Incidence of 4 Lysosomal Storage Disorders From 4 Years of Newborn Screening

Abstract

This study describes the incidence rates for 4 lysosomal storage disorders from 4 years of full-population testing of all newborns in Missouri.

Newborn screening is recognized as a highly effective public health program to detect certain diseases before detrimental long-term health consequences occur. With advances in screening technologies and therapeutic options becoming available, the US Department of Health and Human Services recently added 2 lysosomal storage disorders (LSDs), Pompe disease and mucopolysaccharidosis I (MPS I), to the Recommended Uniform Screening Panel.¹ In addition, several states have legislative mandates to screen for other LSDs not on the Recommended Uniform Screening Panel. The Missouri State Public Health Laboratory has used a fluorimetric enzyme activity test on a digital microfluidic platform to screen all samples from newborns that were received since January 11, 2013, for Pompe, MPS I, Gaucher, and Fabry disorders.² We herein present our findings on incidence rates for these LSDs from 4 years of full-population testing. These results represent, to our knowledge, the longest prospective, unblinded, full-population testing and follow-up for these LSDs in the United States.

Methods

Enzyme activity for acid α-glucosidase deficiency (Pompe disease), acid α-galactosidase deficiency (Fabry disease), acid β-glucocerebrosidase deficiency (Gaucher disease), and acid α-l-iduronidase deficiency (MPS I) was measured from dried blood spots using a fluorescence enzyme assay on the digital microfluidic platform (Baebies, Inc) as previously described.^2,3 Missouri newborn specimens received for screening from January 11, 2013, through January 10, 2017, were tested; approximately 308 000 newborns were screened. All 4 LSDs were screened simultaneously from a single newborn dried blood spot sample. Samples with positive findings (with mean triplicate screening values breaching referral cutoff limits for 1 of the LSDs) were referred to 1 of 4 state-contracted genetic referral centers for confirmatory testing and follow-up. The Department of Health and Senior Services received approval from the Institutional Review Board Committee after a full review to waive informed parental consent for the LSD implementation. Missouri had a legislative mandate to screen for LSDs and full population screening would be conducted on every infant equally with referral of positive screening results to our contracted genetic referral centers for follow-up confirmatory testing and treatment if needed.

Results

We identified 133 newborns who were confirmed through diagnostic testing results to have 1 of the 4 LSDs (Table), including 32 with Pompe disease (8 infantile and 24 late-onset), 5 with Gaucher disease, 94 with Fabry disease, and 2 with MPS I. An additional 19 infants were confirmed to have genotypes of unknown significance or onset. These infants need continual follow-up to monitor for potential late-onset disorders. The Table also includes the number of newborns identified with pseudodeficiency, as carriers, or with false-positive findings (confirmatory enzyme activity was in the reference range, and no DNA testing was conducted). False-positive rates ([pseudodeficient + carrier + false-positive findings]/total number screened), incidence rates (confirmed disorder/total number screened), and positive predictive values ([confirmed disorders + genotypes of unknown significance]/number with positive screen results) were also calculated.

Table. Results From 4 Years of Full-Population Newborn Dried Blood Spot Screening in Missouri^a.

Lysosomal Storage Disease	Positive Screen Result	Confirmed Disorder	Genotypes of Unknown Significance or Onset	Pseudodeficiency	Carrier	False-Positive Findings (False-Positive Rate, %)b	Lost to Follow-up or Refused Further Testing	Incidence in Missouric	Positive Predictive Value,d %
Pompe	161	32e	9	31	39	48 (0.04)	2	1:9625	26
Gaucher	37	5	2	0	6	22 (0.01)	2	1:61 600	20
Fabry	179	94	6	1	0	66 (0.02)	12	1:3277	60
MPS I	133	2	2	71	8	45 (0.04)	5	1:154 000	3
All	510	133	19	103	53	181	21	1:2316	NA

Abbreviations: MPS I, mucopolysaccharidosis I; NA, not applicable.

^aIncludes approximately 308 000 newborns undergoing screening. Unless otherwise indicated, data are expressed as numbers of newborns.

^bCalculated as those with pseudodeficient, carrier, and false-positive findings divided by the total number screened.

^cIncludes only confirmed disorders.

^dCalculated as those with confirmed disorders and genotypes of unknown significance or onset divided by the number with positive screen results.

^eIncludes 8 infantile and 24 late onset.

Discussion

We report findings from, to our knowledge, the longest unblinded, full-population, prospective study of 4 LSDs in the United States. Although many pilot studies have been performed on blinded samples, Taiwan has the only other collection of newborn screening programs worldwide that has performed population screening for Pompe and Fabry diseases with clinical follow-up for a longer period.⁴ Incidence rates for Pompe and Fabry diseases in Missouri are similar to those reported in Taiwan, whereas the false-positive rates in Missouri are lower and positive predictive values are higher.⁴ Incidence rates for Pompe and Fabry disease in Missouri are also higher than recently published rates in Illinois.⁵ The incidence rates for Gaucher disease and MPS I are similar to those previously reported in other pilot studies.^4,5 Rates of pseudodeficiency and genotypes of unknown significance for Pompe disease and MPS I are similar to published rates in Illinois.⁵ False-positive rates compare well with other newborn screening assays currently performed in Missouri. Missouri State Public Health Laboratory monitors for any false-negative cases, and to date we have had no reports of missed LSD cases. The fluorimetric multiplexed assay streamlines the workflow, makes efficient use of limited newborn screening materials, technical staff, and laboratory space, and allows a same-day turn-around time.