.

The ketotic GSD subtypes 0, III, VI, IX, and XI are associated with fasting ketotic hypoglycemia. In these patients, the breakdown of glycogen (glycogenolysis) is defective. Their fasting intolerance is considered relatively mild compared to GSD type I patients, in whom both glycogenolysis and the generation of glucose from non-carbohydrate substances (gluconeogenesis) are impaired.

The first patient with GSD type III (GSD-III) was described in 1928 by the Dutch pediatrician Simon van Creveld. He described a 7-year-old boy with marked enlarged liver, obesity and small genitals. The fasting blood glucose concentration appeared to be very low, and concentrations of ketone bodies in urine were high. Based on additional investigations in the patient, Dr Van Creveld concluded that the body increasingly burned fat, resulted from “insufficient mobilization of glycogen”.

Symptoms

The median age at the first clinical presentations is in the first year of life. Most common presenting symptoms are enlarged liver (hepatomegaly) (98%), low blood sugar (hypoglycemia) (53%), failure to thrive (49%) and recurrent illness and/or infections (17%). Symptoms and signs of GSD-III, at least during the first 4 to 6 years of life, may be indistinguishable from GSD type I. The amount of glycogen in the liver and muscles is abnormally high, the liver is enlarged, and the abdomen protrudes. The muscles tend to be flaccid or weak.

A typical child with GSD-III has short stature, low blood sugar after fasting that does not respond to the hormone glucagon, and an elevated level of fatty substances in the blood, known as hyperlipidemia. Hypoglycemia is usually associated with increased ketone bodies, and ketonemia can precede hypoglycemia, reflecting activation of burning fat stores. Patients with GSD-III may also have difficulty fighting infections, and may experience unusually frequent nosebleeds. Enlarged heart muscle (cardiac hypertrophy) is common in individuals with GSD-IIIa and can already appear in early childhood. However, in most children, heart function remains within normal limits. Children with GSD-III often grow slowly during childhood and puberty may be delayed, but their adult height is usually normal. Most signs and symptoms improve significantly with adequate dietary management.

In adulthood, the liver manifestations of the disease usually subside, but progression to liver scarring (cirrhosis) and malignancy (carcinoma) may occur. Despite dietary management, muscle disease can get worse. As the cohort of adult GSD-III patients is still relatively young and small, the course of the disease over time is incompletely described.

Some affected individuals may have virtually no symptoms (asymptomatic) other than a protruding abdomen and an enlarged liver in childhood. These patients tend to lose these few symptoms during adolescence when their liver decreases progressively in size.

Classification

There are four subtypes of GSD-III:

GSD-IIIa is the most common type, affecting 85%, and affects both the liver and (cardiac and/or skeletal) muscles.

GSD-IIIb affects about 15% of individuals and only affects the liver. AGL molecular testing can display mutations specific to GSD-IIIb.

GSD-IIIc is extremely rare and believed to be caused by loss of activity of the glucosidase active site of the glycogen debranching enzyme.

GSD-IIId is extremely rare and believed to be caused by loss of activity of the transferase active site of the glycogen debranching enzyme.

Causes

GSD-III is an inborn error of metabolism caused by mutations in the AGL gene that is located on chromosome 1p21. The AGL gene is responsible for the production of the debranching enzyme.

Glycogen is stored in the liver and muscles for future energy needs. Glycogen can then be converted into sugar (glucose). Glucose is used as a readily available source of energy during fasting or exercise. The debranching enzyme has two active (catalytic) sites called amylo-1,6-glucosidase and 4-alpha-glucanotransferase. Both sites on the enzyme are together with the phosphorylase and phosphorylase kinase enzymes (impaired in GSD types VI and IX, respectively) responsible for breaking down glycogen to raise the blood sugar concentration. Without normal debranching enzyme function, two changes take place. If glycogen can only be broken down partially, an insufficient amount of energy/glucose can be produced. The structure that is left, resembling a molecule called a “limit dextrin”, is excessively stored in liver, and (skeletal and cardiac) muscle tissues.

Inheritance/genetics

GSD-III is a genetic disorder characterized by variable liver, cardiac muscle and skeletal muscle abnormalities. Symptoms are associated with abnormalities in the AGL gene, causing deficiency of the glycogen debranching enzyme. GSD-III is inherited as an autosomal recessive trait.

Recessive genetic disorders occur when an individual inherits two copies of an altered gene for the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry mutations/variants in ± 4-5 genes. Parents who are close relatives (consanguineous) or who originate from closed communities have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Affected populations

All glycogen storage diseases together affect fewer than 1 in 40,000 persons in the United States. GSD-III has an incidence of about 1 in 100,000. The incidence of GSD-III is higher in North African Jews (± 1 in 5,400), Faroese (± 1 in 3,100) and the Inuit population in Nunavik, Canada (± 1 in 2,500).

Disorders with Similar Symptoms

The following diseases are similar to GSD-III. Comparisons may be useful for a differential diagnosis. Several GSD subtypes can be considered:

GSD type 0 (GSD-0) is caused by the inability to store glycogen in the liver. This explains why the liver size is normal and the biochemical observation of postprandial hyperglycemia and increase of blood lactate concentrations.

GSD type I (GSD-I), also known as von Gierke disease, is a more severe form of GSD. GSD-I is a hereditary metabolic disorder caused by an inborn lack of either the enzyme glucose-6-phosphatase or the enzyme glucose-6-phosphate translocase. These enzymes are needed to convert glucose-6-phosphate into glucose that the body uses for its energy needs. A deficiency of these enzymes causes abnormal deposits of glycogen in the liver and kidney cells. Unlike GSD-III, uric acid and lactic acid levels are elevated in GSD-I and hypoglycemia and hypertriglyceridemia (high triglycerides) are more severe.

GSD type IV (GSD-IV), also known as Andersen disease, is characterized by scarring of the liver (cirrhosis) which may lead to liver failure. GSD-IV is an autosomal recessive genetic disorder caused by mutations in the GBE1 gene that provides instructions for making the glycogen branching enzyme. Deficient activity of the glycogen branching enzyme leads to a generalized accumulation of structurally abnormal glycogen.

GSD type VI (GSD-VI), also known as Hers disease, is a relatively mild hepatic form of glycogen storage disease. The disorder is caused by mutations in the PYGL gene that provides instructions for making an enzyme called liver glycogen phosphorylase. Deficient activity of this enzyme leads to enlargement of the liver, moderately low blood sugar (hypoglycemia), elevated levels of ketone bodies in the blood (ketosis), and growth retardation. Symptoms are not always evident during childhood.

GSD type IX (GSD-IX) affecting the liver can be inherited via both X-linked (caused by PHKA2 mutations) and autosomal recessive (caused by mutations in PHKAB or PHKG2) inheritance. The mutations cause a deficiency of the enzyme liver phosphorylase kinase. The disorder is characterized by slightly low blood sugar (hypoglycemia) during fasting. Excess amounts of glycogen are deposited in the liver, causing enlargement of the liver. Untreated patients may present with failure to thrive and hypotonia, but can remain undiagnosed, like GSD-0 and GSD-VI patients.

Patients with fructose-1,6-bisphosphatase deficiency present with fasting associated hypoglycemia, hepatomegaly and increased blood concentrations of liver enzymes. In contrast with GSD-III patients, blood lactate concentrations increase upon fasting.

Patients with certain lysosomal storage diseases (like Niemann Pick type B and Gaucher disease) may present with hepatomegaly, stunted growth and hyperlipidemia. In contrast with GSD-III patients, fasting intolerance is absent.

For more information on the above disorders, search the Rare Disease Database.

Diagnosis

An enlarged liver and low blood sugar with high levels of ketones, transaminases, lipids and creatine kinase is indicative of GSD-III. Uric acid and fasting lactic acid levels are usually normal. In GSD-IIIb creatine kinase can be normal. Molecular genetic testing for mutations in the AGL gene can be used to confirm the diagnosis. Nowadays, liver and muscle biopsies are uncommon. In many countries besides the United States, studies in blood cells and skin fibroblasts are clinically available to confirm GDE deficiency.

Standard Therapies

Treatment

Dietary management is the cornerstone.

Infants and children with GSD-III are treated with a high-protein diet every 3-4 hours. The recommended daily amount of protein is ± 3-4 grams per kg bodyweight per day and should be well divided during the day. Cornstarch may already be introduced in the first year of life. This is a dietary complex starch like glycogen and the dose/frequency of supplementation is titrated to maintain normoglycemia. Although fructose and galactose can be metabolized, the (extend of) restrictions of so-called simple/fast carbohydrates is a matter of debate. These simple sugars include glucose, galactose (dairy sugar), lactose (galactose + glucose), fructose (fruit sugar), sucrose (fructose + glucose) and maltodextrin. The latter is frequently used as a food additive and typically a mixture of 3-17 glucose units. Special formulas are not required. Fasting should be avoided and for the overnight fast, (a combination of) a bedtime snack, frequent feeds, cornstarch, and/or continuous nocturnal gastric drip feeding may be needed.

Adolescents and adults have lower basic carbohydrate requirements. The recommended daily amount of protein is ± 25 % of the total caloric intake. A bedtime snack or an overnight high protein formula may be prescribed for patients with myopathy.

Good dietary control includes at home monitoring of blood glucose and ketones. Based on clinical observations, it is believed that the diet can prevent or resolve heart and/or muscle disease.

The role of and indications for ketogenic diets (and variations, including Atkins diet) and medium chain triglycerides (MCT) oil are debatable and deserve further, systematic research.

Liver transplantation is indicated only for patients with severe hepatic cirrhosis, liver dysfunction and /or liver cancer (hepatocellular carcinoma).

Clinical Testing and Follow-Up

Emergency letters should be provided and shared care with local physicians should be organized. Liver ultrasound and baseline heart tests (electrocardiogram and echocardiograms) are usually recommended to determine the medical needs for individual patients based on the severity of the condition.

Genetic counseling is recommended for families of children with glycogen storage diseases

Type of Doctor Department : A Metabolic Specialist