An analysis of clinical characteristics and gene mutation in two patients with medium-and short-chain acyl-CoA dehydrogenase deficiency

TAN Jian-Qiang; CHEN Da-Yu; LI Zhe-Tao; HUANG Ji-Wei; YAN Ti-Zhen; CAI Ren

doi:10.7499/j.issn.1008-8830.2016.10.021

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Chinese Journal of Contemporary Pediatrics ›› 2016, Vol. 18 ›› Issue (10) : 1019-1025. DOI: 10.7499/j.issn.1008-8830.2016.10.021

CLINICAL RESEARCH

An analysis of clinical characteristics and gene mutation in two patients with medium-and short-chain acyl-CoA dehydrogenase deficiency

TAN Jian-Qiang, CHEN Da-Yu, LI Zhe-Tao, HUANG Ji-Wei, YAN Ti-Zhen, CAI Ren

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Abstract

Medium-and short-chain acyl-CoA dehydrogenase deficiency is a disorder of fatty acid β-oxidation. Gene mutation prevents medium-and short-chain fatty acids from entry into mitochondria for oxidation, which leads to multiple organ dysfunction. In this study, serum acylcarnitines and the organic acid profile in urea were analyzed in two children whose clinical symptoms were hypoglycemia and metabolic acidosis. Moreover, gene mutations in the two children and their parents were evaluated. One of the patients was a 3-day-old male who was admitted to the hospital due to neonatal asphyxia, sucking weakness, and sleepiness. The serum acylcarnitine profile showed increases in mediumchain acylcarnitines (C6-C10), particularly in C8, which showed a concentration of 3.52 μmol/L (reference value: 0.02-0.2 μmol/L). The analysis of organic acids in urea gave a normal result. Sanger sequencing revealed a reported c.580A>G (p.Asn194Asp) homozygous mutation at exon 7 of the ACADM gene. The other patient was a 3-month-old female who was admitted to the hospital due to cough and recurrent fever for around 10 days. The serum acylcarnitine profile showed an increase in serum C4 level, which was 1.66 μmol/L (reference value: 0.06-0.6 μmol/L). The analysis of organic acids in urea showed an increase in the level of ethyl malonic acid, which was 55.9 (reference value: 0-6.2). Sanger sequencing revealed a reported c.625G > A (p.Gly209Ser) homozygous mutation in the ACADS gene. This study indicates that screening tests for genetic metabolic diseases are recommended for children who have unexplained metabolic acidosis and hypoglycemia. Genetic analyses of the ACADM and ACADS genes are helpful for the diagnosis of medium-and shortchain acyl-CoA dehydrogenase deficiency.

Key words

Fatty acid β-oxidation disorder / Medium-chain acyl-CoA dehydrogenase / Short-chain acyl-CoA dehydrogenase / Child

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TAN Jian-Qiang, CHEN Da-Yu, LI Zhe-Tao, HUANG Ji-Wei, YAN Ti-Zhen, CAI Ren. An analysis of clinical characteristics and gene mutation in two patients with medium-and short-chain acyl-CoA dehydrogenase deficiency[J]. Chinese Journal of Contemporary Pediatrics. 2016, 18(10): 1019-1025 https://doi.org/10.7499/j.issn.1008-8830.2016.10.021

References

[1] Rhead WJ, Amendt BA, Fritchman KS, et al. Dicarboxylic aciduria: deficient [1-14C] octanoate oxidation and mediumchain acyl-CoA dehydrogenase in fibroblasts[J]. Science, 1983, 221(4605): 73-75.
[2] Amendt BA, Greene C, Sweetman L, et al. Short-chain acylcoenzyme A dehydrogenase deficiency. Clinical and biochemical studies in two patients[J]. J Clin Invest, 1987, 79(5): 1303-1309.
[3] Nichols MJ, Saavedra-Matiz CA, Pass KA, et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A>G mutation in the New York state population[J]. Am J Med Genet A, 2008, 146A(5): 610-619.
[4] Corydon MJ, Gregersen N, Lehnert W, et al. Ethylmalonic aciduria is associated with an amino acid variant of short chain acyl-coenzyme A dehydrogenase[J]. Pediatr Res, 1996, 39(6): 1059-1066.
[5] Finocchiaro G, Ito M, Tanaka K. Purification and properties of short-chain acyl-CoA, medium-chain acyl-CoA, and isovaleryl-CoA dehydrogenases from human liver[J]. Adv Neurol, 1988, 48: 221-230.
[6] Pedersen CB, Kølvraa S, Kølvraa A, et al. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level[J]. Hum Genet, 2008, 124(1): 43-56.
[7] van Maldegem BT, Duran M, Wanders RJ, et al. Clinical, biochemical, and genetic heterogeneity in short-chain acylcoenzyme A dehydrogenase deficiency[J]. JAMA, 2006, 296(8): 943-952.
[8] Khalid JM, Oerton J, Besley G, et al. Relationship of octanoylcarnitine concentrations to age at sampling in unaffected newborns screened for medium-chain acyl-CoA dehydrogenase deficiency[J]. Clin Chem, 2010, 56(6): 1015-1021.
[9] Nichols MJ, Saavedra-Matiz CA, Pass KA, et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985A>G mutation in the New York state population[J]. Am J Med Genet A, 2008, 146A(5): 610-619.
[10] Gramer G, Haege G, Fang-Hoffmann J, et al. Medium-chain acyl-CoA dehydrogenase deficiency: evaluation of genotypephenotype correlation in patients detected by newborn screening[J]. JIMD Rep, 2015, 23: 101-112.
[11] Karaceper MD, Chakraborty P, Coyle D, et al. The health system impact of false positive newborn screening results for mediumchain acyl-CoA dehydrogenase deficiency: a cohort study[J]. Orphanet J Rare Dis, 2016, 11: 12.
[12] Andresen BS, Lund AM, Hougaard DM, et al. MCAD deficiency in Denmark[J]. Mol Genet Metab, 2012, 106(2): 175-188.
[13] Houten SM, Wanders RJ. A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation[J]. J Inherit Metab Dis, 2010, 33(5): 469-477.
[14] Grünert SC, Wehrle A, Villavicencio-Lorini P, et al. Mediumchain acyl-CoA dehydrogenase deficiency associated with a novel splice mutation in the ACADM gene missed by newborn screening[J]. BMC Med Genet, 2015, 16: 56.
[15] 顾学范. 临床遗传代谢病[M]. 北京: 人民卫生出版社, 2015: 146-149.
[16] 张惠文, 顾学范. 中链酰基辅酶A 脱氢酶缺乏症研究进展[J]. 国外医学(儿科学分册), 2003, 30(4): 218-220.
[17] 姜涛, 欧阳文献, 谭艳芳, 等. 中链酰基辅酶A 脱氢酶缺乏症1 例肝脏病理分析及基因检测[J]. 临床儿科杂志, 2016, 34(4): 249-252.
[18] 李甫棒, 黄晓磊, 陈洁, 等. 以黄疸为首发症状中链酰基辅酶A 脱氢酶缺乏症1 例报告[J]. 临床儿科杂志, 2010, 28(9): 880-881.
[19] 王立娜, 任常军, 李云, 等. 中链酰基辅酶A 脱氢酶缺乏症合并先天性心脏病1 例[J]. 河北医药, 2011, 33(22): 3520.
[20] Derks TG, Touw CM, Ribas GS, et al. Experimental evidence for protein oxidative damage and altered antioxidant defense in patients with medium-chain acyl-CoA dehydrogenase deficiency[J]. J Inherit Metab Dis, 2014, 37(5): 783-789.
[21] Gregersen N, Andresen BS, Pedersen CB, et al. Mitochondrial fatty acid oxidation defects-remaining challenges[J]. J Inherit Metab Dis, 2008, 31(5): 643-657.
[22] Jethva R, Bennett MJ, Vockley J. Short-chain acyl-coenzyme A dehydrogenase deficiency[J]. Mol Genet Metab, 2008, 95(4): 195-200.
[23] Pedersen CB, Kølvraa S, Kølvraa A, et al. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level[J]. Hum Genet, 2008, 124(1): 43-56.
[24] Van Calcar SC, Baker MW, Williams P, et al. Prevalence and mutation analysis of short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) detected on newborn screening in Wisconsin[J]. Mol Genet Metab, 2013, 110(1-2): 111-115.
[25] Bok LA, Vreken P, Wijburg FA, et al. Short-chain acyl-CoA dehydrogenase deficiency: studies in a large family adding to the complexity of the disorder[J]. Pediatrics, 2003, 112(5): 1152-1155.
[26] Jethva R, Ficicioglu C. Clinical outcomes of infants with shortchain acyl-coenzyme A dehydrogenase deficiency (SCADD) detected by newborn screening[J]. Mol Genet Metab, 2008, 95(4): 241-242.
[27] van Maldegem BT, Kloosterman SF, Janssen WJ, et al. High prevalence of short-chain acyl-CoA dehydrogenase deficiency in the Netherlands, but no association with epilepsy of unknown origin in childhood[J]. Neuropediatrics, 2011, 42(1): 13-17.