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The long-term consequences and need for therapy in children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBDD) identified via newborn screening (NBS) remains controversial. Initial clinical descriptions were severe; however, while most cases identified through NBS have remained asymptomatic, clinical concerns have been raised in these populations. It is not clear whether these children are asymptomatic because of the success of NBS, or because the normal clinical course of these disorders is relatively benign. To evaluate these possibilities in our program, we evaluated the clinical outcomes of children with SCADD or IBDD identified by the Georgia NBS compared to the health status of a healthy age-matched control group. We also assessed parental anxiety during a phone interview both subjectively and objectively using the Pediatric Inventory for Parents (PIP), a validated measure of illness-related parental stress. The general health of 52 SCADD and nine IBDD cases from 2007 to 2016 were compared to the general health of unaffected control children obtained through the Centers for Disease Control and Prevention (CDC) parent listserv. We also collected statements from parents who participated in a phone survey regarding events they experienced during and after their diagnostic process. Overall, the children with SCADD and IBDD had no major health problems. There was no significant difference in cognitive development (p = .207). We identified a slightly higher incidence of reported neonatal hypoglycemia in the SCADD group; two of these occurred in the context of maternal diabetes. All interviewed parents reported extreme anxiety during the diagnostic period and current feelings of uncertainty about their child's future. PIP scores for all six caregivers who responded to that portion of the survey were consistent with some degree of parental stress. The greatest reported stressor was the unknown long-term impact of the illness. All children with SCADD and IBDD had no significant long-term sequelae. The phone interviews revealed substantial parental anxiety about the identification and follow-up of SCADD and IBDD. Based on our findings, the anxiety parents experience may be unwarranted given that we see no disease-associated morbidity or mortality in these children. Consideration should be given to the removal of these conditions from NBS panels, or if that is not possible, clinicians could educate parents on the benign nature of these diagnoses and release them from follow-up without treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: As exome and genome sequencing using high-throughput sequencing technologies move rapidly into the diagnostic process, laboratories and clinicians need to develop a strategy for dealing with uncertain findings. A commitment must be made to minimize these findings, and all parties may need to make adjustments to their processes. The information required to reclassify these variants is often available but not communicated to all relevant parties., Methods: To illustrate these issues, we focused on three well-characterized monogenic, metabolic disorders included in newborn screens: classic galactosemia, caused by GALT variants; phenylketonuria, caused by PAH variants; and medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, caused by ACADM variants. In 10 years of clinical molecular testing, we have observed 134 unique GALT variants, 46 of which were variants of uncertain significance (VUS). In PAH, we observed 132 variants, including 17 VUS, and for ACADM, we observed 64 unique variants, of which 33 were uncertain., Conclusion: After this review, 17 VUS (37%; 7 in ACADM, 9 in GALT, and 1 in PAH) were reclassified from uncertain (6 to benign or likely benign and 11 to pathogenic or likely pathogenic). We identified common types of missing information that would have helped make a definitive classification and categorized this information by ease and cost to obtain.Genet Med 19 1, 77-82.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a rare but important component of the differential diagnosis for adults with a history of premortem mental status changes and the postmortem finding of hepatic steatosis. This case report describes a 30-year-old white man who, following a period of nausea and vomiting, was admitted to the hospital with sudden mental status deterioration followed rapidly by clinical deterioration and death. Treating physicians in this case suspected acute illicit drug toxicity with synthetic cathinones based on social history. Clinicians and medical examiners should be aware that the presentation, signs, and symptoms described may indicate an underlying inborn error of metabolism such as MCAD deficiency and take action accordingly., (© 2015 American Academy of Forensic Sciences.)

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is a fatty acid oxidation disorder included on newborn screening (NBS) panels in many regions that have expanded to using tandem mass spectrometry for acylcarnitine screening. False positive (FP) screening results for MCAD deficiency have previously been linked to very low birth weight (VLBW) infants and those who are heterozygous for the common mutation, p.K324E. Previous studies have identified these causes of FP screens by sequencing residual dried blood spots. From our cohort of FP screens in Georgia, we identified an elevation at the same mass as octenoylcarnitine (C8:1) causing elevations of octanoylcarnitine (C8) not due to MCAD deficiency. We reviewed biochemical results from 2011 to 2013 for all newborn screens positive for MCAD deficiency in Georgia to identify screening criteria to allow these cases to be identified prospectively, thus saving families the stress of additional testing on their newborn and reducing healthcare costs while improving screening performance for the screening program. We identified the C8/C8:1 ratio as an effective marker, and developed criteria that will reduce FP screening results due to this interfering substance., (Copyright © 2014 Elsevier Inc. All rights reserved.)