221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative

Abstract

INTRODUCTION There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. METHODS Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism – Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. RESULTS The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45 days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2 umol/L (median 8.6, range 0.36–43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A>G ACADM gene mutation or compound heterozygous for the c.985A>G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A>G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. CONCLUSIONS This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

Inborn Errors of Metabolism in the Era of Untargeted Metabolomics and Lipidomics

“…These protocols cover a selected panel of diseases by quantifying the metabolites in a disease pathway and metabolite levels are then compared to the range of healthy (normal) metabolic concentrations [66,119,120]. For some diseases, metabolite measurements are assembled into panels [121,122]. The most commonly screened panels of IEMs are using markers of amino acids, fatty acid oxidation, and organic acid metabolism disorders [123,124,125].…”

New Ratios for Performance Improvement for Identifying Acyl-CoA Dehydrogenase Deficiencies in Expanded Newborn Screening: A Retrospective Study

“…According to previous reports, each nation or ethic group shows a unique spectrum of ACADM gene mutations. The c.985A > G was the most common mutation for MCAD deficiency in many countries and regions, including the United Sates (Bentler et al, 2016), Germany (Maier et al, 2005), Denmark (Andresen et al, 2001), Portugal (Ventura et al, 2014; Janeiro et al, 2019), Caucasia (Grosse et al, 2006), and other European countries (Tanaka et al, 1997). However, the c.985A > G is rare in Asian patients with MCAD deficiency.…”

Follow-up status during the first 5 years of life for metabolic disorders on the federal Recommended Uniform Screening Panel

“…Many studies have examined LTFU data to describe the clinical outcomes associated with expanded NBS using tandem mass spectrometry, including inborn errors of metabolism, 14 mitochondrial fatty acid beta-oxidation defects, 15 VLCAD, 16,17 malonic acidemia, 18 MCAD, 19 and urea cycle disorders. 20 Using LTFU data collected in California, Gallant 21 described the biochemical, molecular, and clinical characteristics of children with short-chain acyl CoA dehydrogenase deficiency (listed as a secondary RUSP disorder) and concluded that this disorder was not associated with significant morbidity or mortality in newborns followed through age 5.…”