Glycogen Storage Diseases Types I-VII Treatment & Management

Updated: Jul 28, 2017
  • Author: Catherine Anastasopoulou, MD, PhD, FACE; Chief Editor: George T Griffing, MD  more...
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Treatment

Medical Care

GSD type I

There is no specific treatment available for patients with GSD type I. Symptomatic therapy is the mainstay of medical care. The primary goals are good control of hypoglycemia and other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia. Maintaining nutritional support for these patients is crucial. It helps to prevent hypoglycemia and support growth and development. [33]  In the past, treatment had been focused on correcting hypoglycemia and other metabolic disturbances using raw cornstarch. At present, a novel form of physically modified cornstarch (WMHM20, Glycologic Ltd; Glasgow, Scotland) is in clinical practice. It differs from classic cornstarch in regard to amylopectin content. Evidence suggests better control of hypoglycemia in persons with GSD types I and III and an extended duration of euglycemia and better metabolic control for patients. [44, 45]

Prevention of gouty attacks are important in the event dietary modifications fail to lower uric acid levels. Allopurinol is used to prevent these events. Renal protection is also very important. Urinary calculi are also commonly seen and supplementation with citrate can help prevent renal calculi from forming. ACE inhibitors may also be utilized to treat microalbuminuria. [33]

Frequent infections in patients with GSD type Ib require intravenous therapy to correct hypoglycemia and intensive intravenous antibiotic treatment to control infections. Patients may even require granulocyte colony-stimulating factor (G-CSF) if infections are recurrent to help boost immune system. 

Lipid control is also important with lipid lowering therapy, such as statins. This helps to avoid pancreatitis and atherosclerotic disease. [33]

Additionally, for patients with GSD type I, the future may bring adeno-associated virus vector–mediated gene experimental therapy, which may result in curative therapy, as is possible in patients with GSD type II. [46]

GSD type II

Enzyme replacement therapy (ERT)

At present, effective specific treatment for infantile and adult form can be achieved using recombinant DNA alglucosidase alfa (Myozyme®, Lumizyme®), which degrades lysosomal glycogen. On the basis of clinical trials, treatment with ERT, markedly improves survival and ventilator-free survival in patients with infantile-onset Pompe disease especially if therapy is started before muscle damage. Alglucosidase alfa may be administered by intravenous infusion only. [47, 48]  The recommended dosing is 20 mg/kg as a 4-hour infusion every 2 weeks. The initial rate of infusion should be 1 mg/kg/h, which may then be increased by 2 mg/kg/h every 30 minutes to a maximum rate of 7 mg/kg/h using an infusion pump.

Approximately 20% of patient with infantile form lack cross-reactive immunologic material (CRIM-), no endogenous acid alpha glucosidase enzyme is produced, IgG against the exogenous enzyme can be produced, hence ERT is ineffective. For this, immunomodulation protocols with rituximab and methotrexate with or without intravenous immunoglobulin have been developed, to prevent and eliminate immune response, giving CRIM- patient the opportunity to receive ERT. Knowing CRIM status previous to initiation of therapy is important to improve outcomes. [49, 50]

Contraindications are not known. However, some risk of different hypersensitivity reactions exist for treated patients, and some of these reactions are life-threatening anaphylaxis, including anaphylactic shock.

Preliminary results of alglucosidase alfa treatment have shown prolonged survival for patients with cardiomyopathy and those with motor deficit.

Experimental therapies

Gene therapy is an encouraging mode of treatment but is not yet available. However, in 2002, Martin-Touaux et al reported using a GSD type II mouse model, a new mode of gene therapy using muscle as a secretary organ, and an adenovirus vector encoding AdGAA. [51] They injected adenovirus vector encoding AdGAA in the gastrocnemius of neonates and detected a strong expression of GAA in the injected muscle, secretion into plasma, and uptake by the peripheral skeletal muscle and the heart. Furthermore, the glycogen content in these tissues decreased and the destruction foci usually present in untreated mice and visible by electron microscopy disappeared. Other models are trying to restore the ability of producing the enzyme by transducing the normal gene in the liver or in stem cells.

Exercise therapy, by inspiratory muscle strengthening is also under study, diaphragm pacing has potential rehabilitative to decrease the need of mechanical ventilation.

Other therapies

Respiratory muscle weakness develops, hence, patients are at high risk of infections and respiratory insufficiency, for this, respiratory therapy and noninvasive ventilation (CPAP, BiPAP) can ameliorate symptoms

Physical therapy is necessary not only to develop motors skills and to prevent contractures, but to strengthen respiratory muscles and to manage airway secretion (percussion, suctioning)

Occupational therapy may assist the patient to remain independent, orthopedic braces or surgical intervention may be necessary to alleviate scoliosis and muscle contractures to alleviate pain and/or disability. Audiology testing and sleep studies are warranted in these patients. 

GSD type III

No specific therapy exists. The treatment is somewhat simpler than that of GSD type I. In infancy, high protein diet and frequent feedings every 3-4 hours are required to maintain euglycemia. After the age of 1, patients may transition to cornstarch (1-3g/kg three times daily) and protein (3g/kg) if tolerated and maintaining euglycemia overnight. [6]  Proof that frequent protein meals and overnight nasogastric infusion of proteins can prevent progressive myopathy is not conclusive.

GSD type IV 

Treatment is based on the symptoms. The ultimate treatment is liver transplantation. The prognosis even after liver transplant is poor, due to other systemic comorbidities. 

No medication is necessary.

GSD type V 

No specific therapy is available. Hospital treatment is necessary during renal insufficiency due to rhabdomyolysis. In GSD type V, moderate intensity aerobic exercises should be performed. To increase exercise tolerance and reduce the risk of rhabdomyolysis, simple carbohydrates (sports drinks) are utilized. To prevent symptoms of GSD type V and to avoid rhabdomyolysis, avoiding isometric and maximal aerobic exercise is required. [19]

GSD type VI 

Patients with hypoglycemia, should have frequent small meals. Uncooked cornstarch can be used between meals and at bedtime. Delayed puberty, osteoporosis and short stature can be prevented with good metabolic control, avoiding episodes of hypoglycemia.  

 

 

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Surgical Care

GSD type I

In view of short- and long-term complications, orthotopic liver transplantation is a last resort when other conservative measures have failed or if hepatic adenomas become malignant. A large liver adenoma may be successfully treated with ethanol injection under ultrasonographic or CT control. Kidney transplantation has been performed in cases of end-stage renal insufficiency. If a surgical procedure is to be performed, a bleeding test must be performed and any metabolic disturbances must be corrected. In patients with prolonged bleeding times, treatment with 1-deamino-8-D-arginine vasopressin (DDAVP) together with an intravenous 10% glucose infusion 1-2 days before and again during the procedure can be useful. Avoid administering lactated Ringer solution alone because it contains lactate but does not contain glucose.

In the setting of hepatic adenomas, interventions such as percutaneous ethanol injections and radiofrequency ablation have been utilized in lieu of surgery.  [33]

 

GSD type III

Liver transplantation is not commonly performed in patients with GSD type III. It is usually for patients with severe liver cirrhosis or hepatocellular carcinoma. [6]

GSD type IV

In case of progressive liver cirrhosis, liver transplantation may be performed. However, because of the systemic nature of the disease, the long-term favorable effects of the procedure are not feasible.

GSD type VI

Surgical care is not necessary.

GSD type VII

Surgical care should be performed if necessary for other reasons, such as muscle biopsy and hemodialysis.

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Consultations

The following specialists may be consulted for patients with GSD type II:

  • Intensive care therapists to perform assisted ventilation during respiratory insufficiency
  • Pediatric cardiologist to treat cardiovascular insufficiency
  • Clinical geneticist to counsel families
  • Neurologist for EMG investigations
  • Orthopedics for contractures and scoliosis and other musculoskeletal complications.
  • Nutritionist, physical therapy, speech therapy.
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GSD type IV

  • Cardiology
  • Neurology
  • Genetics
  • Nutrition
  • Child development
  • Hepatology
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Diet

GSD type I

The primary goal of treatment is to correct hypoglycemia and maintain a normoglycemic state. The normoglycemic state can be achieved with overnight nasogastric infusion of glucose, its polymers and elemental enteral formula, parenteral nutrition, or peroral administration of raw cornstarch.

In young infants, the best results are obtained with nocturnal nasogastric tube feeding with elemental enteral formula, glucose, or glucose polymers. One third of the total caloric need should be provided by nasogastric drip feeding. An infant should receive 8-10 mg/kg/min of glucose, and an older child should receive 5-7 mg/kg/min of glucose. The infusion should be administered with a special pump. In the daytime, patients should consume frequent meals that contain higher quantities of carbohydrates (eg, carbohydrates 65-70%, proteins 10-15%, fat 20-25%). The first meal should be consumed no longer than 15-30 minutes after stopping the nasogastric infusion.

In older infants and children, raw cornstarch is administered instead of continuous overnight feeding by means of a nasogastric tube. Glucose molecules are continuously released by hydrolysis of raw cornstarch in the digestive tract over 4 hours following its intake. The cornstarch is administered between meals in a dose of 1.6 g/kg every 4 hours in children younger than 2 years and in a dose of 1.75-2.5 g/kg every 6 hours in children older than 2 years. The cornstarch is usually dissolved in lukewarm water in a weight-to-volume ratio of 1:2. In children with diminished pancreatic function, the treatment is not effective. In young adult patients, a single dose of uncooked cornstarch given at bedtime can be enough to maintain overnight blood glucose concentration in the reference range.

The intake of fructose and galactose should be restricted because it has been shown that they cannot be converted to glucose but that they do increase lactate production.

Limited intake of lipids is advisable for the existing hyperlipidemia.

GSD type II

A specific diet is not available. However, because of difficulties in swallowing and risks of aspiration, many children require feeding by means of a nasogastric or gastrostomy tube.

In 2006, Roe and Mochel reported a clinical benefit with anaplerotic diet therapy in an adult-onset GSD type II patient with skeletal muscle weakness. [52] Because patients with adult-onset disease have cataplerotic events as a result of acid maltase deficiency (from muscle to liver), triheptanoin may have a beneficial effect. Triheptanoin is a medium-odd-chain triglyceride and serves as an anaplerotic substrate for the citric acid cycle in all tissue. Heptanoate and C5-ketone bodies derived from partial oxidation of triheptanoin (C7 triglyceride) in the liver are precursors of anaplerotic propionyl-coenzyme A in peripheral tissues, including skeletal muscle, where they increase ATP production, resulting in augmentation of mass and strength of striated muscle. Besides the anaplerotic effect, triheptanoin is a gluconeogenic compound in the liver and kidney cortex.

According to data from Kinman et al from 2006, triheptanoin may be safely administered intravenously for the treatment of decompensated, energy-depleted patients. [53]

In adult form, high protein, low carbohydrate diet with exercise can slow the progression of the muscle dysfunction. 

GSD type III

A specific diet is not available. In addition, no need exists for any dietary restrictions as in patients with GSD type I. Similarly to GSD type I, patients with hypoglycemia may benefit from frequent and nocturnal tube feeding, as well as cornstarch and a high-protein diet. See section on "medical care" for further details. 

GSD type IV

A specific diet is not available. Hypoglycemia should be corrected. A balanced diet favorably influences liver disease.

GSD type V

To increase exercise tolerance and reduce the risk of rhabdomyolysis, simple carbohydrates (sports drinks) are utilized. A high-protein diet may also increase the patient's tolerance of physical exertion.

GSD type VI

A specialized diet is not necessary unless hypoglycemia with ketosis is a problem. Frequent carbohydrate meals are then recommended.

GSD type VII

Patients should be instructed to avoid carbohydrate-rich foods.

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Activity

GSD type I

Physical activity is not restricted. Patients or their parents should be informed about the risks of aggressive and dangerous sports in view of the bleeding tendency and a possibility of a traumatic injury to the liver.

GSD type II

In the juvenile and adult forms, physical activity is not restricted. Activity is limited by the capacity of the patient's musculature.

GSD types III and VI

Physical activity is not restricted. Avoid contact sports when hepatomegaly is present. 

GSD types V and VII

Patients should be instructed to avoid maximal aerobic exercise. In GSD type V, moderate aerobic exercise is beneficial for cardiorespiratory and muscle oxidative capacity. [19]

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Long-Term Monitoring

GSD type I

After the initial diagnostic hospitalization, conduct further follow-up on an outpatient basis.

In infants and young children, follow-up is usually planned bimonthly. Laboratory testing, such as liver function tests, PT/INR, renal function tests are to be performed every 6-12 months. Examine the patient regularly for other metabolic disturbances, such as hyperlactatemia, hyperuricemia, and hyperlipidemia, in addition to glycemia. Check arterial blood pressure and renal function regularly. As per guidelines from the American College of Medical Genetics and Genomics, liver ultrasound should be performed every 12-24 months until age of 16. Liver CT/MRI is to be performed every 6-12 months if the patient has hepatic adenomas. [33]

Importantly, monitor for infections in patients with GSD type Ib. For patients on G-CSF therapy, complete blood count should be performed every 3 months. Routine splenic imaging should also be performed to monitor size of the spleen for patients on G-CSF. [33]

Pulmonary hypertension screening is to be performed in patients after the age of 10 in the form of echocardiography. It should be done every 3 years. [33]

GSD type II

Counsel patients with juvenile and adult forms concerning possible complications and risks of respiratory disorders.

Provide genetic counseling for prenatal diagnosis in further pregnancies.

GSD type III

Follow-up examination of glycemia and transaminase levels is indicated.

Follow-up with a cardiologist is required.

GSD type IV

Regular checkup of liver function is indicated.

Genetic counseling concerning recurrent risks in future pregnancies is necessary.

GSD types V and VII

Instruct patients to avoid strenuous physical activities.

GSD type VI

Liver ultrasound for tumor surveillance should be performed annually starting at age 5. 

Annual measurement and monitor of growth is recommended. 

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