Diagnosing Pompe Disease
The diagnosis of Pompe disease is challenging due to the wide variations in symptoms and severity.
The diagnosis of Pompe disease is usually established by demonstrating a deficiency in GAA enzyme activity and disease-causing mutations of the GAA gene.
Newborn screening of Pompe disease is highly recommended by most Pompe disease experts. Unfortunately, Pompe disease is not on NBS panels in Canada. It is, however, performed in places like Taiwan and most of the US states where the majority of newborns are screened.
Diagnostic tests should be conducted when the following symptoms are presented:
- Infantile-onset Pompe disease 
- Poor feeding/failure to thrive
- Motor delay/muscle weakness
- Respiratory infections/difficulty
- Cardiac problems.
- Late-onset Pompe disease 
- Proximal muscular weakness and respiratory insufficiency without clinically apparent cardiac involvement.
A dried blood sample can be used to assess GAA enzyme activity. The enzyme analysis is convenient as well as time- and cost-effective. However, the risk of false positive tests is high and a diagnosis of Pompe disease will require a confirmatory DNA test. The GAA enzyme activity will allow clinicians to suspect a patient as having infantile-onset or late-onset Pompe disease.
- GAA enzyme activity <1% of normal controls is associated with infantile-onset Pompe disease.
- GAA enzyme activity 2%- 40% of normal controls is associated with late-onset Pompe disease
This test can also be used for newborn screening.
A confirmation of Pompe disease can be done with a DNA test. There are several options, including a single gene test, a multigene panel, or a targeted analysis for pathogenic variants.
The single gene test sequences the GAA gene which looks for mutations along that gene.
A multigene panel would be employed to include the GAA gene, along with other genes, to help in a differential diagnosis. Since the early symptoms of late-onset Pompe are similar to other neuromuscular conditions, a multigene panel is helpful for a differential diagnosis.
A targeted analysis for pathogenic variants can be performed in individuals with the following ancestry and clinical findings: 
- African Americans with infantile-onset Pompe disease.An estimated 50%-60% have the pathogenic variant Arg854Ter
- Chinese with infantile-onset Pompe disease.An estimated 40%-80% have the pathogenic variant Asp645Glu
- Adults with late-onset Pompe disease.An estimated 50%-85% have the pathogenic variant 336-13T>G typically in the compound heterozygous state.
While a GAA enzyme test and GAA genetic mutation analysis can be used to confirm a diagnosis of Pompe disease, numerous other tests are conducted to help develop a treatment program specific for that individual. These tests include blood test, electromyography, chest x-ray, echocardiogram, electrocardiogram, muscle biopsy, and many more. As stated previously, Pompe disease can affect many organs in the body and that means that tests looking multiple parameters are needed to help the clinical team monitor treatment progress.
Shared Symptoms   
|Shared symptoms with late-onset Pompe disease
|Limb girdle muscular dystrophy
|Progressive muscle weakness (pelvis, lower limbs)
|Becker muscular dystrophy
|Progressive muscle weakness (shoulders)
|Muscle weakness (pelvis, lower limbs)
|Glycogen storage diseases IIIa, IV
|Glycogen storage diseases V
Muscle cramps during exercise
|Muscle myopathy with glycogen accumulation
|Spinal muscular atrophy
|Voluntary muscle weakness and atrophy
|Amyotrophic lateral sclerosis
|Progressive muscle weakness
|Weakness of shoulder girdle
In 2017, the Pompe Disease Newborn Screening Working Group (US) strongly recommend that newborn screening should include Pompe disease since there is a relatively easy, cheap, and reliable means to test for this condition using dried blood samples. While the tests are not 100% accurate (there is a concern for false positives or ‘pseudodeficiencies’), being able to rapidly identify a baby with infantile-onset Pompe disease and start them on a treatment program before the disease has caused irreversible damage is worth the minimal expense.
The Canadian Association of Pompe agrees with this statement. Unfortunately, Pompe disease is currently not included in newborn screening in Canada. In the United States, it is recommended and the majority of newborns are being screened for Pompe disease. This doesn’t only lead to better outcomes for infantile babies, but it also provides an opportunity for timely treatment for late-onset patients. Almost as important, it builds a more robust understanding of the evolving natural history of Pompe disease.
- Leslie N, Bailey L. Pompe Disease. 2007 Aug 31 [updated 2017 May 11]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available at http://www.ncbi.nlm.nih.gov/books/NBK1261/
- Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267-288.
- American Association of Neuromuscular and Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40:149-160.
- Barba-Romero MA, Barrot E, Bautista-Lorite J, et al. Clinical guidelines for late-onset Pompe disease. Rev Neurol. 2012;54:497-507.
- Boadamer OA, Scott CR, Giugliano R. Newborn screening for Pompe disease. Pediatrics. 2017; 140(suppl 1):e20160280C