Changing Recommendations for Newborn Screening

The recommendations surrounding newborn screening are constantly in flux. Newly discovered treatments or emerging laboratory technologies are enabling additional recommendations for newborn screening. Although each state is responsible for overseeing the scope of its own newborn screening program, standards and recommendations issued by the U.S. Secretary of Health and Human Services (HHS) are intended to guide the expansion of these programs. The Recommended Uniform Screening Panel (RUSP) currently includes 34 primary conditions and more than 25 secondary conditions. The most recent additions to the panel include disorders that are categorized as lysosomal storage and peroxisomal disorders. An increasing number of states have already passed or proposed legislation requiring screening for one or more of these disorders, although only a handful have implemented testing to date.

A New Standard of Neonatal Care

With three recent additions to the RUSP and newly passed legislation in many states, gaps exist between the screening required by state law or recommended by HHS and the screening provided by state health departments. Health care providers may wish to meet this new standard of care as soon as possible rather than wait for implementation at the state health departments.

The most recent additions to the panel include Pompe disease in 2015, Mucopolysaccharidosis type I (MPS-I), and X-linked adrenoleukodystrophy (XALD) in 2016. In addition to these conditions, four other lysosomal storage disorders have been added or are being considered for newborn screening programs in some states, including Krabbe disease, Fabry disease, Gaucher disease, and Niemann-Pick disease types A and B (NPAB). With the exception of NPAB, disease-specific therapies are now available for these disorders. A number of studies have shown evidence of benefits of early identification and intervention, meaning that improved outcomes are achieved when treatment is initiated at the earliest possible time before the onset of clinical symptoms, making these disorders suited for newborn screening when sensitive and specific laboratory tests become available.

Supplemental Newborn Screening at Mayo Clinic

Mayo Medical Laboratories (MML) offers two screening assays to detect lysosomal storage and peroxisomal disorders. Both screening assays use tandem mass spectrometry to measure the activity of six enzymes each associated with a lysosomal storage disorder. One of these assays, LDALD, also measures the concentrations of four lysophosphatidylcholines, which are elevated at birth in patients affected with XALD.

Mayo Medical Laboratories’ newborn screening tests are specifically designed to allow a hospital to voluntarily supplement the routine testing process already established with the state health department, allowing newborns to receive the highest recommended standard of care without delays.

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The False Positive Problem

For the team at the Mayo Clinic Biochemical Genetics Laboratory, as more conditions are added to RUSP, the overreaching priority is test performance and minimizing false positives, which still occur too often nationwide. False positives require additional patient contact and can cause lasting emotional stress to families during that delicate time when parents should be bonding with their newborns. At Mayo Clinic, we define the false positive rate as the proportion of positive tests in individuals proven by follow-up evaluation not to have one of the conditions identifiable by newborn screening. For the purpose of objective comparison, we believe that all cases requiring follow-up testing beyond the analysis of the initial blood spot should be included in the determination of the false positive rate, with the exception of specimens considered unsatisfactory for a legitimate reason.

Mayo Medical Laboratories’ newborn screening assays are designed to keep the false positive rate as low as possible. Our strategy has two main post-analytical components: data analysis using an internally developed multivariate pattern-recognition software (Collaborative Laboratory Integrated Reports or CLIR) and an extensive menu of second-tier tests.

Second-tier tests employ more sensitive methodologies that may not be suitable as a primary, high-throughput screening test. These tests are performed on the original newborn screening specimen when the primary screening assay yields abnormal results. This approach requires no additional patient contact and significantly increases the positive predictive value of the screening.

Some examples of second-tier testing for lysosomal storage and peroxisomal disorders include:

  • Psychosine levels and testing for the 30kb deletion of the GALC gene when the primary screening test indicates abnormal galactocerebrosidase enzyme activity (Krabbe disease).
  • Glucopsychosine levels when the primary screening test indicates abnormal acid beta-glucosidase activity (Gaucher disease).
  • Heparan sulfate and dermatan sulfate levels when the primary screening test indicates abnormal alpha-L-iduronidase enzyme activity (MPS-I).
  • Lysophosphatidylcholines when the primary screening test indicates abnormal C26:0 lysophosphatidylcholine species (XALD).
  • Additional tests under validation, including one for Pompe disease.

The CLIR software creates and maintains an integrated database of clinical and laboratory data, which is used to produce on-demand, post-analytical tools. The CLIR database consists of laboratory data from thousands of true positive cases submitted by participating collaborators worldwide. Rather than relying on a standard cut-off value, these tools merge the analysis of multiple analytes, each ranked according to clinical significance, into a single score that measures the likelihood of disease. The CLIR score is ranked against the data of true positive cases stored in the database. This analysis is more informative than a simple cut-off value traditionally found in newborn screening because it scores how similar is an individual result profile is to those observed in patients known to have a disease.

Raising the Bar for Performance Standards

Between 2004 and 2013, Mayo Clinic performed the tandem mass spectrometry testing for the state of Minnesota. In 2013, the Mayo Clinic Biochemical Genetics Laboratory performed screening for amino acid, organic acid, and fatty acid oxidation disorders on 71,000 babies, and there were only 17 false positives. The corresponding false positive rate was 0.024%, which compares favorably to an approximate average of 0.5% for other programs in the United States.

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Comprehensive Follow-Up

Positive newborn screening results require prompt follow-up to confirm a diagnosis and plan for appropriate treatment. The Mayo Clinic Biochemical Genetics Laboratory offers a comprehensive test menu for lysosomal storage and peroxisomal disorders. Our test menu includes traditional enzyme activity assays, novel biomarker testing, and molecular genetic analyses, including full-gene sequencing, mutation analysis, and known mutation testing. Guidance on appropriate test selection is available through the American College of Medical Genetics newborn screening ACT sheets, MML test algorithms, or by consultation with the directors and genetic counselors of the Mayo Clinic Biochemical Genetics Laboratory.

How to Order

Many hospitals across the country have already established an account with Mayo Medical Laboratories. Please click on the links below to register for an account, sign-in, or request a MML representative contact you to discuss your current account status and ordering options.

Registration for an account takes less than 10 minutes, and new accounts are typically processed and available in one business day. Once registered, sign in and locate either Lysosomal Storage Disorders Newborn Screen, Blood Spot or the Lysosomal and Peroxisomal Disorders Newborn Screen, Blood Spot  in the Test Catalog and click the "Order This Test" button. Follow the prompts to provide billing and contact information. Print the test requisition form to ship with the specimen.

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Mayo Medical Laboratories

This post was authored by the Marketing Team at Mayo Medical Laboratories.