Denise Salazar

Maternal Glutaric Acidemia, Type I Identified by Newborn Screening

We report two women with glutaric acidemia type I in whom the diagnosis was unsuspected until a low carnitine level was found in their newborn children. Both mothers had low carnitine in plasma. In the first, organic acid analysis was only done after fibroblast studies revealed normal carnitine uptake. Having learned from the first family, organic acid analysis was done immediately in the mother of family 2. In both, the plasma acylcarnitine profile was normal but both excreted the metabolites typical of their disorder. One of the women was a compound heterozygote for distinct mutations in the glutaric acid dehydrogenase gene, whereas the second was either homozygous or hemizygous for a mutation in Exon 6 of the gene.

Asymptomatic maternal combined homocystinuria and methylmalonic aciduria (cblC) detected through low carnitine levels on newborn screening.

A symptom-free woman gave birth to a girl with a low carnitine level on newborn screening. The baby was unaffected, but the mother had biochemical abnormalities and mutations characteristic of the cblC defect of vitamin B(12) metabolism (late-onset form). This patient with cblC was detected through her infants newborn screening.

Racial disparity in maternal and fetal-cord bisphenol A concentrations.

Objective:To determine if racial disparities exist in maternal and fetal cord serum concentrations of bisphenol A (BPA).Study Design:A nested cross-sectional study was performed from a cohort of 600 term nulliparas. In 27 patients (8 Caucasian, 8 African-American and 11 Hispanic), term pre-labor maternal serum and corresponding fetal-cord serum were analyzed for BPA.Result:African-Americans had the highest maternal serum concentrations, 10-fold higher than Caucasians (30.13 vs 3.14 ng ml−1; P=0.038). Hispanics had intermediate concentrations with a trend towards higher concentrations compared with Caucasians (24.46 vs 3.14 ng ml−1; P=0.051). Overall concentrations were 10-fold higher in maternal samples than fetal samples (14.1 vs 1.3 ng ml−1; P=0.001). Hispanics had higher fetal concentrations than non-Hispanics (2.05 vs 0.35 ng ml−1; P=0.025).Conclusion:We found significant racial/ethnic differences in maternal/fetal BPA concentrations. Further study is needed to determine if these differences reflect disparities in exposure, metabolism or placental transfer.

Improving Accuracy of Tay Sachs Carrier Screening of the Non-Jewish Population: Analysis of 34 Carriers and Six Late-Onset Patients With HEXA Enzyme and DNA Sequence Analysis

The purpose of this study was to determine whether combining different testing modalities namely β-hexosaminidase A (HEXA) enzyme analysis, HEXA DNA common mutation assay, and HEXA gene sequencing could improve the sensitivity for carrier detection in non-Ashkenazi (AJ) individuals. We performed a HEXA gene sequencing assay, a HEXA DNA common mutation assay, and a HEXA enzyme assay on 34 self-reported Tay-Sachs disease (TSD) carriers, six late-onset patients with TSD, and one pseudodeficiency allele carrier. Sensitivity of TSD carrier detection was 91% for gene sequencing compared with 91% for the enzyme assay and 52% for the DNA mutation assay. Gene sequencing combined with enzyme testing had the highest sensitivity (100%) for carrier detection. Gene sequencing detected four novel mutations, three of which are predicted to be disease causing [118.delT, 965A→T (D322V), and 775A→G (T259A)]. Gene sequencing is useful in identifying rare mutations in patients with TSD and their families, in evaluating spouses of known carriers for TSD who have indeterminate enzyme analysis and negative for common mutation analysis, and in resolving ambiguous enzyme testing results.

Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening

INTRODUCTION 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases. METHOD A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. RESULTS There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common. DISCUSSION Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.

The sensitivity and specificity of hyperglycosylated hCG (hhCG) levels to reliably diagnose clinical IVF pregnancies at 6 days following embryo transfer

ObjectiveTo determine the sensitivity and specificity of hyperglycosylated hCG (hhCG) measurements for the diagnosis of clinical pregnancies in the IVF setting and how soon post embryo transfer (ET) a pregnancy can be detected using an ultrasensitive (hhCG) assay. To determine if a single, early hhCG measurement can discriminate between biochemical and clinical pregnancies.DesignA 4 center prospective blinded clinical trial was performed with patients undergoing IVF-ET. Patients had blood drawn and submitted for hhCG analysis on the day of ET and at days 4, 6, 8, and 12 thereafter. First morning urines were collected and submitted for hhCG analysis on days 0, 4, 6, 8, 10 and 12.SettingFertility CentersOutcome MeasuresClinical pregnancies were defined as an ultrasound study demonstrating a gestational sac and/or heart beat at appropriate gestational ages.ResultsFifty-six of 58 enrolled patients completed the study. There were 25 clinical and 6 biochemical pregnancies. For blastocyst transfers, a single serum or urine hhCG measurement identified pregnancies (both biochemical and clinical) at 6 days post ET with 100% sensitivity and specificity. There were 6 biochemical pregnancies, all following blastocyst transfers. All of these pregnancies were identified by lower values.