Pompe Disease

About Pompe disease

Pompe disease, also known as acid maltase deficiency, is a rare, autosomal recessive lysosomal storage disease with a wide range of clinical phenotypes, presenting in infancy, childhood, or adulthood. Pompe disease is caused by an absence or deficiency of the lysosomal enzyme acid α-glucosidase, essential for the degradation of glycogen. Mutations in the GAA gene lead to absence or deficiency of the acid α-glucosidase enzyme resulting in progressive accumulation of lysosomal glycogen that can affect all muscle types.

Pompe disease is classified into Infantile-onset (IOPD) or Late-onset (LOPD)

  • Infantile-onset Pompe disease presents prior to 1 year of age and is characterized by elevated CK, profound muscle weakness, cardiomegaly, and cardiomyopathy. IOPD is rapidly progressive, typically leading to death by cardiorespiratory failure by 1 year of age if left unmanaged. IOPD may be suspected in infants with muscle weakness, hypotonia (“floppiness”), delayed motor milestones, a weak suck, feeding and swallowing defects, and failure to thrive.
  • Late-onset Pompe disease can present in childhood or adulthood with progressive proximal muscle weakness and respiratory insufficiency. CK may or may not be elevated. When abnormal, muscle biopsy typical findings include vacuolated muscle fibers, PAS-positive vacuoles (glycogen storage) and increased acid phosphatase activity in muscle fibers. Normal biopsy does not rule out Pompe. Significant morbidity is associated with LOPD, and there is a wide phenotypic range. LOPD may be suspected in children or adults with progressive proximal weakness, respiratory insufficiency, and feeding/swallowing difficulties.

Incidence

Overall incidence estimates for the United States for all forms: 1 in 40,000* (based off ethnically diverse New York population)

*Incidence varies depending on geography and ethnic background

Program Eligibility

The Lantern Project* consists of an acid α-glucosidase enzyme assay with reflex to GAA sequencing if deficient, and is for individual patients suspected of having Pompe disease via:

  1. Symptoms consistent with Pompe disease
  2. Presumptive positive newborn screen for Pompe disease (expedited testing available)
*This testing program is not appropriate for carrier testing as enzyme assay will not reliably detect carriers

About the Test

Testing algorithm:

  1. Acid α-glucosidase will be assayed and if deficient will reflex to,
  2. GAA sequencing analysis (with copy number variant analysis if needed)*
  3. If either enzyme assay or GAA sequencing has already been performed, these tests can be ordered individually, if needed.

*Expedited GAA sequencing with turnaround time of 3 days is available for infants with symptoms of infantile-onset Pompe disease, or those with presumptive positive Pompe disease based on newborn screening.

Acid α-glucosidase Enzyme Assay

  • Dried blood spots are preferred, but whole blood (EDTA) is also acceptable.

GAA Gene Sequencing

  • Dried blood spots (DBS) are preferred, but whole blood (EDTA) is also acceptable. A saliva sample can be used if only gene sequencing is being ordered.

Bundled Testing (Enzyme assay with reflex to sequencing)

  • Dried blood spots (DBS) are preferred, but whole blood (EDTA) is also acceptable. A saliva sample cannot be used for enzyme assay.

Click Here for detailed sample instructions and required quantities.

Enzyme Assay

  • Acid α-glucosidase activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS).

Gene Sequencing Assay

  • GAA sequencing is performed using NGS and analysis of all coding exons and 10bp of flanking intronic regions. This assay cannot detect variants in regions of the exome that are not covered, such as deep intronic, promoter, and enhancer regions, or areas containing large numbers of tandem repeats. Of note, this assay is designed to detect the exon 18 deletion [c.2481 + 102_2646 + 31del (p.Gly828_Asn882del)] and the intronic mutation c.-32-13T > G, if present. Copy number variation (CNV) of three exons or more is reported. Single exon CNVs can also be predicted, but reported after follow-up confirmation is performed.

Acid alpha-glucosidase Enzyme Assay: 3 days

GAA Gene Sequencing: 3 weeks

Ordering Instructions

Ultragenyx and PerkinElmer Genomics have partnered to offer sponsored MPS panel testing to patients who are suspected of having an MPS disorder, or who have been clinically diagnosed with MPS and need confirmatory testing. For Health Care Professionals already familiar with MPS disorders, please use the links below to learn about eligibility, the MPS panel, or to order a collection pack & submit a specimen.

Select the correct test for your patient, and fill out The Lantern Project Requisition Form.

  1. Obtain a sample for testing from the patient using one of the provided PerkinElmer Genomics test packs. If you do not have a kit available in your office, please contact us here and we can have one sent out to your office.
    • Ensure that the patient sample is labeled with the patient name and date of birth.
    • Please note that all biochemical assays require a dried blood spot sample or whole blood. Step-by-step instructions for collecting a DBS sample can be found here.
    • Samples may be submitted without a collection kit by following the guidelines for specimen requirements and completing the requisition form.
  2. Package the patient sample, informed consent form, and test requisition form back into the test kit, and utilize the included pre-paid shipping label to return the kit to PerkinElmer Genomics for processing.
    • As a patient’s clinical presentation is an essential part of fully interpreting genetic test results, we ask that you kindly include any applicable medical records or clinical notes with the sample at the time of test submission.

Once PerkinElmer receives the sample, you will receive phone call to report abnormal findings, with a written report to follow within the established turnaround time for the ordered test. Bundled tests will be reported together in one comprehensive result.

Other Conditions in the Lantern Project

  • To learn more about The Lantern Project, Click Here
  • To learn more about Fabry disease, Click Here
  • To learn more about Gaucher disease and Niemann-Pick Type A/B (ASMD), Click Here
  • To learn more about Mucopolysaccharidoses I (MPS I) and Other MPS Disorders, Click Here
  • To learn more about Limb Girdle Muscular Dystrophy (LGMD) and Overlapping Myopathies, Click Here

References

  1. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40:149-160.
  2. Martiniuk F et al. Carrier frequency for glycogen storage disease Type II in New York and Estimates of affected individuals born with the disease. Am J Med Genet. 1998;79:69-72.
  3. Burton B et al. The Initial Evaluation of Patients After Positive Newborn Screening: Recommended Algorithms Leading to a Confirmed Diagnosis of Pompe Disease. Pediatrics Jul 2017, 140 (Supplement 1) S14-S23; DOI: 10.1542/peds.2016-0280D