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Genetics of Glycogen-Storage Disease Type III Treatment & Management

  • Author: David H Tegay, DO, FACMG; Chief Editor: Maria Descartes, MD  more...
 
Updated: Oct 24, 2014
 

Medical Care

Because measuring debrancher activity in skin fibroblasts or lymphocytes is not as reliable as measuring debrancher activity in liver and muscle, a brief hospitalization is usually required to obtain the required tissue samples. Glucagon, galactose, or fructose stimulation tests are not recommended because patients with glycogen-storage disease (GSD) type I (GSD I) may develop severe lactic acidosis. Also, these test results are only suggestive; they are never diagnostic. Many patients with GSD type III (GSD III) whose diagnosis is not yet established are already hospitalized to evaluate hepatomegaly and/or hypoglycemia.

Provide frequent daytime feedings to infants and continuous nasogastric tube (NGT) feedings at night to ensure they maintain satisfactory blood glucose levels. Once a child has reached age 2-3 years, nocturnal NGT feedings can usually be replaced by feedings containing raw cornstarch (ie, a slow-release form of glucose) dispersed in room-temperature water or a diet drink. This suspension maintains blood glucose levels at satisfactory levels for 3-6 hours. Warn caregivers never to substitute any other type of starch (eg, rice, potato) for cornstarch because only cornstarch achieves the desired results. Moreover, do not use hot water to achieve a more homogeneous suspension; aqueous cornstarch suspensions prepared with hot water may maintain blood glucose levels at satisfactory levels for only 1-2 hours.[32]

Some studies suggest benefit in determining individual fasting tolerance between cornstarch administrations to tailor feeding intervals for improved hypoglycemia avoidance and growth support.[33]

Significant hypoglycemia sometimes develops in patients receiving adequate dietary control. This complication is usually caused by deviations from the patient's dietary therapy, either because of an intercurrent illness or because of occasional adolescent rebelliousness. When a patient experiences more than a very occasional episode of hypoglycemia, providing the family with a glucometer and the associated paraphernalia and instructions on how to use the device may be best.

Treatment of hypoglycemic episodes depends on the patient's mental status. For a patient who is awake and alert, a sufficient dose should be 15 g of simple carbohydrate (ie, 4 oz of most fruit juices, 3 tsp table sugar, 15 g glucose either as tablets or gel by mouth). If the patient's symptoms do not improve promptly, or if the blood glucose level does not rise above 39 mmol/L (ie, 70 mg/dL) within 15 minutes, repeat the carbohydrate dosage. Failure to respond adequately to a second dose is most unusual; indeed, such a failure mandates a search for other causes of hypoglycemia (eg, overwhelming infection, exogenous insulin administration, adrenal insufficiency). Waiting 15 minutes after the initial treatment before retesting or administering a second dose of carbohydrate is important because overtreatment of low blood sugars can lead to hypoglycemia, probably because of hyperinsulinemia.

When a patient's mental status is depressed to the point that it causes concern that the patient may aspirate orally administered carbohydrate, the appropriate form of treatment depends on the setting.

Home treatment

Subcutaneous glucagon administration may be tried for patients at home, but remember that patients with GSD III who have not eaten recently may not respond to glucagon because their glycogen supplies may be depleted of glucose moieties that can be cleaved in the absence of debrancher activity. All caregivers should have this hormone available and should know how to administer it.

Administer glucagon subcutaneously, 0.5 mg for patients who weigh less than 20 kg (ie, 44 lb) or 1 mg for patients who weigh more than 20 kg. Immediately contact local emergency medical services if the patient does not respond promptly to subcutaneous administration because intravenous glucose administration is then necessary.

Hospital treatment

If a hospitalized patient does not respond to oral administration of 30 g of glucose, administer glucagon only if venous access is a problem; remember that glucagon may provide little benefit to a nutritionally depleted patient with GSD III.

The preferred inpatient treatment is prompt administration of intravenous glucose, which always proves beneficial. Moreover, intravenous glucose does not provoke the nausea and vomiting that may follow glucagon administration.

The treatment for acute hypoglycemia is an intravenous bolus of 2.5 mL/kg of 10% dextrose in sterile water. Follow the bolus with an intravenous infusion of glucose at a rate that matches normal endogenous hepatic glucose production. This rate in infants is approximately 8-10 mg/kg/min; the rate in older children is approximately 5-7 mg/kg/min. These rates are only guidelines; actual rates vary from patient to patient. Always adjust the dose to maintain plasma glucose levels above 2.5 mmol/L (45 mg/dL). A higher maintenance level may be chosen.

Concurrent infections or other illnesses that interfere with the patient's oral dietary intake may necessitate intravenous glucose support until the condition resolves. The response to parenteral dextrose administration is virtually immediate.

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Surgical Care

Most patients with GSD III require no special surgical care other than that required to obtain a liver specimen, if the specimen cannot be safely obtained percutaneously. Patients with GSD IIIa or IIId who develop end-stage cirrhosis or hepatocellular carcinoma require surgical intervention, which sometimes includes liver transplantation.[34] Liver transplantation has also been used with success in patients who are recalcitrant to medical therapy.[35]

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Consultations

A biochemical geneticist should have active and regular involvement in the care of all patients with GSD III, regardless of subtype.

Annual evaluation by a nutritionist or dietitian who specializes in metabolic diseases is an important component of GSD III management because a patient's energy needs increase with growth. Only a portion of the glucose content of glycogen is metabolically available in a patient with GSD III because of the debrancher activity deficiency; therefore, a goal of dietary therapy is to ensure optimal glycogen stores in these patients.

Involve a gastroenterologist in the management of patients with GSD III because these patients may develop cirrhosis and even hepatocellular carcinoma. Some gastroenterologists have considerable expertise in GSD III management.

Periodic consultations with a neurologist are advisable for patients with GSD IIIa and IIId because they may develop a significant myopathy, especially upon entering their teenage years.

Consultation with a cardiologist is advisable because patients with GSD IIIa and IIId may develop a hypertrophic cardiomyopathy.

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Diet

Meticulous dietary management is the mainstay therapy for all forms of GSD III. Management requires regular involvement by a nutritionist or dietitian who specializes in metabolic diseases. The goal is to ensure adequate blood glucose levels throughout the day and night (especially at night) and optimal glycogen stores.

For infants, frequent feedings of breast milk or formula provide adequate amounts of glucose and glucose precursors during the day, even though both forms of milk contain almost 50% of their energy value as fat, which provides little gluconeogenic substrate. For example, 1000 calories of fat provides less than 0.08 moles (14 g) of carbohydrate precursors, whereas the same number of calories of lactose provides more than 1.4 moles (>250 g) of carbohydrate.

Maintain euglycemia in infants at night by continuous NGT feedings. The feedings may consist of formula or breast milk, elemental enteral formula, or solutions of either glucose or glucose polymers (eg, Polycose, Moducal). Set the infusion rate to provide approximately 8-10 mg/kg/min of glucose in an infant and approximately 5-7 mg/kg/min of glucose in an older child. The pump delivering the nocturnal feedings must be equipped with an effective alarm; hypoglycemia and even deaths have occurred from pump malfunction or NGT dislodgement.

As an infant begins to ingest solid food, formula or breast milk can be supplemented with various foods. The goal is to achieve a diet that contains approximately 55-65% of its energy value as carbohydrate, 20-25% as fat, and 15-20% as protein.

Because the entire pathway of gluconeogenesis is intact in patients with GSD III, the diet may include all precursors of glucose (ie, proteins, galactose, fructose, lactate, pyruvate, glycerol). Unlike patients with GSD I, no restrictions are necessary for sucrose, lactose, galactose, and fructose intake because these carbohydrates are not obligatory sources of lactic acid in patients with GSD III. Fatty acids cannot be converted to glucose, so the best method is to restrict dietary fat content to 20-25% of energy intake, a limitation that has the added benefit of being heart healthy.

When a child is about age 2 years, continuous nocturnal NGT feedings can be replaced with suspensions of cornstarch in water or in a diet drink. Although the duodenal concentration of pancreatic amylase reaches levels approaching that in an adult by age 6-8 months, the wise course is to delay replacing nocturnal continuous NGT infusions with cornstarch suspensions until the child is aged 2-3 years because younger children do not usually accept the raw cornstarch suspension, probably because of its somewhat unpalatable texture.

The initial dose of cornstarch in 2-year-old children is approximately 1.6 g/kg of body weight every 4 hours. Prepare the cornstarch as a 1:2 ratio (weight-to-volume) suspension of cornstarch in room-temperature water or diet drink.[32] As the child ages, the interval between nocturnal cornstarch ingestions can usually be extended to every 6 hours at a dose of 1.75-2.5 g/kg body weight. Be cautious about the amount of carbohydrate administered because overtreatment may elicit symptomatic hypoglycemia, probably because of induced hyperinsulinism.

The myopathies of GSD IIIa and IIId possibly result from the breakdown of muscle protein to provide amino acids as substrates for gluconeogenesis. The recommended treatment to overcome this problem is a high-protein diet (ie, 25% of energy intake). Such a diet reportedly has improved and even reversed the myopathy in patients with GSD III. However, benefits from this approach appear unlikely because all gluconeogenesis, amino acid synthesis, and amino acid catabolism reactions remain intact in patients with GSD III. Most investigators now believe no satisfactory treatment is available for the progressive myopathy or cardiomyopathy of GSD IIIa and IIId.

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Activity

Encourage patients to participate in physical activities, including contact sports, to their personal limits. Ruptured livers or spleens secondary to contact sports have not been reported in patients with any form of GSD III.

Caution patients with GSD IIIa or IIId against vigorous activity at times when their blood glucose levels are not within references ranges. For example, one of the author's teenaged patients quarreled with his mother and left for school without eating breakfast. The boy skipped lunch, then participated in a prolonged volleyball match. He subsequently developed severe muscle cramps and voided dark urine that tested positive for myoglobin. The boy then went into acute renal failure and required dialysis for 7 days before his kidneys resumed urine production. His depleted energy stores presumably caused the rhabdomyolysis that led to myoglobinuria and renal shutdown. The boy was fortunate and had no long-term sequelae.

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Contributor Information and Disclosures
Author

David H Tegay, DO, FACMG Associate Professor and Chair, Department of Medicine, NYIT College of Osteopathic Medicine; Director, Genetics Division, Department of Pediatrics, Nassau University Medical Center

David H Tegay, DO, FACMG is a member of the following medical societies: American College of Medical Genetics and Genomics, American College of Osteopathic Internists, American Osteopathic Association, Federation of American Societies for Experimental Biology, American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Lois J Starr, MD, FAAP Assistant Professor of Pediatrics, Clinical Geneticist, Munroe Meyer Institute for Genetics and Rehabilitation, University of Nebraska Medical Center

Lois J Starr, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Edward Kaye, MD Vice President of Clinical Research, Genzyme Corporation

Edward Kaye, MD is a member of the following medical societies: American Academy of Neurology, Society for Inherited Metabolic Disorders, American Society of Gene and Cell Therapy, American Society of Human Genetics, Child Neurology Society

Disclosure: Received salary from Genzyme Corporation for management position.

Acknowledgements

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Howard R Sloan, MD, PhD to the development and writing of this article.

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Schematic illustration of the degradation of glycogen by the concerted action of the enzymes phosphorylase and debranching enzyme. First, phosphorylase removes glucose moieties (linked to their neighbors via alpha1,4 glucosidic bonds and depicted as the 7 black circles) from the unbranched outer portions of the glycogen molecule until only 4 glucosyl units (depicted as the 3 green circles and the 1 red circle) remain before an alpha1,6 branch point. The transferase component of debranching enzyme then transfers the 3 (green) glucose residues from the short branch to the end of an adjacent branch of the glycogen molecule. The glucosidase component of debranching enzyme then removes the glucose moiety (depicted as the red circle) remaining at the alpha1,6 branch point. In the process, the branch point formed by the alpha1,6 glucosidic bond is removed, hence the name debrancher.Unlike phosphorylase, which removes glucose moieties from glycogen in the form of glucose-1-phosphate, debrancher releases 1 free glucose moiety from each branch point. After the cleavage of the branch site, phosphorylase attacks unbranched portions of the glycogen molecule until the enzyme is stymied by the appearance of another branch point, at which point debranching enzyme once again is called into play. Eventually, large portions of the glycogen molecule are degraded to free glucose by the action of the amylo-alpha1,6-glucosidase activity of debranching enzyme and to glucose-1-phosphate by the action of phosphorylase.
Schematic representation of a portion of a molecule of glycogen. Open circles represent the glucose moieties connected to each other via alpha1,4 linkages. Solid circles represent the glucose moieties connected to their neighbors via alpha1,6 linkages. Thus, each solid circle represents a branch point in the molecule.
 
 
 
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