About limit dextrinosis
What is limit dextrinosis?
Forbes disease (GSD-III) is one of several glycogen storage disorders (GSD) that are inherited as autosomal recessive traits. Symptoms are caused by a lack of the enzyme amylo-1,6 glucosidase (debrancher enzyme). This enzyme deficiency causes excess amounts of an abnormal glycogen (the stored form of energy that comes from carbohydrates) to be deposited in the liver, muscles and, in some cases, the heart.
There are two forms of this disorder. GSD-IIIA affects about 85% of patients with Forbes disease and involves both the liver and the muscles. GSD-IIIB affects only the liver.
What are the symptoms for limit dextrinosis?
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.
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.
What are the causes for limit dextrinosis?
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.
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.
What are the treatments for limit dextrinosis?
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.