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

In newborn screening, false-negative results can be disastrous, leading to disability and death, while false-positive results contribute to parental anxiety and unnecessary follow-ups. Cutoffs are set conservatively to prevent missed cases for Pompe and MPS I, resulting in increased falsepositive results and lower positive predictive values. Harmonization has been proposed as a way to minimize false-negative and false-positive results and correct for method differences, so we harmonized enzyme activities for Pompe and MPS I across laboratories and testing methods (Tandem Mass Spectrometry (MS/MS) or Digital Microfluidics (DMF)). Participating states analyzed proofof- concept calibrators, blanks, and contrived specimens and reported enzyme activities, cutoffs, and other testing parameters to Tennessee. Regression and multiples of the median were used to harmonize the data. We observed varied cutoffs and results. Six of seven MS/MS labs reported enzyme activities for one specimen for MPS I marginally above their respective cutoffs with results classified as negative, whereas all DMF labs reported this specimen's enzyme activity below their respective cutoffs with results classified as positive. Reasonable agreement in enzyme activities and cutoffs was achieved with harmonization; however, harmonization does not change how a value would be reported as this is dependent on the placement of cutoffs.

Newborn tandem mass spectroscopy screening for adenosine deaminase deficiency.

BACKGROUND: Newborn screening (NBS) by means of T cell receptor excision circles (TREC) is now universal in the United States, Puerto Rico, and the Navajo Nation as a strategy to identify severe combined immunodeficiency (SCID) in newborns. Owing to the characteristics of adenosine deaminase (ADA) deficiency, a small but important number of cases can be missed by this screening. OBJECTIVE: To evaluate the results of the first year statewide NBS for ADA by means of dried blood spot NBS. METHODS: On October 7, 2019, the state of Michigan began screening newborn dried blood spots for ADA deficiency by means of the Neobase-2 tandem mass spectroscopy (TMS) kit. We report 1 known case of ADA deficiency in the 18 months before screening. We then reviewed the results of the first 2 years of TMS ADA screening in Michigan. RESULTS: There was 1 patient with ADA deficiency known to our centers in the 18 months before initiation of TMS ADA screening; this patient died of complications of their disease. In the first 2 years of TMS ADA NBS, 206,321 infants were screened, and 2 patients had positive ADA screen results. Both patients had ADA deficiency confirmed through biochemical and genetic testing. One patient identified also had a positive TREC screen and was confirmed to have ADA-SCID. CONCLUSION: In our first 2 years, TMS NBS for ADA deficiency identified 2 patients with ADA deficiency at negligible cost, including 1 patient who would not have been identified by TREC NBS. This report provides initial evidence of the value of specific NBS for ADA deficiency.

A cautionary tale of pyridoxine toxicity in cystathionine beta-synthase deficiency detected by two-tier newborn screening highlights the need for clear pyridoxine dosing guidelines.

Classic homocystinuria is due to deficiency of cystathionine beta-synthase (CBS), a pyridoxine-dependent enzyme that, depending on the molecular variants, may be co-factor responsive. Elevated methionine is often used as the primary analyte to detect CBS deficiency (CBSD) on newborn screening (NBS), but is limited by increased detection of other biochemical disorders with less clear clinical significance such as methionine aminotransferase (MAT) I/III heterozygotes. Our state has implemented a two-tier NBS algorithm for CBSD that successfully reduced the number of MATI/III heterozygotes, yet effectively detected a mild, co-factor responsive form of CBSD. After initial diagnosis, newborns with CBSD often undergo a pyridoxine challenge with high-dose pyridoxine to determine responsiveness. Here we describe our NBS-identified patient with a mild form of pyridoxine responsive CBSD who developed respiratory failure and rhabdomyolysis consistent with pyridoxine toxicity during a pyridoxine challenge. This case highlights the need for weight-based dosing and duration recommendations for pyridoxine challenge in neonates.