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Beyond Detection: Comparing State-Based Newborn Screening Methods for Effective Mucopolysaccharidosis I Diagnosis
Rithika Thampy1, Nishitha R Pillai2, Michael Evans3
1Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76706, USA.
International Journal of Neonatal Screening
|March 27, 2026
Summary
Second-tier glycosaminoglycan (GAG) analysis in newborn screening for Mucopolysaccharidosis type I (MPS I) improves detection of severe cases and reduces false positives. However, it shows minimal impact on pseudodeficiency detection and comparable rates for attenuated MPS I cases.
Area of Science:
- Biochemistry and Metabolic Disorders
- Genetics and Genomics
- Public Health and Newborn Screening
Background:
- Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder characterized by glycosaminoglycan (GAG) accumulation.
- MPS I screening is crucial for differentiating severe (Hurler syndrome) from attenuated (Scheie, Hurler-Scheie syndromes) forms.
- The Recommended Uniform Screening Panel (RUSP) included MPS I in 2016, with widespread adoption in US newborn screening (NBS) programs.
Purpose of the Study:
- To evaluate the impact of second-tier GAG analysis on the diagnostic outcomes of MPS I newborn screening.
- To compare the detection rates of severe, attenuated, false-positive, and pseudodeficiency cases between NBS programs with and without second-tier GAG analysis.
- To assess the effectiveness of second-tier GAG analysis in mitigating false positives and improving diagnostic resolution.
Main Methods:
- A nationwide survey of US NBS programs was conducted to collect data on MPS I screening.
- Data included total screen-positive results, final diagnostic outcomes (false-positive, pseudodeficiency, severe MPS I, attenuated MPS I, undetermined phenotype), and testing methodologies.
- Responses from 32 NBS programs were analyzed, comparing cohorts with and without second-tier blood spot GAG determinations.
Main Results:
- Programs using second-tier GAG analysis detected a higher proportion of severe MPS I cases (48% vs. 29%).
- The proportion of attenuated MPS I cases remained consistent across both groups (13% vs. 14%).
- Second-tier GAG analysis slightly reduced pseudodeficiency detection (85% vs. 91%) and false positives, but the difference in pseudodeficiency was marginal.
Conclusions:
- Second-tier GAG analysis enhances the detection of severe MPS I cases and reduces false positives in newborn screening.
- While effective for severe forms, the impact on pseudodeficiency detection is minimal, and attenuated case detection remains comparable.
- The higher rate of 'undetermined phenotype' cases in the second-tier cohort warrants further investigation for long-term diagnostic clarity.
