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

Updated: Oct 12, 2023
Author: Germaine L Defendi, MD, MS, FAAP; Chief Editor: Maria Descartes, MD 



Glycogen-storage disease type II (GSD II), also known as Pompe disease, is part of a group of metabolic diseases called lysosomal storage disorders (LSDs).[1] GSD II is an autosomal-recessive disorder that results from deficiency of acid alpha-glucosidase (also known as acid maltase), a lysosomal hydrolase. The cellular role of acid alpha-glucosidase is to convert glycogen into glucose within the lysosomes. The Danish pathologist Joannes Cassianus Pompe first described this disease in 1932 when he was presented with a 7-month-old girl who died after developing idiopathic hypertrophic cardiomyopathy. Pompe observed an abnormal accumulation of glycogen in all postmortem tissues examined and described the cardinal pathologic features of this lysosomal storage disorder.

Pompe disease (GSD II) has a broad clinical spectrum. Classification is based on age of onset, organ involvement, severity, and the rate of disease progression. Three major forms of GSD II are recognized: classic infantile-onset, non-classic variant of infantile-onset, and late-onset (includes childhood, juvenile, and adult-onset).

Classic infantile-onset Pompe disease may be apparent in utero, but more often presents within the first 2 months of life. In this form, cardiac, skeletal, and respiratory muscles are involved. Clinical hallmarks of classic infantile-onset Pompe disease include hypotonia, generalized muscle weakness, cardiomegaly, hypertrophic cardiomyopathy, feeding difficulties, failure to thrive, respiratory distress, and hearing loss. Classic infantile-onset GSD II is marked by a progressive and rapidly fatal course. Without enzyme replacement therapy (ERT), classic infantile-onset Pompe disease commonly results in death within the first year of life due to cardiac disease from progressive left ventricular (LV) outflow obstruction.

The non-classic variant of infantile-onset Pompe disease presents within the first year of life. Patients older than 6 months present with motor delays and/or slowly progressive muscle weakness. Death results from ventilatory failure in early childhood. In this form, cardiac disease is not found to be a major cause of morbidity; however, cardiomegaly may be seen.

Late-onset GSD II is characterized by proximal muscle weakness and respiratory compromise. Adults with late-onset GSD II typically present with proximal muscle weakness between the second and sixth decades of life. These individuals ultimately die of respiratory failure. Cardiac involvement is less likely among individuals with disease onset at an older age.[2, 3]

The photomicrographs below document liver findings in GSD II.

Glycogen-storage disease type II (Pompe disease). 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). 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).


Acid alpha-glucosidase (also known as acid maltase) is a lysosomal hydrolase that is required for the degradation of a small percentage (1-3%) of cellular glycogen. The main pathway for glycogen degradation is not deficient in GSD II; therefore, energy production is not impaired, and hypoglycemia does not occur. However, the deficiency of acid alpha-glucosidase activity does result in the accumulation of structurally normal glycogen in lysosomes and in the cytoplasm of affected individuals. Excessive glycogen storage within lysosomes interrupts normal functioning of other organelles and leads to cellular injury. In turn, this leads to enlargement and dysfunction of the entire organ involved (eg, cardiomyopathy).

In the classic infantile form of Pompe disease, clinically significant glycogen storage occurs in cardiac muscle. Over time, cardiomegaly with LV thickening occurs, eventually leading to outflow tract obstruction. Glycogen storage in skeletal muscle leads to hypotonia and weakness. The respiratory muscles are also affected, resulting in hypoventilation and progressive respiratory compromise. Central nervous system (CNS) involvement is primarily limited to the anterior horn cells of the spinal cord and brain stem nuclei. Despite CNS involvement, intellect remains normal. In non-classic variant infantile-onset Pompe disease, skeletal and respiratory involvement is common; the level of cardiac involvement varies. In cases of late-onset GSD II, significant cardiac involvement is not observed.


The combined incidence of all forms of Pompe disease (GSD II) varies depending on ethnicity and geographic region.

United States

The total incidence of Pompe disease (all variants of GSD II) is estimated at 1 per 40,000 population. This calculation is based on estimated gene frequencies in healthy individuals from various US ethnic groups. The highest incidence has been observed in the African-American population, in which the combined incidence may be as high as 1 per 14,000 population.[4]


Among individuals of European descent, the incidence of infantile-onset Pompe disease is reported as 1 per 100,000 population and the incidence of late-onset Pompe disease is reported as 1 per 60,000 population.[5]

The combined incidence of Pompe disease in Taiwan and southern China is estimated at 1 per 50,000 population.[6]

The combined incidence of Pompe disease in the Netherlands is estimated at 1 per 40,000 population (1 per 138,000 population for infantile-onset, 1 per 57,000 population for late-onset [adult]).[7] A common GAA pathogenic variant among the Dutch people is c.525delT, which is found in 34% of cases.[8]

In Portugal, the combined incidence of Pompe disease is estimated at 1 per 600,000 population.[9]

In Australia, the combined incidence of Pompe disease is estimated at 1 per 145,000 population.[10]


Classic infantile-onset GSD II usually is fatal during the first year of life. As weakness progresses, affected individuals develop feeding difficulties and respiratory insufficiency. Cardiac enlargement of the LV leads to outflow tract obstruction and ventricular failure. Death results from cardiopulmonary failure. Non-classic infantile-onset Pompe disease presents later, within the first year of life, with clinical findings of motor delays and progressive muscle weakness. Death due to ventilatory failure occurs in early childhood.

Late-onset Pompe disease (childhood and juvenile) progresses more slowly and is uniformly fatal. Affected individuals generally do not survive beyond the second or third decade of life. All affected individuals have involvement of pulmonary system, and most die of respiratory failure. Several patients with this form are reported to have died of basilar artery aneurysm[11] ; all were found to have abnormal glycogen storage within the lysosomes of arterial smooth muscle fibers.

Patients with late-onset (adult) Pompe disease may survive for decades following diagnosis. Muscle weakness may interfere with normal daily activities, and respiratory insufficiency is often associated with sleep apnea. Death usually results from respiratory failure.


Common mutations within the GAA gene associated with the infantile-onset forms of Pompe disease have been discovered in Taiwanese, Dutch, and African-American populations. A common mutation associated with the late-onset form has been found in Whites.


GSD II has no sexual predilection.

GSD II is inherited as an autosomal recessive disorder with the gene locus at 17q25.3; hence, the inheritance of this disease is not related to the sex chromosomes.


Age of onset helps distinguish the current three defined age-onset categories of GSD II. The classic and non-classic infantile-onset forms present from birth to 2 months of life and within the first year of life, respectively. The late-onset definition includes childhood, juvenile, and adult.




Infantile-onset forms (classic and non-classic) of Pompe disease

Affected infants typically present with muscle weakness, hypotonia, and motor delay within the first 6 months of life (20-63% of patients).

Feeding difficulties and failure to thrive are described in 44% to 97% of patients.

Early cardiac failure results from LV enlargement and outflow obstruction (50-92% of patients), along with respiratory concerns (27-78% of patients). ​Electrocardiography (ECG) findings show a shortened PR interval with a broad and wide QRS complex. In one infant described, the presenting sign was Wolff-Parkinson-White syndrome.[12]

Family histories are usually noncontributory. Families with a history of consanguinity should raise concern.

Late-onset form of Pompe disease

TThe history of childhood and juvenile-onset glycogen-storage disease type II (GSD II) is as follows:

  • Patients present with delayed motor milestones, muscle weakness, and hypotonia.
  • Intelligence is normal.

The history of adult-onset GSD II is as follows:

  • Patients present with physical challenges related to proximal muscle weakness, such as difficulty climbing stairs.
  • Respiratory symptoms are present in about 33% of cases.
  • Other symptoms may include exercise intolerance, orthopnea, somnolence, and headaches.
  • Cardiac involvement is not a significant component.


Infantile-onset form of GSD II

Abnormal glycogen storage (eg, macroglossia, hepatomegaly, normal or increased muscle bulk) is clinically evident.

Involvement of respiratory muscles manifests as respiratory distress (eg, tachypnea).

Cardiomegaly or cardiomyopathy leads to murmur and signs of cardiac failure, such as feeding difficulties.

Profound diffuse hypotonia and muscle weakness occurs.

Cognitive development is normal.

Late-onset form of GSD II

The juvenile form is characterized by the following:

  • Respiratory distress
  • Hypotonia (typically more proximal than distal)
  • Macroglossia and hepatomegaly (not common)
  • No associated cardiomegaly or cardiomyopathy

The adult form is characterized by the following:

  • Proximal muscle weakness
  • Decreased bulk of involved muscles
  • Diminished deep tendon reflexes


Pompe disease, or glycogen-storage disease type II (GSD II), is inherited in an autosomal-recessive manner. Clinical presentation requires 2 copies of pathogenic variants of the gene, GAA. GAA codes for the enzymatic activity of acid alpha-glucosidase and is the only human gene mutation known to cause GSD II. GAA has been localized in the human karyotype to the long arm of chromosome 17 at band q25.2 - q25.3. Heterozygotes, or carriers (persons with one normal copy and one pathogenic variant copy of the gene), are asymptomatic and hence have no clinical manifestations of the disease. Two copies of the mutated variant are needed to express the clinical disease, GSD II.

Allelic variants have been identified within GAA and include missense, nonsense, intragenic deletions/insertions, and splice-site mutations.[13, 14] The spectrum of mutations can result in the following:

  • No detectable messenger RNA (mRNA) and complete absence of enzymatic protein
  • A normal amount of enzyme with reduced activity (eg, reduced affinity for glycogen)
  • A reduced amount of enzyme with normal activity
  • No detectable enzyme activity in infantile form; varying amounts of residual enzyme activity in late-onset forms

Molecular genetic testing enables for the identification of the more common allelic variants within the GAA gene. Ethnicity and phenotype can help identify the more likely pathogenic variants, such as p.Arg854Ter, p.Asp645Glu, and c.336-13T>G.

  • p.Arg854Ter is present in 50-60% of African Americans with infantile-onset GSD II. [4]
  • p.Asp645Glu is identified in 40-80% of patients of Chinese ancestry with infantile-onset GSD II. [4]
  • The c.336-13T>G mutation is most commonly found in late-onset adult patients with GSD II. [15] This mutation is present in 50-85% of affected persons. [4, 16] No individuals with this mutation have the classic infantile-onset form. Cardiac involvement is rare among patients with this genotype. [17]


Diagnostic Considerations

Infantile-onset (classic and non-classic variant) Pompe disease

Disorders to be considered in the differential diagnoses include the following:

  • Spinal muscular atrophy 1 (Werdnig-Hoffman disease): Hypotonia, feeding difficulties, progressive proximal muscle weakness, and areflexia; no cardiac involvement; caused by a defect in the SMN1 gene located on chromosome 5; inheritance is autosomal recessive
  • Danon disease: Hypotonia, hypertrophic cardiomyopathy, and myopathy due to excessive glycogen storage caused by defects in lysosome-associated membrane protein 2 (LAMP2); inheritance is X-linked–dominant with LAMP2 gene locus of Xq24
  • Endocardial fibroelastosis: Respiratory and feeding difficulties, cardiomegaly, and heart failure without significant muscle weakness; etiology often is viral, but familial cases with X- linked, autosomal-dominant, and autosomal-recessive inheritance have been described
  • Carnitine uptake disorder: Muscle weakness and cardiomyopathy without elevated serum concentration of creatine kinase (CK); inheritance is autosomal recessive; mutations in the SLC22A5 gene (cytogenetic location on chromosome 5) cause primary carnitine deficiency
  • Glycogen storage disease type IIIa (Cori disease; debrancher deficiency; GSD IIIa): Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of CK with more dramatic liver involvement than typically seen in GSD II; inheritance is autosomal recessive and results from mutation of the AGL gene located on chromosome 1
  • Glycogen storage disease type IV (Andersen disease; branching-enzyme deficiency; GSD IV): Hypotonia, cardiomegaly, muscle weakness, and elevated serum concentration of CK with more dramatic liver involvement than typically seen in GSD II (similar to GSD IIIa); inheritance is autosomal recessive
  • Idiopathic hypertrophic cardiomyopathy: Biventricular hypertrophy without hypotonia or pronounced muscle weakness
  • Myocarditis: Inflammation of the myocardium leading to cardiomegaly without hypotonia or muscle weakness
  • Mitochondrial/respiratory chain disorders: Wide variation in clinical presentation; may include hypotonia, respiratory failure, cardiomyopathy, hepatomegaly, seizures, deafness, and elevated serum concentration of CK ; distinguishable from GSD II by the absence of hypotonia and presence of cognitive involvement [18]

Late-onset Pompe disease (ie, childhood, juvenile, and adult-onset)

Early involvement of the respiratory muscles is useful in distinguishing juvenile-onset Pompe disease from many other neuromuscular disorders. The following disorders are to be considered in the differential diagnoses:

  • Limb-girdle muscular dystrophy: Progressive muscle weakness in the legs, pelvis, and shoulders with sparing of the truncal muscles
  • Duchenne-Becker muscular dystrophy: Progressive proximal muscle weakness, respiratory insufficiency, and difficulty ambulating; primarily affects males; inheritance is X-linked
  • Polymyositis: Progressive, symmetric, unexplained muscle weakness
  • Glycogen-storage disease type V (McArdle disease; muscle phosphorylase deficiency; GSD V): Elevated serum concentration of CK and muscle cramping with exertion; inheritance is autosomal recessive; GSD V is caused by mutations in the PYGM gene, which codes for the myophosphorylase enzyme; the PYGM gene locus is on chromosome 11 at 11q13
  • Glycogen-storage disease type VI (Hers disease; GSD VI): Hypotonia, hepatomegaly, muscle weakness, and elevated serum concentration of CK; inheritance is autosomal recessive; GSD VI is caused by mutations of the liver glycogen phosphorylase ( PYGL) gene located on chromosome 14 (14q21-q22) [18]

Differential Diagnoses



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 IU/L-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.[19]

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.[4]

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.[20]

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.[21, 22]

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.[18]

Imaging Studies

Chest radiography

Chest radiography shows cardiomegaly in patients with infantile-onset GSD II. Radiography also allows for pulmonary field evaluation.[23]


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.



Medical Care

Enzyme replacement therapy (ERT) for the treatment of glycogen-storage disease type II (GSD II) has been available since 2006.[24, 25] A 3-year follow-up revealed significant reductions in the risk of death and invasive ventilation among treated patients.[26] Approximately one half of patients on ERT develop infusion-associated reactions. However, these are readily managed with premedication using various combinations of antipyretic, anti-inflammatory, and antihistamine medications. The findings of one study suggest that the use of ERT in patients with late-onset Pompe disease did not affect cardiovascular parameters and no cardiovascular safety concerns were noted. Identified cardiovascular abnormalities noted may be related to Pompe disease or other comorbid conditions rather than to ERT.[27]

Symptomatic treatment of cardiac and respiratory failure is available but does not significantly alter the clinical course.

Anecdotal evidence suggests that a high-protein diet can provide temporary improvement; however, such a diet does not alter the disease course.

Preclinical investigation of gene therapy is ongoing.

The use of pharmacological chaperones (oral therapy) to enhance efficacy and reduce degradation of rhGAA have also been approved by the FDA. 


A clinical geneticist in concert with a genetic counselor are advised to counsel families regarding risk to future pregnancies.

GSD II (Pompe disease) is inherited in an autosomal-recessive manner. In most cases, the parents of a proband are heterozygotes and thus carry a single copy of a GAA pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Historically, children with classic infantile-onset GSD II have not survived to reproduce. Individuals with later-onset disease can reproduce, as they can survive into their sixth and seventh decades of life.

Carrier testing using molecular genetic testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic GAA variants in the family are known.

A pediatric cardiologist can provide assessment of all infants, children, and adolescents suspected of having GSD II disease. Experienced interpretation of ECG and echocardiography findings are necessary.

A neurologist can assist with the results and interpretation of EMG findings.


As noted above, alterations in diet do not provide lasting improvement. Weakness can contribute to feeding difficulty in all patients. Infants ultimately may require tube feeding to provide adequate caloric intake. Nutritional support does not change the disease course; hence, some families may choose not to pursue tube feeding for their child when facing such a fatal illness.


Proximal muscle weakness may interfere with the normal daily activities of adult patients. Physical and occupational therapy may prove beneficial.



Medication Summary

Several recombinant human enzymes alpha-glucosidase (rhGAA) have been approved by the FDA and are indicated for treatment of glycogen-storage disease type II (GSD II; Pompe disease).

Enzyme replacement

Class Summary

Enzyme replacement therapy is approved in the United States and may ameliorate clinical symptoms. Enzyme replacement therapies are available for all age groups (ie, infantile [early onset] or late onset [juvenile/adult]) affected by Pompe disease. 

Replaces rhGAA, which is deficient or lacking in persons with Pompe disease. Alpha-glucosidase is essential for normal muscle development and function. It binds to mannose-6-phosphate receptors and then is transported into lysosomes, then undergoes proteolytic cleavage that results in increased enzymatic activity and ability to cleave glycogen. Infant survival is improved without requiring invasive ventilatory support compared with historical controls without treatment. 

Alglucosidase alfa (Lumizyme, Myozyme)

Myozyme has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease compared with untreated historical controls. It has not been adequately studied for treatment of other forms of Pompe disease. Lumizyme is indicated for infantile-onset Pompe disease and also for late (non-infantile) Pompe disease. 

Avalglucosidase alfa (Nexviazyme)

Indicated for treatment of patients aged 1 year and older with late-onset Pompe disease. 

Cipaglucosidase alfa (Pombiliti)

Indicated in combination with miglustat (Opfolda) for adults with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) who weigh ≥40 kg and are not improving on their current enzyme replacement therapy (ERT). 

Cipaglucosidase alfa is an rhGAA with optimized carbohydrate structures to enhance uptake into muscle cells. It is used with miglustat, which binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa in blood.  

Pharmacologic Chaperones

Class Summary

Miglustat binds with, stabilizes, and reduces inactivation of cipaglucosidase alfa in the blood after infusion. Bound miglustat is dissociated from cipaglucosidase alfa after it is internalized and transported into lysosomes. Miglustat alone has no pharmacological activity in cleaving glycogen. 

Miglustat (Opfolda)

Indicated in combination with cipaglucosidase alfa, a hydrolytic lysosomal glycogen-specific enzyme, for adults with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency) weighing ≥40 kg who are not improving on their current enzyme replacement therapy (ERT). 



Further Outpatient Care

Counsel parents of children with glycogen-storage disease type II (GSD II) regarding the autosomal-recessive inheritance pattern and the 25% recurrence risk for each subsequent pregnancy. Provide options for prenatal diagnosis with subsequent pregnancies.[28]

Chorionic villus sampling (CVS) and amniocentesis both can be used to determine GAA enzyme activity in a fetus. CVS enables prenatal diagnoses as early as 10 weeks' gestation.

Emphasize the genetic basis to family members and encourage communication among family members. Molecular genetic testing for at-risk family members is available if the pathogenic GAA variants have been identified.


The major complication among individuals with infantile-onset Pompe disease is aspiration pneumonia.