Type Ib Glycogen Storage Disease 

Updated: Apr 11, 2017
Author: Wayne E Anderson, DO, FAHS, FAAN; Chief Editor: George T Griffing, MD 

Overview

Background

A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but, in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms, such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.

The image below illustrates the metabolic pathways for carbohydrates.

Metabolic pathways of carbohydrates. Metabolic pathways of carbohydrates.

Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency). One form, Von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity. The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, there also is a GSD type 0, which is due to defective glycogen synthase.

These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms. In general, GSDs are inherited as autosomal recessive conditions. Several different mutations have been reported for each disorder.

Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations.[1] In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

Diagnosis depends on muscle biopsy, electromyelography, ischemic forearm test, creatine kinase levels, patient history, and physical examination. Biochemical assay for enzyme activity is the method of definitive diagnosis.

Acid maltase catalyzes the hydrogenation reaction of maltose to glucose. Acid maltase deficiency is a unique glycogenosis since glycogen accumulation is lysosomal rather than in the cytoplasm. It also has a unique clinical presentation depending on age at onset, ranging from fatal hypotonia and cardiomegaly in the neonate to muscular dystrophy in adults.

Glucose-6-phosphatase (G-6-P) is the specific enzyme deficiency in Von Gierke disease. GSD type 1b is a similar condition with a defective G-6-P transporter protein.[2, 3] A newly described form, GSD type 1c, is not thought to be related to a transporter protein mutation.

Pathophysiology

With an enzyme defect, carbohydrate metabolic pathways are blocked, and excess glycogen accumulates in affected tissues. Each GSD represents a specific enzyme defect, and each enzyme is in specific, or most, body tissues. The G-6-P transporter protein is found in the liver and kidney.

GSD type Ib is an autosomal recessive condition.

Glucose-6-phosphate is an intermediate in glycogen synthesis and glucose metabolism. GSD type Ib differs from GSD type Ia in that it is not explained by mutations of the phosphohydrolase gene. Veiga-da-Cuhna and colleagues provide evidence that all non-1a cases can be explained by mutations of the glucose-6-phosphate translocase gene.[4]

Epidemiology

Frequency

International

Herling and colleagues studied the incidence and frequency of inherited metabolic conditions in British Columbia. GSDs are found in 2.3 children per 100,000 births per year.

Mortality/Morbidity

See the list below:

  • GSD Ib, unlike GSD Ia, involves bacterial infections including brain abscesses. However, D'Eufemia and colleagues report one case of a 10-year-old boy with GSD II with neutropenia and neutrophil dysfunction but without severe recurrent infections.[5]

  • Immediate morbidity arises from hypoglycemic seizures.

  • Serious long-term complications include nephropathy and hepatic adenoma.

Age

See the list below:

  • In general, GSDs present in childhood. Later onset correlates with a less severe form. Consider Pompe disease if onset is in infancy.

 

Presentation

History

See the list below:

  • Initial presentation may be hypoglycemic seizures.

  • Although muscle weakness is not a uniform feature of glycogen storage disease (GSD), type I, Schwahn and colleagues report an association between reduced muscle force and poor metabolic control.[6]

  • Skin and pulmonary infections are frequent.

  • Patients may report symptoms of inflammatory bowel disease including cramps, fever, and abdominal pain.

Physical

See the list below:

  • Physical examination findings may include hepatomegaly. Because many causes of hepatic injury exist, suspicion must be high.

  • Examination findings may suggest infection of lung or skin.

  • Findings also may include acute abdomen and perioral or perianal infections.

  • Hypotonia is found in infants.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Obtain a creatine kinase in all cases of suspected glycogen storage disease (GSD).

  • Obtain a lipid profile due to changes in glucose metabolism.

  • Because hypoglycemia may be found in some types of GSD, fasting glucose is indicated. Hypoglycemia is concerning and may lead to hypoglycemic seizures.

  • Urine studies are indicated because myoglobinuria may occur in some GSDs.

  • Hepatic failure occurs in some GSDs. Liver function studies are indicated.

  • Biochemical assay is required for definitive diagnosis.

Imaging Studies

See the list below:

  • Imaging may reveal hepatic adenoma, which may become malignant.

Other Tests

See the list below:

  • Ischemic forearm test

    • The ischemic forearm test is an important tool for diagnosis of muscle disorders. The basic premise is an analysis of the normal chemical reactions and products of muscle activity. Obtain consent before the test.

    • Instruct the patient to rest. Position a loosened blood pressure cuff on the arm, and place a venous line for blood samples in the antecubital vein.

    • Obtain blood samples for the following tests: creatine kinase, ammonia, and lactate. Repeat in 5-10 minutes.

    • Obtain a urine sample for myoglobin analysis.

    • Immediately inflate the blood pressure cuff above systolic blood pressure and have the patient repetitively grasp an object, such as a dynamometer. Instruct the patient to grasp the object firmly, once or twice per second. Encourage the patient for 2-3 minutes, at which time the patient may no longer be able to participate. Immediately release and remove the blood pressure cuff.

    • Obtain blood samples for creatine kinase, ammonia, and lactate immediately and at 5, 10, and 20 minutes.

    • Collect a final urine sample for myoglobin analysis.

  • Interpretation of ischemic forearm test results

    • With exercise, carbohydrate metabolic pathways yield lactate from pyruvate. Lack of lactate production during exercise is evidence of pathway disturbance and an enzyme deficiency is suggested. In such cases, muscle biopsy with biochemical assay is indicated.

    • Healthy patients demonstrate an increase in lactate of at least 5-10 mg/dL and ammonia of at least 100 µg/dL. Levels will return to baseline.

    • If neither level increases, the exercise was not strenuous enough and the test is not valid.

    • Increased lactate at rest (before exercise) is evidence of mitochondrial myopathy.

    • Failure of lactate to increase with ammonia is evidence of a GSD resulting in a block in carbohydrate metabolic pathways. Not all GSDs have a positive ischemic test.

    • Failure of ammonia to increase with lactate is evidence of myoadenylate deaminase deficiency.

    • Ischemic forearm test is normal in GSD type Ib.

  • Electromyelography

    • Aminoff reports electromyelographic findings suggestive of myopathy, although abnormal spontaneous activity may be present.

    • Electrical myotonia without clinical myotonia may be present.

    • Myotonic discharges may be found in the paraspinal muscles.

    • Fibrillation potentials, positive sharp waves, and complex repetitive discharges may be found.

    • Myopathic findings of polyphasic responses, decreased duration of potentials, and decreased amplitude usually are present.

  • ECG demonstrates a pan-lead, short PR interval and elevated QRS complexes in the infantile form.

Procedures

Given the association of inflammatory bowel disease, endoscopic procedures may be necessary.

Histologic Findings

Liver histology is characterized by hepatocytes distended by glycogen and fat. Associated fibrosis is minimal.

 

Treatment

Medical Care

See the list below:

  • In general, no specific treatment exists for glycogen storage diseases (GSDs).[7]

  • There is ongoing research into emerging gene therapy treatments.

  • In some cases, diet therapy is helpful. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development.

  • Zingone and colleagues demonstrated the abolition of the murine clinical manifestations of Von Gierke disease with a recombinant adenoviral vector.[8] These findings suggest that corrective gene therapy for GSDs may be possible in humans.

  • An encouraging study by Bijvoet and colleagues provides evidence of successful enzyme replacement for the mouse model of Pompe disease, which may lead to therapies for other enzyme deficiencies.[9]

  • Adequate administration of starch may avoid hypoglycemia.

Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. It is not clear if transplantation prevents further complications, although a study by Matern and colleagues demonstrated post-transplantation correction of metabolic abnormalities.[10]

Consultations

Gastroenterology consult may be necessary to evaluate the presence or absence of inflammatory bowel disease.

Diet

See the list below:

  • A high-protein diet may provide increased muscle function in cases of weakness or exercise intolerance. A high-protein diet also may slow or arrest disease progression.

  • Patients must receive adequate glucose.

  • In a 2-year study of 7 patients with GSD type Ib, Melis et al examined whether the administration of vitamin E could improve or prevent the clinical manifestations of neutropenia and neutrophil dysfunction.[11] Vitamin E supplementation was provided to patients only during the second year of the study, and neutrophil counts from the first and second years were compared. The investigators found that during the second year, mean neutrophil counts were significantly greater than they were during the first. Reductions in the frequency and severity of infections, mouth ulcers, and perianal lesions also occurred during the second year. However, no changes in neutrophil function were found in association with vitamin E supplementation. Another study by Melis et al reported that during vitamin E supplementation, frequency and severity of infections in a caseload of 18 GSD1b patients were lower and mean value of neutrophil count were higher.[12]

 

Follow-up

Deterrence/Prevention

See the list below:

  • Early diet therapy may help prevent hepatic disease, including hepatocellular carcinoma.

Complications

See the list below:

  • Hypoglycemic seizures

  • Nephropathy with renal failure

  • Hepatic adenoma with potential malignant transformation

  • Inflammatory bowel disease (Recent evidence of an elevated platelet count in patients may be a warning sign of inflammatory bowel disease.)

  • Recurrent pulmonary and skin infections, likely secondary to neutropenia.

  • Secondary diabetes mellitus (may be a late complication)

  • Acute myelogenous leukemia (Pinsk and colleagues suggest surveillance for acute myelogenous leukemia as a potential complication of GSD Ib.[13] )

Prognosis

See the list below:

  • The disorder is not curable.