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Genetics of Glycogen-Storage Disease Type II (Pompe Disease) Workup

  • Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD  more...
Updated: Feb 29, 2016

Laboratory Studies

The studies listed below are indicated in Pompe disease (glycogen-storage disease type II [GSD II]).

Serum creatine kinase concentration

The serum creatine kinase (CK) concentration is a general reflection of muscle disease (nonspecific, as many disease processes are characterized by elevated CK levels).

The greatest elevation is seen in patients with infantile, childhood, and juvenile GSD II variants. Values may be 10 times the reference range (ie, elevated abnormal values of 2000 IU/L, with a normal range of 60-305 IU/L).

CK values may be normal in adult-onset GSD II.

Serum aspartate aminotransferase (AST)

Serum aspartate aminotransferase (AST) is a general indicator of hepatic involvement (nonspecific, as many disease processes are characterized by elevated AST levels).

Hepatic transaminase levels are highest among GSD II infantile forms.

Urinary oligosaccharides

Elevated urinary glucose tetrasaccharide is sensitive for GSD II but nonspecific, as this elevation is seen in other glycogen-storage diseases.[18]

Enzyme activity of acid alpha-glucosidase

Definitive diagnosis of Pompe disease requires measurement of acid alpha-glucosidase (GAA) activity. Generally, lower GAA enzyme activity indicates an earlier age onset of the disease process. Complete deficiency (GAA activity <1% of normal controls) is associated with classic infantile-onset GSD II. Partial deficiency (GAA activity 2%-40% of normal controls) is associated with the non-classic infantile-onset and the late-onset forms.[3]

Per the Pompe Disease Diagnostic Working Group 2008, confirmation of GAA activity is recommended from two sample types. GAA enzyme activity can be determined on dried blood spots, cultured skin fibroblasts, or muscle tissue.

Reliable diagnosis can be determined from a dried blood spot, such as sample collection used for State Metabolic Newborn Screening Tests. This test approach is rapid and sensitive.

Historically, cultured skin fibroblasts were used to assess for GAA enzyme activity. This sample type is problematic as it takes 4-6 weeks to harvest the cells, causing a delay in diagnosis and potential initiation of treatment.

A muscle biopsy can help establish a diagnosis, as GSD II is a lysosomal storage disease. Glycogen storage may be seen in the lysosomes of muscle cells as vacuoles that stain with periodic acid-Schiff (PAS). Obtaining this sample type is invasive, and adult-onset Pompe disease among patients with partial GAA enzyme activity may not be confirmed, as 20%-30% of samples from these patients may not show these muscle changes.[19, 20]

Molecular analysis of the GAA gene

Molecular analysis of the GAA gene is available. However, the assay may fail to reveal both mutations in an affected individual. Therefore, DNA testing cannot be used in place of GAA enzyme activity to establish the diagnosis. DNA analysis can be helpful in the identification of carriers in a family with an affected member.

Further confirmation of diagnosis is made when two disease-causing GAA alleles are identified.

Ethnicity and phenotype of the patient help to direct focused testing for one of the three common pathogenic GAA gene variants: p.Asp645Glu, p.Arg854Ter, or c.336-13T>G.

If none of the common variants is detected, a complete gene sequence can be performed.[17]


Imaging Studies

Chest radiography

Chest radiography shows cardiomegaly in patients with infantile-onset GSD II. Radiography also allows for pulmonary field evaluation.[21]


Echocardiography is used to establish the degree of cardiac involvement.

Echocardiography is an important study, especially in patients diagnosed with infantile-onset GSD II.

Echocardiography findings may assist medical providers to distinguish between the infantile and juvenile-onset forms of GSD II.

Echocardiography is used to determine overall cardiac enlargement (hypertrophic cardiomyopathy) and to diagnose isolated LV thickening, biventricular thickening, or outflow obstruction in advanced disease.


Other Tests


Electrocardiography (ECG) is also used to establish the presence of cardiac involvement, as conduction disturbance is shown.

The characteristic finding is shortening of the PR interval.

Enlargement of the QRS complex also may occur.


Electromyography (EMG) reveals a myopathic pattern in all patients with Pompe disease.

Many patients with Pompe disease exhibit pseudomyotonic discharges (ie, myotonic discharges in the absence of clinical myotonia), fibrillation potentials, and positive waves due to anterior horn cell involvement.



Skin biopsy findings reveal acid alpha-glucosidase activity in cultured fibroblasts.

Muscle biopsy can help establish a diagnosis. Glycogen storage is seen in the lysosomes of muscle cells as vacuoles that stain with PAS.


Histologic Findings

Histopathological examination of muscle is not necessary to establish diagnosis.

Light microscopy

Light microscopy reveals large glycogen-containing vacuoles in nearly all muscle fibers.

These vacuoles can be further characterized histochemically as secondary lysosomes.

Type I and type II muscle fibers are equally affected.

Electron microscopy

Electron microscopy is used to classify subtypes of the vacuoles in which glycogen accumulates.

Contributor Information and Disclosures

Germaine L Defendi, MD, MS, FAAP Associate Clinical Professor, Department of Pediatrics, Olive View-UCLA Medical Center

Germaine L Defendi, MD, MS, FAAP is a member of the following medical societies: American Academy of Pediatrics

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.

Margaret M McGovern, MD, PhD Professor and Chair of Pediatrics, Stony Brook University School of Medicine

Margaret M McGovern, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society of Human Genetics

Disclosure: Nothing to disclose.


Jennifer Ibrahim, MD Chief, Genetics Division, St Joseph's Children's Hospital

Jennifer Ibrahim, MD is a member of the following medical societies: American Society of Human Genetics

Disclosure: Nothing to disclose.

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Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the intensively stained vacuoles in the hepatocytes (periodic acid-Schiff, original magnification X 27).
Glycogen-storage disease type II (Pompe disease). Photomicrograph of the liver. Note the regular reticular net and hepatocytes vacuolization (Gordon-Sweet stain, original magnification X 25).
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