Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia

Sadat, Roa; Hall, Patricia; Wittenauer, Angela; Vengoechea, Elizabeth D.; Park, Kevin; Hagar, Arthur F.; Singh, Rani H.; Moore, Reneé H.; Gambello, Michael J.

doi:10.1016/j.ymgme.2019.11.008

Cited by 17 publications

(22 citation statements)

References 21 publications

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“…Nevertheless, elevated C4-acylcarnitine concentrations always exist. Neonatal hypoglycemia in patients with IBDD that reported elsewhere was absent here [ 20 ], while 10 patients had anaemia instead. However, Acad8 mutant mice showed significantly elevated transaminase levels and presented progressive hepatic steatosis [ 24 ].…”

Section: Discussionmentioning

confidence: 43%

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8

Feng

Yang

Zhu

et al. 2021

Orphanet J Rare Dis

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Background Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder resulting from variants in ACAD8, and is poorly understood, as only dozens of cases have been reported previously. Based on a newborn screening program, we evaluated the incidence, phenotype and genotype of IBDD as well as the prognosis. Moreover, we reviewed the variant spectrum in ACAD8 associated with IBDD. Methods Forty unrelated patients with IBDD were retrospectively screened for newborns between Jan 2012 and Dec 2020. Tandem mass spectrometry (MS/MS) was used to determine the concentrations of C4-acylcarnitine, C4/C2 (acetylcarnitine), and C4/C3 (propionylcarnitine). All suspected cases were genetically tested by metabolic genes panel. Results The incidence of IBDD here was 1: 62,599. All patients presented continuously elevated C4-acylcarnitine levels with higher ratios of C4/C2 and C4/C3. Isobutyrylglycine occurred in only 8 patients. During follow-up, four patients had a transient motor delay, and two patients had growth delay. Notably, one case harbored both ACAD8 compound heterozygous variants and a KMT2A de novo variant (c.2739del, p.E914Rfs*35), with IBDD and Wiedemann–Steiner syndrome together, had exact severe global developmental delay. All patients were regularly monitored once they were diagnosed, and each patient gradually had a normal diet after 6 months of age. After 3–108 months of follow-up, most individuals were healthy except the case harboring the KMT2A variant. A total of 16 novel variants in ACAD8, c.4_5delCT, c.109C > T, c.110–2A > T, c.236G > A, c.259G > A, c.381–14G > A, c.413delA, c.473A > G, c.500delG, c.758 T > G, c.842–1G > A, c.911A > T, c.989G > A, c.1150G > C, c.1157A > G and c.1165C > T, were identified. Along with a literature review on 51 ACAD8 variants in 81 IBDD patients, we found that the most common variant was c.286G > A (27.2%), which has been observed solely in the Chinese population to date, followed by c.1000C > T (8.6%), c.1176G > T (3.7%) and c.455 T > C (3.1%). Conclusion The concentration of C4-acylcarnitine in NBS plus subsequent genetic testing is necessary for IBDD diagnosis. Both the genotypes and ACAD8 variants in IBDD are highly heterogeneous, and no significant correlations between genotype and phenotype are present here in patients with IBDD. Our IBDD cohort with detaied clinical characteristics, genotypes and long-term prognosis will be helpful for the diagnosis and management of patients with IBDD in the future.

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Section: Discussionmentioning

confidence: 43%

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8

Feng

Yang

Zhu

et al. 2021

Orphanet J Rare Dis

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“…Butyl carnitine is also associated with several other related metabolic disorders, as mentioned above including EE, GA2, and FIGLU, which exhibit low testing specificity and sensitivity (28,29). The use of acylcarnitine ratios, such as C4/C2, improves sensitivity, but routine screening methods do not provide further distinguishment, and the differential rate for C4associated disorders remains poor (24). This poor differentiation necessitates further diagnostic detection, which may result in an unbalanced cost-benefit ratio for NBS and might impose an unnecessary emotional burden on the families of unaffected neonates (24).…”

Section: Discussionmentioning

confidence: 99%

“…The use of acylcarnitine ratios, such as C4/C2, improves sensitivity, but routine screening methods do not provide further distinguishment, and the differential rate for C4associated disorders remains poor (24). This poor differentiation necessitates further diagnostic detection, which may result in an unbalanced cost-benefit ratio for NBS and might impose an unnecessary emotional burden on the families of unaffected neonates (24). Based on the current understanding, the initial screening results in this retrospective study suggest that most recalled cases screened by MS/MS do not need resampling after a second-tier test, which emphasizes the importance of optimizing analyses with second-tier tests to determine which individuals are truly at risk for SCADD or IBDD clinical disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Fortunately, a second-tier test would also assist in the followup of positive cases, particularly as it may be performed within a rapid time frame and without sample recollection. This robust method determined EMA/IBG with a high differential rate and may also be applied to monitor patients under treatment (24).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, to contribute to current data on these conditions, we evaluated the clinical biochemical outcomes of infants who were identified by the NBS program as having SCADD or IBDD from 2015 to 2020 and compared them to the health status of an age-matched control group. We also performed phone interviews to collect statements from parents on their experiences with the NBS and the clinical diagnosis of their children with SCADD/IBDD (24).…”

Section: Introductionmentioning

confidence: 99%

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Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population

Zhou

Cai

Li³

et al. 2021

Front. Pediatr.

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Background: Although newborn screening (NBS) for metabolic defects using the marker butyl carnitine (C4) combined with the C4-to-acetylcarnitine ratio is adequate, the incorporation of novel parameters may improve differential testing for these disorders without compromising sensitivity.Methods: Analytical and clinical performance was evaluated by MS/MS using 237 initially positive neonatal samples between March 2019 and March 2020 at the Newborn Screening Center of Xuzhou Maternity and Child Health Care Hospital. Additionally, second-tier testing by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with the quantification of ethylmalonate (EMA) or isobutyryl-glycine (IBG) in dried blood spots (DBSs) was performed to reduce the false-positive rate.Results: We reviewed initial MS/MS data for DBSs from 469,730 neonates, and a second-tier test was performed using 237 samples that exceeded the C4 concentration cutoff value. Eleven variants of the ACADS gene were identified, with c.1031A>G (p.E344G) being the most common. Fifteen ACAD8 mutations were identified in seven patients, and Swiss modeling and amino acid conservation analyses were conducted for the novel variants. Based on a retrospective analysis of EMA and IBG, the application of second-tier tests before the release of neonatal screening results reduced referrals by over 91.89% and improved the positive predictive value (PPV) for short-chain acyl-CoA dehydrogenase deficiency/isobutyryl-CoA dehydrogenase deficiency (SCADD/IBDD) screening.Conclusion: A screening algorithm including EMA/IBG improves target differential testing for NBS and may eliminate unnecessary referrals while maintaining 100% sensitivity. Second-tier screening using UPLC-MS/MS as a rapid and convenient supplemental DNA sequencing method may be beneficial for differential detection.

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Isobutyryl‐CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

Eleftheriadou

Herik

Stuurman

et al. 2021

Molec Gen & Gen Med

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Background Isobutyryl‐CoA dehydrogenase (IBD) is a mitochondrial enzyme catalysing the third step in the degradation of the essential branched‐chain amino acid valine and is encoded by ACAD8. ACAD8 mutations lead to isobutyryl‐CoA dehydrogenase deficiency (IBDD), which is identified by increased C4‐acylcarnitine levels. Affected individuals are either asymptomatic or display a variety of symptoms during infancy, including speech delay, cognitive impairment, failure to thrive, hypotonia, and emesis. Methods Here, we review all previously published IBDD patients and describe a girl diagnosed with IBDD who was presenting with autism as the main disease feature. Results To assess whether a phenotype‐genotype correlation exists that could explain the development or absence of clinical symptoms in IBDD, we compared CADD scores, in silico mutation predictions, LoF tolerance scores and C4‐acylcarnitine levels between symptomatic and asymptomatic individuals. Statistical analysis of these parameters did not establish significant differences amongst both groups. Conclusion As in our proband, trio whole exome sequencing did not establish an alternative secondary genetic diagnosis for autism, and reported long‐term follow‐up of IBDD patients is limited, it is possible that autism spectrum disorders could be one of the disease‐associated features. Further long‐term follow‐up is suggested in order to delineate the full clinical spectrum associated with IBDD.

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Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia

Cited by 17 publications

References 21 publications

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8

Phenotype, genotype and long-term prognosis of 40 Chinese patients with isobutyryl-CoA dehydrogenase deficiency and a review of variant spectra in ACAD8

Quantification of Differential Metabolites in Dried Blood Spots Using Second-Tier Testing for SCADD/IBDD Disorders Based on Large-Scale Newborn Screening in a Chinese Population

Isobutyryl‐CoA dehydrogenase deficiency associated with autism in a girl without an alternative genetic diagnosis by trio whole exome sequencing: A case report

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