Genetics of Glycogen-Storage Disease Type IV Workup

Updated: Jan 08, 2016
  • Author: Lynne Ierardi-Curto, MD, PhD; Chief Editor: Maria Descartes, MD  more...
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Workup

Laboratory Studies

In patients suspected to have the classic form of glycogen-storage disease type IV (GSD IV), perform laboratory evaluations to assess the degree of liver dysfunction. Patients may exhibit all, some, or none of the associated biochemical abnormalities, depending on the degree of liver dysfunction and counter-regulatory processes.

In general, prolonged prothrombin time (PT) and decreased plasma albumin levels correlate with the degree of hepatic cirrhosis. Increased plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT) correlate with the degree of hepatocellular insufficiency. Patients with primary muscle, nervous system, or cardiac involvement and minimal or no liver dysfunction may demonstrate laboratory values within reference ranges.

CBC count: Normochromic anemia or normocytic anemia usually results from chronic blood loss due to coagulopathy, folate deficiency, and hemolysis. Morphologically abnormal erythrocytes on peripheral blood smear findings result from decreased splenic function. Thrombocytopenia and leukopenia result from splenic sequestration.

PT, activated partial thromboplastin time, and fibrinogen: Liver disease causes decreased synthesis of vitamin K–dependent coagulation factors and fibrinogen, inadequate absorption of vitamin K, and thrombocytopenia; therefore, progressive liver failure leads to prolonged PT and prolonged activated partial thromboplastin time (aPTT), decreased fibrinogen levels with progressive coagulopathy, and risk of disseminated intravascular coagulation.

ALT and AST: Measurement of liver enzyme levels usually reveals progressive elevation consistent with hepatocellular damage and release of enzymes into the blood.

Total and indirect (conjugated) bilirubin: In the early stages of liver dysfunction, conjugated bilirubin levels rise because the liver can conjugate this fluid but cannot adequately excrete it. In patients with progressive liver failure, both conjugated and unconjugated bilirubin levels rise.

Serum alkaline phosphatase, GGT, and 5' nucleotidase: Levels of these hepatocellular enzymes may be normal or slightly elevated and may vary with the degree of hepatic bile secretory function.

Serum albumin: Hypoalbuminemia is a result of decreased hepatic synthetic function but also depends on dietary protein intake and on fluid and electrolyte dynamics.

Electrolytes: Associated renal dysfunction causes electrolyte imbalance with hyponatremia, hypokalemia, and decreased serum calcium and magnesium levels.

BUN: BUN levels are abnormally low despite associated renal dysfunction, secondary to impaired hepatic synthetic function.

Creatinine: Creatinine levels are usually within the reference range.

Serum creatine kinase: Serum creatine kinase levels are within the reference ranges, even in patients with severe hypotonia.

Blood glucose: Hypoglycemia may result from severe hepatocellular damage and from glycogenolysis and gluconeogenesis that are inadequate to maintain serum glucose.

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Imaging Studies

Abdominal Doppler ultrasonography may reveal the presence of portal hypertension, esophageal varices, and liver echogenicity. Ultrasonography may also reveal portal vein diameter and blood flow directionality.

Abdominal MRI or CT scanning may reveal evidence of cirrhotic changes in liver parenchyma and the vascular system. Liver and spleen volume quantitation may be performed.

Characteristic features on liver-spleen scintigraphy using technetium-99m sulfur colloid include decreased uptake in the liver with an irregular pattern and increased uptake in the spleen and bone marrow.

MRI of the head may reveal leukoencephaly and cortical atrophy in patients with adult polyglucosan body disease (APBD) and CNS involvement. MRI typically demonstrates medullary and spinal atrophy, mild thinning of corpus callosum, and symmetric periventricular white matter changes with occipital predominance. [5]

Proton MR spectroscopy of the head may reveal changes consistent with white matter degeneration. [8]

Echocardiography may reveal evidence of dilated cardiomyopathy and impaired myocardial function.

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Other Tests

Definitive biochemical diagnosis of glycogen-storage disease type IV relies on demonstration of deficient glycogen-branching enzyme activity in the liver or in the muscle tissue.

Because glycogen-storage disease type IV is a multisystem disorder, evidence of abnormal glycogen content can be demonstrated in many tissues and cells, including the liver, leukocytes, erythrocytes, and cultured skin fibroblasts. The sole exception is APBD in Ashkenazi Jewish patients whose deficient glycogen-branching enzyme activity may be demonstrated only in leukocytes and nerve cells.

Patients demonstrate approximately 1-10% of the glycogen-branching enzyme activity found in persons without glycogen-storage disease. Heterozygotes may be identified based on an intermediate reduction in glycogen-branching enzyme activity.

The demonstration of homozygous or compound heterozygous mutations in the GBE1 gene by sequence analysis is considered definitive molecular diagnosis of glycogen-storage disease type IV. Targeted mutation analysis may be considered in Ashkenazi Jewish patients with suspected APBD and when a familial mutation has been previously identified.

Prenatal testing is based on the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Histological evaluation of placental biopsy samples for the presence of polyglucosan bodies may provide another method of prenatal diagnosis. [9] Molecular diagnosis may be performed if the parental GBE1 mutations have been identified.

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Procedures

Definitive biochemical diagnosis of glycogen-storage disease type IV may require obtaining a biopsy of the liver or other affected organs (eg, muscle, nerve, heart) for microscopic examination and enzyme assay.

Esophagogastroduodenoscopy is the definitive procedure to document the presence and position of esophageal varices.

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Histologic Findings

Characteristic microscopic findings in liver sections include a distorted architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic inclusions within their cytoplasm.

Liver section from a patient with glycogen-storage Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with hematoxylin and eosin. Characteristic findings include distorted hepatic architecture with diffuse interstitial fibrosis and wide fibrous septa surrounding micronodular areas of parenchyma. Hepatocytes are typically enlarged 2-fold to 3-fold, with faintly stained basophilic cytoplasmic inclusions.

Histological analysis of the liver and other affected tissues demonstrates periodic acid-Schiff (PAS)–positive, diastase-resistant, coarsely clumped material consistent with abnormal glycogen. Iodine staining forms a characteristic complex with a distinctive blue color. Electron microscopic examination of affected tissues reveals normal alpha- and beta-glycogen particles in addition to fibrillary aggregates typical of amylopectin. In many reports, the cytoplasm of affected cells contains many of these abnormal aggregates, termed polyglucosan bodies. Histological analysis of muscle fibers from affected patients demonstrates severe depletion of myofibrils. [1]

Liver section from a patient with glycogen-storage Liver section from a patient with glycogen-storage disease type IV (GSD IV) stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped material cytoplasmic material representing the accumulated abnormal glycogen is resistant to diastase treatment and is readily stained with PAS.
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