Validation and Implementation of a Highly Sensitive and Efficient Newborn Screening Assay for Mucopolysaccharidosis Type II

Abstract

Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome, is a lysosomal storage disorder (LSD) caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). MPS II satisfies all criteria defined by the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) for inclusion in the Recommended Uniform Screening Panel (RUSP) for newborn screening, apart from the fact that only minimal prospective population screening data are available. This report details the analytical validation, clinical validation, and implementation of a fluorometric assay for measurement of IDS activity in newborn dried blood spot (DBS) specimens at the Missouri State Public Health Laboratory (MSPHL). The assay is performed in a microwell plate format requiring approximately 15 min of hands-on time per plate and an incubation time of two hours. The analytical validation of this assay included linearity, analytical sensitivity, precision, and carry-over testing. Clinical validation was completed using more than 5000 deidentified presumptive normal newborn DBS specimens as well as seven specimens from patients known to be affected with MPS II. Following validation, MSPHL began prospective screening using the IDS assay on 1 November 2018. In the first 18 months of screening (to 30 June 2020), 146,954 specimens were prospectively screened using the method. Two newborns were identified with severe Hunter syndrome and the assay had a presumptive positive rate of 0.022%.

Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II

“…As a result, deficiencies in IDS enzyme activity associated with MPS-II phenotypes leads to an accumulation of heparan sulfate and dermatan sulfate in the lysosomes of cells throughout the body. The measurement of these GAGs has been explored using multiple methods, and current NBS programs report GAG biomarker levels as part of genetic diagnostic assessments following first-tier IDS activity population screens [ 2 , 3 ].…”

“…Currently, Newborn screening (NBS) programs in Taiwan, Illinois, and Missouri are conducting population screening for MPS-II using IDS enzymatic activity in DBS as a first-tier method [ 1 , 2 ]. The results from these studies indicate that the prevalence of MPS-II is between 0.9 and 1.96 per 100,000 live male births [ 1 , 2 , 3 ]. Some female cases of MPS-II have been reported, though the X-linked recessive disorder is expected to mainly be found in males [ 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

Newborn Screening Program for Mucopolysaccharidosis Type II and Long-Term Follow-Up of the Screen-Positive Subjects in Taiwan

“…An early diagnosis of MPS II through such newborn screening programs can promote more timely and appropriate management plans for these patients, and allow for more detailed genetic counseling for the family members. Newborn screening programs for MPS II are currently conducted in Taiwan, Illinois, and Missouri [ 19 , 20 , 21 ]. The pilot newborn screening program for MPS II was launched in Taiwan in August 2015, and infants who fail to pass the recheck at recall are referred to MacKay Memorial Hospital for a comprehensive confirmatory diagnosis.…”

Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair

“…Early detection is a critical problem. The technology is in place to identify Hunter syndrome with newborn screening (NBS) and active screening programs exist in Taiwan, Illinois and Missouri [16] , [17] , [18] . The advent of NBS technology, combined with the 2006 FDA approval of ERT to treat Hunter syndrome, position this disorder to be considered by the U.S. Secretary of Health and Human Services for addition to the Recommended Uniform Screening Panel (RUSP).…”