Introduction:
A genetic disorder known as glycogen storage disease type III (GSD III) is brought on by accumulating a complex substance called glycogen in the body's cells. The structural abnormality of the stored glycogen affects the function of some organs and tissues, particularly the liver and muscles. The other names for this disease are
-
AGL deficiency.
-
Cori disease.
-
Cori's disease.
-
Debrancher deficiency.
-
Forbes disease.
-
Glycogen debrancher deficiency.
-
GSD III.
-
GSD3.
-
Limit dextrinosis.
What Are the Types and Symptoms of GSD III?
Glycogen storage diseases are divided into different types based on their pattern of signs and symptoms. The different types of GSD III are GSD IIIa, IIIb, IIIc, and GSD IIId.
-
GSD types IIIa and IIIc mainly affect the liver and muscle.
-
GSD IIIb and IIId affect only the liver.
The different symptoms of type III glycogen storage diseases are
-
Hypoglycemia - Decreased blood glucose level.
-
Hyperlipidemia - Increased fat in the blood.
-
Hepatomegaly - Enlarged liver.
-
Elevated liver enzymes level in blood.
-
Cirrhosis - Chronic liver disease.
-
Liver failure.
-
Liver Adenoma - Small, noncancerous tumor in the liver.
-
Full Cheeks - Soft tissue between the zygomata and the mandible has a greater prominence or is more rounded.
-
Immunodeficiency - The immune system cannot appropriately protect the body from infection due to the lack of or insufficiency of a specific mechanism or substance.
-
Mild Intellectual Disability - An intelligence quotient (IQ) between 50 and 69 is considered a mild intellectual impairment.
-
Short Stature - A height shorter than what is typical for one's age and gender. Although there is not a single, agreed-upon definition of ‘short stature,’ most people think of it as the height that is more than two standard deviations below the average for one's age and gender (or below the 3rd percentile for age and gender-dependent norms).
-
Myopathies - A muscle condition unrelated to a malfunctioning neuromuscular junction or innervation.
-
Hypotonia - Abnormally decreased muscle tone.
What Is the Inheritance Pattern of GSD III?
Most genes are passed on in pairs to all individuals. The number of gene copies containing a disease-causing variation determines how a disease is passed down through the family. This disease is inherited in an autosomal recessive pattern. When a gene is autosomal, it can be found on any chromosome other than the X or Y chromosomes (sex chromosomes). Like chromosomes, genes frequently exist in pairs. Recessive means that for a person to have the disease, both copies of the disease-causing gene (pathogenic variation) must have the disease-causing alteration. Pathogenic variants are sometimes referred to as mutations, an older term. Each parent passes on a gene with a harmful mutation to a child with an autosomal recessive illness. Each parent carries the gene's pathogenic variation in one copy, making them each carrier. Typically, carriers of autosomal recessive diseases do not exhibit any disease symptoms. A 25 percent (1 in 4) probability of having a kid with an autosomal recessive disease results from the pregnancy of two carriers.
What Are the Causes of GSD III?
AGL gene mutations cause GSD III. The glycogen debranching enzyme is made according to instructions from the AGL gene. An essential source of the body's stored energy, glycogen, is broken down by this enzyme. The body uses energy reserves, including glycogen, for fuel between meals. The majority of AGL gene mutations result in the creation of an inactive glycogen debranching enzyme. These mutations typically cause GSD types IIIa and IIIb. It is believed that the mutations that cause GSD types IIIc and IIId result in the development of an enzyme with decreased function. All AGL gene abnormalities cause cells to store abnormal, partially degraded glycogen molecules. GSD III symptoms are caused by an accumulation of faulty glycogen that harms many body organs and tissues, especially the muscles and liver.
How Is Type III Glycogen Storage Disease Diagnosed?
Type III glycogen storage disease is diagnosed based on clinical and laboratory findings.
-
Clinical Findings
-
Hepatomegaly (which manifests in 98 percent of cases and usually occurs in infancy or early childhood).
-
Short stature or failure to thrive (presenting the character in about 49 percent).
-
Cirrhosis and adenomas of the liver (in adolescence and adulthood).
-
Muscle weakness (myopathy).
-
Intolerance to exercise
-
Cardiomyopathy with hypertrophy.
-
-
Laboratory Findings
-
Ketotoxin elevations following an overnight fast in untreated people; ketotic hypoglycemia or ketotic normoglycemia with fasting.
-
Increasing creatine kinase (once toddlers become active).
-
Postprandially (after food), hyperlipidemia, raised blood triglycerides, and elevated cholesterol rise and then fall, reaching their lowest amounts preprandial (before food).
-
An increase in transaminase levels.
-
Although lactate can rise postprandially, uric acid and lactate are often normal.
-
-
Molecular Genetic Testing - A diagnosis of GSD III is confirmed by discovering biallelic AGL pathogenic mutations during molecular genetic testing.
-
Biopsy - Analysis for debranching enzyme activity deficiency might be evaluated in either circulating blood cells (leukocytes or erythrocytes), cultured skin fibroblasts, or liver or muscle tissue following biopsy.
How Is Type III Glycogen Storage Disease Treated?
Type III glycogen storage disease is treated in the following ways.
-
Medicinal Nutritional Therapy - A high-protein diet supplemented with cornstarch is the cornerstone of managing GSD III, helping to maintain euglycemia (normal blood glucose) while balancing macronutrient and total calorie intake.
-
Frequent Feedings in Infancy - Infants should be fed often (every three to four hours). Fructose and galactose can be included in the diet for infants with GSD III.
-
Cornstarch - Cornstarch can treat hypoglycemia before the end of the first year of life since it is well tolerated. At first, many daily dosages could be necessary (a usual starting dose is 1 g/kg). Based on glucose and ketone monitoring findings, the amounts can be adjusted. Glycoside extended-release cornstarch can be used in place of uncooked cornstarch. In those with GSD III, one gram of cornstarch per kilogram of body weight may be enough to keep blood sugar levels normal for four hours or longer.
-
High-Protein Diet - Intake of 3 g/kg or 25 percent of total calories is advised for adults and children, respectively. Since gluconeogenesis is still active, glucogenic amino acids produced from proteins can be used as a substitute source of glucose when fasting. A high-protein diet protects skeletal and cardiac muscles by preventing the breakdown of endogenous muscle protein during times of glucose requirement. Supplements high in protein can be required.
-
In GSD III, exercise may decrease skeletal muscle metabolism. Maltodextrin or quickly absorbed carbs can be consumed to avoid hypoglycemia while exercising. Prior to exercise, consuming fructose or sucrose may increase exercise tolerance but does not entirely avoid harm from training.
-
The primary treatment for increased cholesterol and triglyceride concentrations, which typically arise from insufficient metabolic regulation, is titration of protein and starches in the diet.
-
The high-fat diet reduces cardiomyopathy in GSD III individuals.
-
-
Emergency Protocol - A customized emergency letter based on an emergency protocol should be created to prevent dangerous hypoglycemia. An intravenous (IV) infusion of 10 percent dextrose (with sodium chloride and potassium chloride) should be administered as soon as feasible if enteral intake cannot be ensured. Ketosis should be avoided because it can increase the catabolic state and cause vomiting. It is important to keep an eye on the levels of glucose, ketones, and creatine kinase (CK) in the serum.
-
Surgery - A 10 percent dextrose IV infusion should be started within two hours of the last dose of cornstarch or the last meal for patients with GSD III who have surgery and should be admitted the night before the procedure. Maintain overnight and procedure-day glucose and ketone monitoring. Avoid quickly stopping the IV dextrose infusion since iatrogenic hyperinsulinemia (increased amount of insulin in the blood) can lead to severe hypoglycemia. Once optimum oral intake has been established and tolerated, IV fluids are gradually reduced.
-
Liver Transplantation - Major complications can be avoided with contemporary treatment methods and effective metabolic control in people with GSD III; hepatic issues are not the primary cause of morbidity in these patients. Therefore, liver transplantation must be considered a last resort for people with GSD III. The fasting intolerance-related hypoglycemias in GSD IIIa and GSD IIIb will be cured by liver transplantation. But in people with GSD IIIa, the (cardio)muscular enzymatic deficiency still exists. Because liver transplantation has been linked to worsening myopathy and cardiomyopathy and the risk of hypoglycemia declines with age in people with GSD III, liver transplantation is only recommended in those with severe hepatic cirrhosis, liver dysfunction, and hepatocellular carcinoma.
-
Vitamin D Supplements - Since acidic surroundings negatively impair bone mineralization, osteoporosis may develop in individuals with GSD III. Ketosis is reduced, muscle strength is raised, and bone mineralization is increased with reasonable metabolic control. It is also advised to take calcium and vitamin D supplements to promote bone mineralization. Supplemental calcium should be recommended if dietary calcium intake is insufficient.
What Should Be Avoided in GSD III?
Certain precautions should be taken to prevent hazardous consequences.
-
Things to Avoid
-
High consumption of carbohydrates. Hepatomegaly is caused when too much sugar is stored as glycogen because it cannot be broken down.
-
Medicines with a steroid base disrupt the consumption and metabolism of glucose. Long-term steroid use can result in muscle weakening and failure to thrive.
-
Growth hormone replacement medication disrupts the metabolism of glucose and makes ketosis worse. Growth hormone therapy should only be used in people with a confirmed growth hormone deficit because it has been linked to adenoma growth and problems in GSD I.
-
Drugs that may result in rhabdomyolysis.
-
-
Things to Do With Caution
-
Female Hormonal (Estrogen) Contraceptives: Hepatocellular tumors can be benign or malignant, and estrogen is known to play a role in both.
-
Using Statins to Manage Hyperlipidemia: Because statin use can potentially worsen GSD IIIa's muscle disease, CK (creatine kinase) monitoring is necessary.
-
Beta- Blockers: Hypoglycemia can be brought on by beta-blockers, which can also mask the symptoms and signs of the adrenergic response that occurs when blood sugar levels are low.
-
Conclusion:
Birth-time identification of at-risk siblings enables early nutritional management to stop the onset of hypoglycemia associated with GSD III. Molecular genetic testing is the most effective method for determining the genetic status of an at-risk sibling when the AGL pathogenic mutations in the family are known.
