Abstract
Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.
Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-assay control) identified 12 true-positive cases. These cases were given nutritional therapy and all of them are asymptomatic, except one. Seventeen individuals were considered disease carriers based on the mild increase in plasma C14:1, in conjunction with the presence of only one mutation and/or intermediate residual activity (18–57%). In addition, seven cases were classified as false positives, with normal biochemical parameters and no mutations in the exonic region of ACADVL. All these carriers and the false positive cases remained asymptomatic. The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment.
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Acknowledgments
The authors would like to thank the families involved in this study for giving their consent. This work was funded by a grant from the Fundación Isabel Gemio. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.
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Communicated by: Piero Rinaldo, MD, PhD
Appendices
A Concise One Sentence Take-Home Message
The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment, as well as close clinical and biochemical monitoring.
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None of the authors have any conflict of interests to declare.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 (5). This project was approved by the Universidad Autónoma Madrid Ethics Committee (reference number CEI 74-1349).
Details of the Contributions of Individuals Authors
All authors approved the final manuscript as submitted.
BM: conception and design, drafting, and coordination of the manuscript.
PA: enzyme activity determinations, statistical analysis, and writing the first draft.
EMH: treating metabolic specialist of patients, drafting of the manuscript.
AM: treating metabolic specialist of patients.
MTGS: treating metabolic specialist of patients.
PQF: treating metabolic specialist of patients.
CPG: treating metabolic specialist of patients.
ED: analysis and interpretation of newborn screening data from Madrid.
RY: analysis and interpretation of newborn screening data from Western Andalucia.
JME: analysis and interpretation of newborn screening data from Murcia.
ABQ: treating metabolic specialist of patients.
JBA: treating metabolic specialist of patients.
MLFR: analysis and interpretation of newborn screening data from Madrid.
BB: analysis of newborn screening data from Madrid.
IFL: acylcarnitines and organic acids analysis.
FL: molecular genetic analysis.
MU: critical review of the manuscript for important intellectual content.
PRS: biochemical and enzyme data analysis.
BP: molecular genetic data interpretation, drafting of the manuscript.
CPC: biochemical data interpretation, drafting of the manuscript.
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Merinero, B. et al. (2017). Four Years’ Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 39. JIMD Reports, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2017_40
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DOI: https://doi.org/10.1007/8904_2017_40
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