MPS I Disease

About Mucopolysaccharidosis I (MPS I) and Other MPS Disorders

The mucopolysaccharidoses (MPS) are a group of inherited multisystem progressive disorders caused by deficiencies of the lysosomal enzymes that degrade complex disaccharides. The progressive accumulation of some of these molecules, called glycosaminoglycans (chondroitin sulfate, heparan sulfate, dermatan sulfate and keratan sulfate) in various tissues leads to the different phenotypes seen in the MPS disorders.

Mucopolysaccharidosis Ι (MPS Ι) is caused by a deficiency of the lysosomal enzyme α-L-iduronidase, leading to a buildup of its major substrates, the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate, resulting in developmental delay and regression, plus respiratory, cardiac, and musculoskeletal dysfunction.1 MPS I is caused by mutations in the IDUA gene responsible for producing α-L-iduronidase.2 Symptoms of MPS I range over a continuum of severity but are generally divided into severe MPS I (historically called Hurler syndrome) and attenuated MPS I (historically called Hurler-Scheie and Scheie syndromes), with a variable age of onset, progression, and organ involvement.1 MPS I is inherited in an autosomal recessive manner.

There is considerable phenotypic overlap among several MPS disorders and the following symptoms may prompt further examination:  Children may have coarse facial features, early frequent upper-respiratory infections (including otitis media), inguinal or umbilical hernia, developmental delay and regression. Both children and adults can have hepatosplenomegaly, joint stiffness, limited range of motion, joint contractures, carpal tunnel and corneal clouding.

Incidence

Together the incidence of the MPS disorders is estimated at 1/25 000 births. Severe MPS I occurs in approximately 1 in 100,000 newborns; the incidence of the attenuated form is estimated at 1 in 500,000 newborns.2-4

Program Eligibility

The Lantern Project* offers two approaches to diagnosing MPS I: directed testing of  α-L-iduronidase enzyme assay and IDUA sequencing,  or testing for 7 MPS disorders via an enzyme panel for patients with:

  1. Symptoms consistent with MPS I, or one of the other MPS disorders
  2. Presumptive positive newborn screen for MPS I

*This testing program is not appropriate for carrier testing as enzyme assay will not reliably detect carriers

About the Test

Testing algorithm:

Patients suspected of having MPS I:

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

Patients suspected of having an unspecified MPS disorder

  1. MPS 7 enzyme panel. If α-L-iduronidase is deficient will reflex to:
  2. IDUA sequencing analysis (with copy number variant analysis if needed)

α-L-iduronidase and 7-Plex Enzyme Assays

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

IDUA 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 Assays

  • α-L-iduronidase activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS).
  • Enzyme activity is measured on dried blood spots (DBS) via Flow Injection Tandem Mass Spectrometry (FIA/MS/MS) for the following analytes:
    1. MPS I, Hurler, Hurler-Scheie, and Scheie syndrome (α-iduronidase)
    2. MPS II, Hunter syndrome (Iduronate-2-sulfatase)
    3. MPS IIIB, Sanfilippo syndrome (α -N-acetylglucosaminidase)
    4. MPS IVA, Morquio syndrome, type A (N-acetyl galactosamine-6-sulfatase)
    5. MPS IVB, GM1 Gangliosidosis (β-galactosidase)
    6. MPS VI, Maroteaux-Lamy syndrome (Arylsulfatase B)
    7. MPS VII, Sly syndrome (β-glucuronidase)

Gene Sequencing Assay

  • IDUA 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. 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.

α-L-iduronidase and 7-Plex Enzyme Assays: 3 days

IDUA Gene Sequencing: 3 Weeks

Ordering Instructions

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 Pompe disease, Click Here
  • To learn more about Gaucher disease and Niemann-Pick Type A/B (ASMD), Click Here
  • To learn more about Limb Girdle Muscular Dystrophy (LGMD) and Overlapping Myopathies, Click Here

References

  1. Arn P, Wraith J, Underhill L. Characterization of surgical procedures in patients with mucopolysaccharidosis type I: findings from the MPS I Registry. J Pediatr 2009; 154:859-64 e3.
  2. Clarke LA. Mucopolysaccharidosis type 1. NCBI Bookshelf, a service of the National Library of Medicine, National Institutes of Health (NIH). Available at: https://www.ncbi.nlm.nih.gov/books/NBK1162/. Accessed July 20, 2018.
  3. Beck M, Arn P, Giugliani R, et al. The natural history of MPS I: global perspectives from the MPS I Registry. Genet in Med. 2014;16(10):759.
  4. Tomatsu S et al  Newborn screening and diagnosis of mucopolysaccharidoses Mol Genet Metab. 2013 Sep-Oct; 110(0): 42–53.