Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance.

Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.

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

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.

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I.

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing.

How a baby with classic galactosemia was nearly missed: When the test succeeds but system fails.

Newborn screening (NBS) is a well-established state-run public health program which has targeted the early identification of treatable diseases like classic galactosemia (CG) for over a decade. We describe the case of a symptomatic newborn with CG and an abnormal screen report, including positive DNA-based test, who still managed to fall through the cracks in a sub-optimally functioning NBS program, despite decades of screening experience. While much attention is paid to testing technology, this case illustrates basic minimum requirements a newborn screening program must fulfill to reliably identify and treat all affected individuals including minimum reporting requirements, case surveillance and a dedicated short-term follow-up program.

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data.

Incidence for the branched-chain intoxication-type disorders, maple syrup urine disease, propionic acidemia and methlymalonic aciduria is dependent on the population screened. Here newborn screening results from three world regions, state screening laboratories in the United States, a region in Germany and Kuwait provides new incidence numbers. Maple syrup urine disease incidence in the United States was calculated to be 1: 220219, in South-West Germany 1: 119573 (Germany nationwide 1:177978), and in Kuwait 1: 59426.

"Mild" hyperphenylalaninemia? A case series of seven treated patients following newborn screening.

Unlabelled: Hyperphenylalaninemia (HPA) is a disorder diagnosed only incidentally by newborn screening, a by-product of screening for classic phenylketonuria (PKU) which, if untreated, causes irreversible neurologic sequelae. In contrast, HPA is thought to have a benign phenotype because phenylalanine (Phe) levels are insufficiently elevated to cause neurological damage, obviating the need for rigorous dietary protein restriction. Phenylalanine below 360μmol/L is generally considered safe, thus this threshold is both the upper therapeutic range for treated PKU and the highest Phe expected to be possible for most individuals with HPA.

Confirmation that p.Ala259Val mutation causes autosomal dominant hypermethioninemia.

Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in , encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance.

Short-term follow-up systems for positive newborn screens in the Washington Metropolitan Area and the United States.

For most inherited metabolic disorders on newborn screening (NBS) panels, prompt, expert confirmation and treatment are critical to optimize clinical outcomes for children with inherited metabolic diseases (IMD). In the Washington Metropolitan Area (WMA), 3 different short-term follow-up (STFU) systems exist for linking infants with positive newborn screens for IMD to appropriate specialty care. We diagrammed the STFU systems for the District of Columbia, Maryland and Virginia and calculated clinically relevant intervals of time between NBS collection and diagnosis/treatment initiation.

Deconstructing Black Swans: An Introductory Approach to Inherited Metabolic Disorders in the Neonate.

Background: Inherited metabolic disorders (IMDs) are individually rare but collectively common disorders that frequently require rapid or urgent therapy.

Purpose: This article provides a generalized approach to IMDs, as well as some investigations and safe therapies that may be initiated pending the metabolic consult.

Methods/search Strategy: An overview of the research supporting management strategies is provided.