DIAGNOSTIC CRITERIA

Due to the progressive nature of Pompe disease, delayed diagnosis and treatment can lead to serious clinical complications, irreversible damage to muscle tissue, permanent disability, and death. The availability of accurate and easy-to-use diagnostic assays and disease-specific treatment make early diagnosis and initiation of therapy an essential part of Pompe disease management.

Delayed diagnosis or misdiagnosis of Pompe disease can be the result of several factors. Pompe disease symptoms, especially among children and adults, can overlap with many other, more common disorders. In one study of 38 patients with late-onset Pompe disease, the mean time from symptom onset to correct diagnosis was 10.4 years.¹

The differential diagnosis of Pompe disease should be guided by medical history (and family medical history), clinical findings, and diagnostic findings.² The process of differential diagnosis may include clinical chemistry (creatine kinase, liver function tests), imaging procedures (x-ray, sonogram, and MRI), electrocardiography, echocardiography, spirometry, electromyography, and muscle biopsy.

While many neuromuscular specialists rely on the results of a muscle biopsy to diagnose Pompe disease, this method of diagnosis may not be a reliable indicator of disease. In a review of cases of Pompe disease described in the literature, 20% (15/74) of muscle biopsies showed normal glycogen content.³ False-negative results are common in Pompe disease when muscle biopsy is used; the lack of glycogen accumulation or specific muscle pathology in a muscle biopsy should not be interpreted to exclude a diagnosis of Pompe disease.

A diagnosis of Pompe disease must be confirmed by quantification of acid α-glucosidase (GAA) activity and/or GAA mutation analysis (genetic testing).⁴ Infants with Pompe disease generally have <1% of the mean GAA activity of healthy individuals in muscle tissue, skin fibroblasts, and blood samples.⁴ Older children and adults with Pompe disease tend to have GAA activity that ranges from <1% to 30% of the mean activity of healthy individuals.

GAA enzyme activity can be measured in several types of samples:

o       Blood samples, including dried blood spots (DBS), mixed leukocytes, and purified lymphocytes

o       Fibroblasts taken from skin biopsies

o       Muscle biopsies

Skin and muscle biopsies are invasive, require anesthesia, and take a significant amount of time (up to 6 weeks) to produce results, which may further delay diagnosis and treatment. Lymphocytes and leukocytes can be easily obtained through a blood draw, while DBS can be obtained through a blood draw or by pricking a finger or heel. An additional benefit to DBS is that they require little special handling and can be used on a large scale as in newborn screening⁵ and high-risk testing programs.⁶

Many different types of genetic mutations cause Pompe disease. Some are found in greater numbers in certain ethnic groups. A complete list of these mutations can be found at www.pompecenter.nl Mutation analysis can be done on blood samples or skin fibroblasts.

1. Muller-Felber W, Horvath R, Gempel K, et al. Late onset Pompe disease: clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord. 2007;17(9-10):698-706.
2. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8(5):267-88.
3. Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classic Pompe's disease; a review of 225 published cases. J Neurol. 2005;252(8):875-84.
4. Winchester B, Bali D, Bodamer OA, et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: Report from an international consensus meeting. Mol Genet Metab. 2008;93:275-81.
5. Chien YH, Chiang SC, Zhang XK, et al. Early detection of Pompe disease by newborn screening is feasible: results from the Taiwan screening program. Pediatrics. 2008. 122(1):e39-45.
6. Goldstein JL, Young SP, Changela M, et al. Screening for Pompe disease using a rapid dried blood spot method – experience of a clinical diagnostic laboratory. Muscle Nerve. 2009. [in press]