What are mucopolysaccharidosis (MPS) disorders?

A: MPS disorders are characterized by abnormal glycosaminoglycan (GAG) accumulation resulting from deficiencies or malfunctions of enzymes involved in GAG degradation. These disorders are clinically heterogeneous and characterized by multi-systemic manifestations, including abnormal GAG accumulation-associated skeletal abnormalities and neurological dysfunctions.

There are seven forms of MPS, some of which have multiple subtypes: I (Hurler/Scheie), II (Hunter), III-A (Sanfilippo Type A), III-B (Sanfilippo Type B), III-C (Sanfilippo Type C), III-D (Sanfilippo Type D), IV-A (Morquio Type A), IV-B (Morquio Type B), VI (Maroteaux-Lamy), VII (Sly), and IX (Natowicz).

How are MPS disorders diagnosed?

Many MPS disorders manifest with similar clinical outcomes, and disease presentation varies from late infancy to adulthood, which renders these disorders difficult to diagnose. Diagnosing an MPS disorder entails a comprehensive clinical evaluation, identifying characteristic findings (e.g., skeletal malformations, coarse facial features, and hepatosplenomegaly), and urine-based tests to detect abnormally high GAG levels. Enzymatic activity assays are also conducted to confirm the decreased levels of lysosomal enzymes associated with excessive GAG levels.

MPS I, which results from a deficiency of the ɑ-L-iduronidase enzyme (IDUA), is currently the only MPS disorder included in the Recommended Universal Screening Panel for newborns. In the case of MPS I, the diagnostic decision-making algorithm begins with a positive newborn screening test—i.e., a dried blood spot-based fluorometric enzyme assay result that indicates low levels of IDUA enzymatic activity. A blood sample is then obtained for IDUA activity analysis in leukocytes. If this test indicates enzymatic deficiency, the patient is referred to a genetic or metabolic disease specialist for comprehensive clinical, molecular, and biochemical assessment. In some cases, identifying the specific genetic variants that cause the observed enzyme dysfunction can guide subsequent treatment.

What methods are used to measure GAG levels?

Urinary total GAG levels are commonly measured using spectrophotometric dye-based binding assays including 1,9-dimethylmethylene blue or alcian blue. However, a drawback to these screening methods is their lack of specificity. Labs can avoid this limitation by using sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays to quantify individual classes of GAGs. These LC-MS/MS methods often incorporate the use of methanolysis (chemical hydrolysis) or specific enzymatic digestion to yield individual GAG-derived disaccharides followed by targeted mass spectrometric data acquisition.

Does laboratory testing have a role in MPS treatment?

Enzyme replacement therapy (ERT) using recombinant lysosomal enzymes is Food and Drug Administration-approved for the treatment of MPS I (Laronidase/Aldurazyme), II (Idursulfase/Elaprase), IV-A (Elosulfase alfa/Vimizim), and VI (Galsulfase/Naglazyme). A growing body of evidence supports the use of urinary GAG concentrations as predictive biomarkers of ERT efficacy. Urinary GAG levels are useful markers of ERT efficacy because they are measured using noninvasive procedures, respond to changes in enzyme dosing, and reflect restoration of enzyme activity in affected tissues. With ERT, urinary GAG concentrations often decrease rapidly over the first 3-6 months of administration followed by a slow continuous decline in subsequent years. However, urinary GAG levels do not precisely predict quantitative changes in specific clinical endpoints.

It is also important to note that ERT does not mitigate central nervous system abnormalities and cognitive decline due to the inability of the enzymes to cross the blood-brain barrier. For patients with severe MPS I, the gold standard treatment is therefore hematopoietic stem cell transplantation. As for MPS disorders without an approved ERT, treatment is directed toward the specific symptoms that a patient exhibits.

Stefani Thomas, PhD, DABCC, NRCC, is an assistant professor of laboratory medicine and pathology at the University of Minnesota and associate medical director of the M Health Fairview West Bank Laboratory in Minneapolis. +Email: [email protected]