Type Ia Glycogen Storage Disease 

Updated: Mar 07, 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.[1]

The diagram below illustrates metabolic pathways of 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 [G-6-P] 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, GSD type 0, which is due to defective glycogen synthase, also is recognized.

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. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.

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

G-6-P deficiency is the specific enzyme deficiency in von Gierke disease. GSD type Ib is a similar condition with the defect in the G-6-P transporter protein. A newly described form, GSD type Ic, does not appear to be related to mutations within the transporter protein.

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. As noted above, G-6-P, which is found in the liver and kidney, is the specific enzyme that is deficient in von Gierke disease. Glucose-6-phosphate is an intermediate in the glycogen pathway.

Von Gierke disease is an autosomal-recessive condition. Von Gierke disease may be explained by mutations of the phosphohydrolase catalytic unit gene of the G-6-P complex, unlike GSD type Ib and GSD type Ic.

Deficiency of G-6-P blocks the final steps of glycogenolysis and gluconeogenesis.[2] This results in severe hypoglycemia. Glucose production increases with age, making hypoglycemia less of an issue.

Because glucose cannot leave the hepatocyte phosphorylated, an increase in glycolytic pathway metabolites occurs. These intermediates are metabolized into lactate. Lactate may provide the brain with a ready-to-use energy source. By competing with uric acid, lactate decreases renal clearance, resulting in hyperuricemia. Glucose also is shunted into making more triglycerides, causing an increase in low-density and very low-density lipoproteins.[3]

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

Immediate morbidity arises from hypoglycemic seizures. Serious long-term complications resulting in morbidity and mortality include nephropathy and hepatic adenoma.[4]

Sex

GSDs are autosomal-recessive conditions, with an equal number of males and females being affected.

Age

In general, GSDs present in childhood. Later onset correlates with a less severe form.

 

Presentation

History

See the list below:

  • Initial presentation may be active seizures, specifically hypoglycemic seizures.

  • Global muscle weakness is not a uniform feature of von Gierke disease. Schwahn and colleagues found height, weight, bone mass and grip force decreased in one group of GSD 1a patients.[5]

  • Patients may give a history of kidney stones or gout.

  • Patients may have had pancreatitis.

Physical

See the list below:

  • Physical examination may reveal hepatomegaly. Because many causes of hepatic injury exist, suspicion of glycogen storage disease (GSD) must be high.

  • Hypotonia is found in infants.

  • Hypoglycemia is concerning and may lead to hypoglycemic seizures.

  • Xanthomas may be present on the buttocks or extensor surfaces.

  • Acute manifestations of gout may be observed.

  • Hypertension or other manifestations of renal failure may be present.

  • Short stature may be seen in the untreated patient.

  • A prospective study by Melis et al found that GSDIa patients had a higher prevalence of insulin resistance and metabolic syndrome.[6]

 

DDx

 

Workup

Laboratory Studies

See the list below:

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

  • Because hypoglycemia may be found in some types of GSD, fasting glucose testing 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.

  • Hyperlipidemia is found in GSD Ia although there is no clear evidence of increased atherosclerosis.[7]

  • Laboratory abnormalities also include hyperuricemia, hyperlactacidemia, hyperlipidemia, hypercalciuria, and azotemia.

  • Normochromic anemia has been documented.

  • Measuring lipase and amylase may be justified in suspected cases of pancreatitis.

  • Renal function studies may reveal renal failure. Nephropathy is a serious long-term complication of von Gierke disease.

  • Obtaining a 24-hour urine collection to measure protein and creatinine clearance may be useful.

  • Nutritional status

    • Kishnani and colleagues reported on 1 patient with von Gierke disease who was compliant with a high-protein diet but who developed emesis, weight loss, weakness, ataxia, agraphia, and oral ulcers. He was found to be deficient in vitamin B-12, folate, and iron. Correction of deficiencies allowed for symptomatic recovery.[8]

    • Other authors note that oral ulcers are secondary to impaired neutrophil migration, one feature of this disorder.

Imaging Studies

See the list below:

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

  • Bone densitometry in older individuals may show low bone mass.

  • Renal ultrasonography may show enlarged kidneys.

  • In a study to determine how well contrast-enhanced ultrasonographic scans can characterize focal liver lesions in patients with GSD type Ia, Nguyen et al examined images from 8 benign hepatic adenomas associated with the disease.[9] The scans revealed marked hypervascularity in all of the lesions during the early arterial phase, with most of the lesions showing sustained enhancement in the portal and late phases.

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 from 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 a 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 mcg/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 patients with GSDs have a positive ischemic test.

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

    • In von Gierke disease, the ischemic forearm test is negative.

  • Molecular genetic analysis

    • Seydewitz and Matern report a study of 40 patients with von Gierke disease. Mutations were found on all 80 alleles, which is evidence that molecular genetic analysis is a reliable diagnostic modality in addition to enzyme assay.[10]

    • Biochemical assay of enzyme activity is required for definitive diagnosis.

Histologic Findings

Biopsy of the kidney reveals focal glomerulosclerosis.

 

Treatment

Medical Care

See the list below:

  • In general, no specific treatment exists to cure glycogen storage diseases (GSDs).

  • 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.[11] These findings suggest that corrective gene therapy of GSDs may be possible for 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.[12]

Surgical Care

Liver transplantation may be indicated for patients with hepatic malignancy. Whether transplantation prevents further complications remains unclear, although a study by Matern and colleagues demonstrated correction of metabolic abnormalities after transplantation.[13]

Consultations

See the list below:

  • Due to the progressive kidney dysfunction, referral to a nephrologist may be appropriate.

  • Consultation with a hepatologist may be necessary for management of liver dysfunction.

Diet

See the list below:

  • Growing evidence indicates that a high-protein diet may provide increased muscle function in cases of weakness or exercise intolerance. Evidence also exists that indicates a high-protein diet may slow or arrest disease progression.

  • Prevention of hypoglycemia in affected infants can be challenging. Nasogastric drip-feeding has allowed continuous feeding during the night. Uncooked starch may be used in older children.

 

Follow-up

Deterrence/Prevention

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

Prognosis

See the list below:

  • Von Gierke disease is not curable.

Patient Education

See the list below:

  • Educate patients in the recognition of hypoglycemia and its appropriate treatment.