Mucopolysaccharidosis type I newborn screening: Importance of second tier testing for ethnically diverse populations

Abstract

Mucopolysaccharidosis type I (MPS I)/Hurler syndrome newborn screening was added to the recommended uniform screening panel (RUSP) in 2016. As states have added screening for MPS I, programs have reported increased rates of false positives. Reasons for false positive screens include carrier status, true false positive, late‐onset/attenuated forms, and in about half of cases, pseudodeficiency alleles. These alleles have DNA variants that can cause falsely decreased enzyme activity on biochemical enzyme studies and have increased frequency in individuals of African American and African descent. We describe the District of Columbia (DC) experience with MPS I screening from December 2017 to February 2019. In the context of a review of the literature on newborn screening and family experiences and this DC‐based experience, we offer potential solutions to address preliminary concerns regarding this screening. The impact of overrepresentation of screen positives in a minority group and unintentional creation of health disparities and community wariness regarding medical genetics evaluations must be considered to improve the newborn screen programs nationally and internationally.

Left-sided valvular heart disease and retinopathy in a 38-year-old woman with attenuated mucopolysaccharidosis: a case report

“…8 , 9 However, it should be noted that the first tier of newborn screening testing (iduronidase activity) can be difficult to interpret, with high rates of false positives. 10 In addition, when presented with a positive screening test, there is no agreed upon standard for second-tier confirmatory testing. 10 This understandably causes families anxiety and uncertainty regarding their child’s diagnosis.…”

“… 10 In addition, when presented with a positive screening test, there is no agreed upon standard for second-tier confirmatory testing. 10 This understandably causes families anxiety and uncertainty regarding their child’s diagnosis. As a response to this, the Centers for Disease Control and Prevention has granted several states funding for improving newborn screening initiatives for six diseases, one of which is MPS I.…”

Harmonization of Newborn Screening Results for Pompe Disease and Mucopolysaccharidosis Type I

“…Coupled with these QI processes has been increased scrutiny regarding laboratory cutoffs that contribute to false-negative results and missed cases leading to disability and even death [ 1 , 3 , 4 ]. Disorders recently added to the Recommended Uniform Screening Panel (RUSP) [ 5 ] all have phenotypic spectrums including X-linked adrenal leukodystrophy (X-ALD), Pompe disease (PD), and mucopolysaccharidosis type I (MPS I), which may contribute to increased false-positive screening reports [ 6 , 7 , 8 ] and potential for unnecessary follow-ups and diagnostic testing.…”

“…This situation creates significant ambiguity and anxiety for families [ 12 , 13 ]. Late-onset or attenuated forms of MPS I and variants of unknown significance with undetermined pathogenicity also create parental stress and psychosocial burden [ 7 , 14 ]. Benign pseudodeficiencies caused by low enzyme activities (e.g., -glucosidase (GAA) for PD and -L-iduronidase (IDUA) for MPS I) and the presence of carriers pose challenges for laboratories screening for these disorders [ 15 , 16 ], since these low activities contribute significantly to high false-positive rates and lower positive predictive values (PPV) [ 7 , 8 ].…”

“…Late-onset or attenuated forms of MPS I and variants of unknown significance with undetermined pathogenicity also create parental stress and psychosocial burden [ 7 , 14 ]. Benign pseudodeficiencies caused by low enzyme activities (e.g., -glucosidase (GAA) for PD and -L-iduronidase (IDUA) for MPS I) and the presence of carriers pose challenges for laboratories screening for these disorders [ 15 , 16 ], since these low activities contribute significantly to high false-positive rates and lower positive predictive values (PPV) [ 7 , 8 ]. While the RUSP serves as a guide for establishing state NBS panels [ 5 ], NBS programs ultimately decide which diseases to screen for and place their screening cutoffs conservatively to avoid missed cases [ 10 , 12 ].…”