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E74.03
Cori Disease (Debrancher enzyme deficiency)
Glycogen Storage Disease type 3 is an inherited condition caused by a defect in a gene that controls the breakdown of a complex sugar called glycogen in the body's cells. Because the glycogen can not break down the accumulated glycogen is structurally abnormal and impairs the function of certain organs and tissues, especially the liver and muscles. It is also called Cori Disease, Forbe's Disease or Debrancher Enzyme Deficiency.
The disorder is caused by a defect in the debrancher enzyme gene, which interferes with the breakdown of glycogen (stored sugar) in the muscles and liver. For more, see Causes/Inheritance.Treatment typically includes a high- protein diet with cornstarch supplementation to maintain a normal level of glucose in the blood.
Synonyms of Glycogen Storage Disease Type III
- amylo-1,6-glucosidase deficiency
- Cori disease
- AGL deficiency
- glycogenosis type III
- Forbes disease
- limited dextrinosis
- GDE deficiency
- glycogen debrancher deficiency
- GSD-III
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”.
Signs & 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.
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