Newborn screening for homocystinuria: Irish and world experience

Abstract

Newborn screening for cystathionine beta-synthase deficiency (homocystinuria; HCU) was started in the late 1960s using a bacterial inhibition assay (BIA). At least seven countries have either national or regional screening programmes; 12 programmes are known to have discontinued. The worldwide incidence of HCU is approximately 1 in 335,000 but varies from 1:65,000 (Ireland) to 1:900,000 (Japan). Methodologies include the BIA, one-dimensional or thin-layer amino acid chromatography and, more recently, tandem mass spectrometry. The BIA diagnostic cut off concentration of blood methionine varies from 67 to 270 micromol/ (10-40 mg/l) with a median of 135 micromol/l (20 mg/l). In Ireland, 25 cases of HCU from 19 families have been identified from 1.58 million newborn infants since 1971; 21 cases were detected through the screening programme. Of the four missed cases, three were breast-fed at the time of blood collection and one was pyridoxine responsive. These findings were in broad agreement with the results from five other programmes, in which approximately one in every five cases was missed by the screening programme. Early hospital discharge, low protein intake, high blood methionine cut-off concentration and pyridoxine responsiveness were all identified as contributing to missed cases.

Damaged goods?: an empirical cohort study of blood specimens collected 12 to 23 hours after birth in newborn screening in California

“…10,18,19,21 To understand the impact of early blood collection in newborn screening, we studied false-negative and false-positive rates in GDSP's blood specimens collected from 12 to 23 hours of age in comparison to the specimens collected from 24 to 48 hours of age. To our knowledge, this is the first study on specimens collected between 12 and 23 hours of age conducted at a population level.…”

“…The other concern is the potential increase of false negatives (true cases reported as negative screening results). 19,20 The primary concern is with disorders of amino acid metabolism, where early collection could mean that the newborn's metabolism has not been functioning independently for long enough for the metabolic disorder to be evident from Purpose: The current Clinical and Laboratory Standards Institute standard recommends blood collection from 24 to 48 hours after birth for newborn genetic disorder screening. We used California population-level data to determine whether early specimens (collected from 12 to 23 hours) would also be considered satisfactory based on screening performance.…”

The Risk of Fatty Acid Oxidation Disorders and Organic Acidemias in Children with Normal Newborn Screening

“…Screening for the aminoacidopathies maple syrup urine disease, homocystinuria and tyrosinaemia using leucine/ isoleucine, methionine and tyrosine, respectively, is known to be problematic with high rates of false-positive screening and missed cases being reported (Estrella et al 2014;Naughten et al 1998). In fact many patients with these conditions can have normal metabolites at the time of newborn screening (https://www.clir-r4s.org/ProjTools/DiseaseRangeComp.aspx) and thus these conditions were not part of this study.…”

Cystathionine beta-synthase deficiency in Central Europe: Discrepancy between biochemical and molecular genetic screening for homocystinuric alleles

“…A recent study from New England showed that lowering the cutoff level for blood methionine from 134 to 67 µmol/l almost doubled the reported incidence of homocystinuria (Peterschmitt et al, 1999). This notion suggests that in various populations the previously determined incidence that employed cutoff levels as high as 270 µmol/l (Naughten et al, 1998) may have underestimated the frequency of this disease. 2.…”

“…Two major phenotypes of this autosomal recessive disease are equally common, a milder pyridoxine-responsive form, and a more severe non-responsive type. However, treatment with pyridoxine, methionine-restricted diet or betaine prevents the development of somatic and mental abnormalities in the more severe forms only when started in infancy (Naughten et al, 1998;Walter et al, 1998). Such a favorable outcome in early treated patients, and a possibility to diagnose the disease from blood spots rank homocystinuria among inborn errors of metabolism that would benefit from newborn screening.…”