Publications about genetic testing for metabolic disorders
  1. Glycogen storage disease II or Pompe disease

Glycogen storage disease II or Pompe disease

February 15, 2018

Disease synonyms

Pompe disease, Glycogen storage disease II, GSD II, GSD2, Acid alpha-glucosidase deficiency, GAA deficiency, Glycogenosis generalized cardiac form, Cardiomegalia glycogenica diffusa, Acid maltase deficiency, AMD, Alpha-1 4-glucosidase deficiency


Inheritance pattern

Autosomal recessive


Clinical features

Pompe disease, also known as glycogen storage disease type 2 (GSD II), is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially muscles, impairs their ability to function normally.

Researchers have described three types of Pompe disease/GSD II, which differ in severity and the age at which they appear. These types are known as classic infantile-onset, non-classic infantile-onset, and late-onset 1.

Infantile-onset Pompe disease is suspected in infants with the following 1, 2, 3:

  • Poor feeding/failure to thrive (44-97% of cases)
  • Motor delay/muscle weakness (20-63%)
  • Respiratory concerns (infections/difficulty) (27-78%)
  • Cardiac problems (shortened PR interval with a broad, wide QRS complex, cardiomegaly, left ventricular outflow obstruction, cardiomyopathy) (50-92%)

The non-classic variant of infantile-onset Pompe disease usually presents within the first year of life and is predominantly characterized by the following 1 :

  • Progressive muscular weakness and motor delays
  • Pseudohypertrophy of the calf muscles and positive Gower sign
  • Cardiomegaly with or without left ventricular outflow obstruction
  • Respiratory failure

Late-onset Pompe disease can present at various ages with muscle weakness and respiratory insufficiency. Progression of the disease is often predicted by the age of onset, as progression is more rapid if symptoms present in childhood. Cardiomegaly is not typically seen, but progressive muscle weakness resulting in motor delays, swallowing difficulties, and respiratory insufficiency usually occurs as in the infantile form, only at a slower rate.

Clinical manifestations of late-onset Pompe disease include the following 1:

  • Progressive proximal muscle weakness (95%)
  • Respiratory insufficiency
  • Exercise intolerance
  • Exertional dyspnea
  • Orthopnea
  • Sleep apnea
  • Hyperlordosis and/or scoliosis (childhood and juvenile onset)
  • Hepatomegaly (childhood and juvenile onset)
  • Macroglossia (childhood onset)
  • Difficulty chewing and swallowing
  • Increased respiratory infections
  • Decreased deep tendon reflexes
  • Gower sign
  • Joint contractures
  • Cardiac hypertrophy (childhood onset)

The current worldwide prevalence of Pompe disease is estimated at 1 in 5,000 to 10,000 people 4, 5.  The prevalence is variable, depending on ethnicity and geographic region, and it is estimated from 1:14,000 in African Americans 6 to 1:100,000 in individuals of European descent 7.

Pathogenic variants in the GAA gene that result in the deficiency or absence of acid alpha-glucosidase (GAA) results in progressive expansion of glycogen-filled lysosomes in multiple tissues, with cardiac and skeletal muscle being the most severely affected.

The severity of clinical presentations, tissue involvement, and age of onset generally correlate well with the nature of the variant and the degree of residual enzyme activity 1, 8. It is assumed that biallelic GAA pathogenic variants which produce essentially no enzyme activity result in infantile-onset Pompe disease. Various combinations of other pathogenic variants resulting in some residual enzyme activity likely cause the disease, but the age of onset and progression are most likely directly proportional to the residual GAA enzyme activity 8.

As a general rule, the lower the GAA enzyme activity is, the earlier the age of onset of disease would be:

  • Complete deficiency of GAA enzyme activity (<1% of normal controls) is associated with IOPD 1, 8, 9.
  • Partial deficiency of GAA enzyme activity (2-40% of normal controls) is associated with LOPD 9.

More than 500 pathogenic variants in GAA have been identified in individuals with Pompe disease 10. Nonsense variants, large and small gene rearrangements, and splicing defects have been observed. Many pathogenic variants are potentially specific to families, geographic regions, or ethnicities. 

Table 1. Proportion of individuals with selected GAA pathogenic variants

GAA Pathogenic Variant Pompe disease subtype % of Affected Individuals Ethnic group/population
p.Glu176ArgfsTer45Infantile onset 34% 11 Dutch
Infantile onset 9% 12 US
p.Gly828_Asn882del Infantile onset 25% 11 Dutch
Infantile onset 25% 11 Canadian
Infantile onset 5% 12 US
c.336-13T>G Late onset 36%-90% 13, 14 Italian
p.Asp645Glu Infantile onset ≤80%  15 Taiwanese & Chinese
p.Arg854Ter Infantile onset ≤60% 16 African

At CENTOGENE we have analyzed over 1500 individuals for GAA gene. 15% of Pompe disease-suspected individuals had pathogenic variant in GAA gene, while 14% were identified as carriers 17.

Out of all GAA identified pathogenic variants 79% were identified as substitution, 13% as deletions, 5% as duplications and 2% as gross/complex rearrangements and other type of variants, each (Figure 1) 17. GAA classification of variants on protein level identified 57% missense variants, 16% frameshift variants, 13% nonsense, 11% splicing and 3% in-frame variants (Figure 2) (CentoMD® 4.1) 17.

Figure 1. Types of GAA clinically relevant variants on DNA level (CentoMD® 4.1) 17.

1.Types of GAA clinically relevant variants on DNA level CentoMD

Figure 2. Types of GAA clinically relevant variants on protein level (CentoMD® 4.1) 17.

Figure 2.Types of GAA clinically relevant variants on protein level CentoMD

Enzyme replacement therapy (ERT) should be initiated as soon as a diagnosis of Pompe disease has been established. Several drugs have been FDA-approved and are available for ERT-treatment of Pompe disease 1. Management includes individualized care of cardiomyopathy, physical therapy for muscle weakness, surgery for contractures, and feeding support. Gene therapy-associated clinical trials, designed in order to correct the underlying enzyme defect, are under investigation.

CENTOGENE offers GAA enzyme (alpha-1,4-glucosidase) testing, full GAA gene sequencing, and deletion/duplication testing. GAA is also part of the following panels:


Differential diagnosis

The differential diagnosis of GAA-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

Infantile onset Pompe disease:

  • Spinal muscular atrophy 1 (caused by pathogenic variants in SMN1)
  • Danon disease (LAMP2)
  • Endocardial fibroelastosis
  • Carnitine uptake disorder (SLC22A5)
  • Glycogen storage disease type IIIa (AGL)
  • Glycogen storage disease type IV (GBE1)
  • Idiopathic hypertrophic cardiomyopathy
  • Mitochondrial/respiratory chain disorders

Late onset Pompe disease:

  • Limb-girdle muscular dystrophy (DYSF, SGCA, SGCB, SGCG, SGCD, CAPN3, CAV3, FKRP, and others)
  • Duchenne-Becker muscular dystrophy (DMD)
  • Polymyositis
  • Glycogen storage disease type V (PYGM)
  • Glycogen storage disease type VI (PYGL)

Diagnostic strategy

To confirm/establish the diagnosis, we offer alpha-1,4-glucosidase enzymatic testing, full GAA gene sequencing, and deletion/duplication gene testing. We also offer a broad selection of NGS panels which are designed for the molecular genetic diagnosis of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for GAA gene testing:

Step 1:   Alpha-1,4-glucosidase /GAA enzyme activity testing

Step 2:   GAA full gene sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.

Step 3:   Deletion/duplication analysis/pathogenic variant scanning of GAA

Step 4:   If no pathogenic variant is identified after analysis of the GAA gene, panel testing with related genes or further genetic testing of related genes is possible.

Step 5:   If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology.


Referral reasons

The following individuals are candidates for GAA gene testing:

  • Individuals with a family history of Pompe disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling Pompe disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of GAA gene and related genes should be performed in all individuals suspected of having Pompe disease. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis of Pompe disease through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Pompe disease, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.


More information on CENTOGENE´s genetic tests for Pompe disease can be found in our genetic test catalogue.