About Pompe Disease^1,2

Pompe disease is a rare, progressive, and often fatal disease that can be diagnosed in infants, children, and adults. The underlying pathology is a deficiency or dysfunction of acid alpha-glucosidase (GAA), a lysosomal enzyme that hydrolyzes lysosomal glycogen to glucose.

Clinical Phenotypes^1,3

Pompe disease is an extremely heterogeneous disorder that varies with respect to age at onset, rate of disease progression, and extent of organ involvement. Disease symptoms may first present during the first months of life or at any time during childhood or adulthood. In some cases, symptoms may first appear in individuals in their 40s or 50s. Muscle weakness is a prominent feature in all forms of Pompe disease.

A broad classification of Pompe patients divides them in 2 categories: infantile-onset (including classical and non-classical presentations) and late-onset (juvenile and adult) patients.

Patients affected with the infantile form of the disease typically present with symptoms within the first 12 months of life. The infantile-onset form is characterized by massive deposition of glycogen in the heart, liver, and skeletal muscle resulting in rapidly progressive cardiomyopathy, hepatomegaly, generalized muscle weakness, hypotonia, and motor delay. Death from cardiac and/or respiratory failure generally occurs before the end of the first year. A subset of patients with infantile-onset Pompe disease has been described by Slonim et al. The clinical course of these patients was characterized by a slower progression of cardiomyopathy and longer survival, generally developing respiratory failure between 1 and 2 years of age. Although generally these patients die before 1 year of age, some may survive beyond 2 years.

Late-onset Pompe disease first appears during childhood or adulthood. Although the first manifestation of symptoms occurs at a later age, late onset Pompe can be considered clinically overlapping with both the classical and non-classical infantile variants described above. For late-onset presentations, the progression of the disease is slower than in the infantile patients. There is a general correlation of later age of onset with both absence of cardiac involvement and slower progression.

Essentially, classification of Pompe disease phenotypes is not clearly defined in that there is a clinical spectrum extending throughout different ages of onset, degrees of organ involvement, and rates of progression.

Most patients with infantile-onset disease have undetectable to minimal GAA activity, whereas those with the late-onset phenotype tend to have a limited amount of residual GAA activity.

Overview of Clinical Manifestations^1,3

The clinical manifestations of Pompe disease reflect a continuous spectrum of disease phenotypes, which differ in terms of age of onset, extent of organ involvement, and rate of symptomatic progression. Muscle weakness is a prominent feature of all forms of disease and leads to respiratory insufficiency due to weakness of the diaphragm and other muscles of respiration. Cardiomegaly is a prominent feature of infantile-onset disease. It is rarely seen in late-onset disease. Hepatomegaly and macroglossia are also more common in infantile disease, particularly the classical form.

The infantile-onset disease progresses much more rapidly than late-onset disease and ultimately proves fatal, usually within the first year of life. Cause of death is often cardiorespiratory failure. In comparison, disease progression is more variable in the
late-onset population and death usually results from respiratory failure.

Major Signs and Symptoms

Infantile-Onset

• Progressive muscle weakness
• Profound hypotonia
• Failure to achieve motor milestones
• Progressive respiratory involvement
• Frequent respiratory infections
• Difficulty feeding
• Failure to thrive
• Progressive cardiomyopathy
• Cardiomegaly

Late-Onset

• Progressive proximal muscle weakness
• Gait abnormalities
• Lordosis/scoliosis
• Hypotonia
• Lower back pain
• Frequent respiratory infections
• Respiratory insufficiency
• Sleep apnea
• Exertional dyspnea
• Difficulty maintaining normal weight

Diagnostic Tools^1,4

A number of tools are available for confirming a clinical diagnosis of Pompe disease, most of which measure GAA enzyme activity in various tissue specimens. Measurement of residual GAA activity in muscle tissue, skin fibroblasts, and blood lymphocytes using glycogen, maltose, or the artificial substrate 4-MUG are the most common diagnostic methods in current clinical practice. Muscle tissue and skin fibroblasts provide the most reliable results, typically showing minimal GAA activity in infantile-onset cases and varying amounts of residual activity in late-onset cases. However, muscle biopsy is an invasive procedure. The skin fibroblast assay is more sensitive and less invasive, but must be cultured for several weeks before assay. Finally, lymphocyte assays have the risk of granulocyte contamination and/or the presence of neutral glucosidases which can lead to false negatives. If the physician has a strong clinical suspicion of Pompe disease but lymphocyte results are negative, follow up testing is warranted.

An immune capture assay for measuring GAA activity in dried blood spots has also been reported, which allows identification of Pompe disease. This method is simple, inexpensive, and requires only a small amount of blood. It may be particularly appropriate for newborn screening, although validation of this assay in a large cohort is warranted.

Genotyping is important in genetic counseling and may be of supportive diagnostic value. It provides a way of determining whether children of carrier parents are also carriers. In cases with a family history of disease, prenatal diagnosis may be made by determining GAA in cultured amniotic cells or chorionic villus biopsies.

To learn more about Pompe disease visit www.pompe.com

References

1. Hirschhorn R, Reuser AJJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Childs B, et al, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 2000:3389-3420.

2. Raben N, Plotz P, Byrne BJ. Acid alpha-glucosidase deficiency (glycogenosis type II, Pompe disease). Curr Mol Med. 2002;2:145-166.

3. Slonim AE, Bulone L, Ritz S, et al. Identification of two subtypes of infantile acid maltase deficiency. J Pediatr. 2000;137:283-285.

4. Umapathysivam K, Whittle AM, Ranieri E, et al. Determination of acid alpha-glucosidase protein: evaluation as a screening marker for Pompe disease and other lysosomal storage disorders. Clin Chem. 2000;46:1318-1325.