Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
-
Yiming Lin
and
Dongmei Chen
Abstract
Objectives
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS.
Methods
From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis.
Results
Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12).
Conclusions
These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.
Funding source: Natural Science Foundation of Fujian Province
Award Identifier / Grant number: 2020J01130
Funding source: Youth Research Project in the Health System of Fujian Province
Award Identifier / Grant number: 2020QNA083
Acknowledgments
We thank all the patients and their families for their participation. We would like to thank Editage (www.editage.cn) for English language editing.
-
Research funding: This work was funded by the Natural Science Foundation of Fujian Province (Grant No. 2020J01130 to Yiming Lin) and the Youth Research Project in the Health System of Fujian Province (Grant No. 2020QNA083 to Yiming Lin).
-
Author contributions: YM Lin designed the study, performed experimental work, and drafted and revised the manuscript; WF Zhang collected the clinical data and drafted and revised the manuscript; ZX Chen assisted with data collection and reviewed and revised the manuscript; CM Lin assisted with data collection; WH Lin collected the clinical data; QL Fu participated in manuscript preparation; WL Peng designed and guided the research study; DM Chen followed the patients, assisted with data collection, and reviewed and revised the manuscript. All authors contributed to the data analysis and revision and approval of the final manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
-
Competing interest: None declared.
-
Ethical approval: The study was approved by the Ethics committee of Quanzhou Maternity and Children’s Hospital. Written informed consent was obtained from the parents of all patients. This study complied with all the relevant national regulations and institutional policies and was performed in accordance the tenets of the Helsinki Declaration.
References
1. Yotsumoto, Y, Hasegawa, Y, Fukuda, S, Kobayashi, H, Endo, M, Fukao, T, et al.. Clinical and molecular investigations of Japanese cases of glutaric acidemia type 2. Mol Genet Metabol 2008;94:61–7. https://doi.org/10.1016/j.ymgme.2008.01.002.Search in Google Scholar PubMed
2. Goodman, SI, Binard, RJ, Woontner, MR, Frerman, FE. Glutaric acidemia type II: gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene. Mol Genet Metabol 2002;77:86–90. https://doi.org/10.1016/s1096-7192(02)00138-5.Search in Google Scholar PubMed
3. Olsen, RK, Andresen, BS, Christensen, E, Bross, P, Skovby, F, Gregersen, N. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat 2003;22:12–23. https://doi.org/10.1002/humu.10226.Search in Google Scholar PubMed
4. van Rijt, WJ, Ferdinandusse, S, Giannopoulos, P, Ruiter, JPN, de Boer, L, Bosch, AM, et al.. Prediction of disease severity in Multiple acyl-CoA dehydrogenase deficiency: a retrospective and laboratory cohort study. J Inherit Metab Dis 2019;42:878–89. https://doi.org/10.1002/jimd.12147.Search in Google Scholar PubMed
5. Grunert, SC. Clinical and genetical heterogeneity of late-onset multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Rare Dis 2014;9:117. https://doi.org/10.1186/s13023-014-0117-5.Search in Google Scholar PubMed PubMed Central
6. Olsen, RK, Olpin, SE, Andresen, BS, Miedzybrodzka, ZH, Pourfarzam, M, Merinero, B, et al.. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain 2007;130:2045–54. https://doi.org/10.1093/brain/awm135.Search in Google Scholar PubMed
7. Liang, WC, Lin, YF, Liu, TY, Chang, SC, Chen, BH, Nishino, I, et al.. Neurite growth could be impaired by ETFDH mutation but restored by mitochondrial cofactors. Muscle Nerve 2017;56:479–85. https://doi.org/10.1002/mus.25501.Search in Google Scholar PubMed
8. Goh, LL, Lee, Y, Tan, ES, Lim, JSC, Lim, CW, Dalan, R. Patient with Multiple acyl-CoA dehydrogenase deficiency disease and ETFDH mutations benefits from riboflavin therapy: a case report. BMC Med Genom 2018;11:37. https://doi.org/10.1186/s12920-018-0356-8.Search in Google Scholar PubMed PubMed Central
9. Van Rijt, WJ, Heiner-Fokkema, MR, du Marchie Sarvaas, GJ, Waterham, HR, Blokpoel, RG, van Spronsen, FJ, et al.. Favorable outcome after physiologic dose of sodium-D,L-3-hydroxybutyrate in severe MADD. Pediatrics 2014;134:e1224–8. https://doi.org/10.1542/peds.2013-4254.Search in Google Scholar PubMed
10. Lin, Y, Zheng, Q, Zheng, T, Zheng, Z, Lin, W, Fu, Q. Expanded newborn screening for inherited metabolic disorders and genetic characteristics in a southern Chinese population. Clin Chim Acta 2019;494:106–11. https://doi.org/10.1016/j.cca.2019.03.1622.Search in Google Scholar PubMed
11. Sahai, I, Garganta, CL, Bailey, J, James, P, Levy, HL, Martin, M, et al.. Newborn screening for glutaric aciduria-II: the New England experience. JIMD Rep 2014;13:1–14. https://doi.org/10.1007/8904_2013_262.Search in Google Scholar PubMed PubMed Central
12. Xi, J, Wen, B, Lin, J, Zhu, W, Luo, S, Zhao, C, et al.. Clinical features and ETFDH mutation spectrum in a cohort of 90 Chinese patients with late-onset Multiple acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis 2014;37:399–404. https://doi.org/10.1007/s10545-013-9671-6.Search in Google Scholar PubMed
13. Wang, ZQ, Chen, XJ, Murong, SX, Wang, N, Wu, ZY. Molecular analysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency (MADD) in southern China confirmed the most common ETFDH mutation and high carrier frequency of c.250G>A. J Mol Med (Berl) 2011;89:569–76. https://doi.org/10.1007/s00109-011-0725-7.Search in Google Scholar PubMed
14. Wen, B, Dai, T, Li, W, Zhao, Y, Liu, S, Zhang, C, et al.. Riboflavin-responsive lipid-storage myopathy caused by ETFDH gene mutations. J Neurol Neurosurg Psychiatry 2010;81:231–6. https://doi.org/10.1136/jnnp.2009.176404.Search in Google Scholar PubMed
15. Er, TK, Liang, WC, Chang, JG, Jong, YJ. High resolution melting analysis facilitates mutation screening of ETFDH gene: applications in riboflavin-responsive Multiple acyl-CoA dehydrogenase deficiency. Clin Chim Acta 2010;411:690–9. https://doi.org/10.1016/j.cca.2010.01.033.Search in Google Scholar PubMed
16. Fan, X, Xie, B, Zou, J, Luo, J, Qin, Z, D’Gama, AM, et al.. Novel ETFDH mutations in four cases of riboflavin responsive Multiple acyl-CoA dehydrogenase deficiency. Mol Gen Metab Rep 2018;16:15–19. https://doi.org/10.1016/j.ymgmr.2018.05.007.Search in Google Scholar PubMed PubMed Central
17. Zhu, M, Zhu, X, Qi, X, Weijiang, D, Yu, Y, Wan, H, et al.. Riboflavin-responsive multiple Acyl-CoA dehydrogenation deficiency in 13 cases, and a literature review in mainland Chinese patients. J Hum Genet 2014;59:256–61. https://doi.org/10.1038/jhg.2014.10.Search in Google Scholar PubMed
18. Lin, Y, Gao, H, Lin, C, Chen, Y, Zhou, S, Lin, W, et al.. Biochemical, clinical, and genetic characteristics of short/Branched chain acyl-CoA dehydrogenase deficiency in Chinese patients by newborn screening. Front Genet 2019;10:802. https://doi.org/10.3389/fgene.2019.00802.Search in Google Scholar PubMed PubMed Central
19. Fu, HX, Liu, XY, Wang, ZQ, Jin, M, Wang, DN, He, JJ, et al.. Significant clinical heterogeneity with similar ETFDH genotype in three Chinese patients with late-onset Multiple acyl-CoA dehydrogenase deficiency. Neurol Sci 2016;37:1099–105. https://doi.org/10.1007/s10072-016-2549-2.Search in Google Scholar PubMed
20. Law, LK, Tang, NL, Hui, J, Fung, SL, Ruiter, J, Wanders, RJ, et al.. Novel mutations in ETFDH gene in Chinese patients with riboflavin-responsive Multiple acyl-CoA dehydrogenase deficiency. Clin Chim Acta 2009;404:95–9. https://doi.org/10.1016/j.cca.2009.02.015.Search in Google Scholar PubMed
Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/jpem-2020-0694).
© 2021 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
Articles in the same Issue
- Frontmatter
- Editorial
- Covid19 pandemic and pediatric endocrinology and metabolism—Are we through with it?
- Original Articles
- Invisible burden of COVID-19: enzyme replacement therapy disruptions
- Anthropometric, biochemical and hormonal profiles of the partially admixed pygmoid group in Rampasasa (Flores, Indonesia)
- Etiologies, profile patterns and characteristics of children with short stature in Jordan
- Sexual maturity assessment in Indian children—a study from western India
- Bone density and bone health alteration in boys with Duchenne Muscular Dystrophy: a prospective observational study
- Sensory, voluntary, and motor postural control in children and adolescents with mucopolysaccharidosis
- Prevalence and MRI findings of incidentally detected pituitary non-enhancing lesion on brain MRI in children
- Oral glucose tolerance response curve predicts disposition index but not other cardiometabolic risk factors in healthy adolescents
- Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity
- Liraglutide combined with intense lifestyle modification in the management of obesity in adolescents
- Exploring the inter-subject variability in the relationship between glucose monitoring metrics and glycated hemoglobin for pediatric patients with type 1 diabetes
- Screening for asymptomatic diabetes and metabolic comorbidities in pediatric patients during therapy for acute lymphoblastic leukemia
- Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry
- Experience with the targeted next-generation sequencing in the diagnosis of hereditary hypophosphatemic rickets
- Newborn screening and molecular features of patients with multiple acyl-CoA dehydrogenase deficiency in Quanzhou, China
- Case Reports
- Dual diagnosis of Ochoa syndrome and Niemann-Pick disease type B in a consanguineous family
- Severe hypercalcemia in an infant with unbalanced translocation of chromosomes 2 and 8: a possible contribution of 2p duplication
- Epileptic phenotype in late-onset hyperinsulinemic hypoglycemia successfully treated by diazoxide
- Precocious sexual development in a male toddler caused by unrecognized transdermal exposure to testosterone: case report and review of the literature
