3-甲基巴豆酰辅酶A羧化酶缺乏症6例患儿的临床特征及遗传学分析

Clinical and genetic features of children with 3-methylcrotonyl-coenzyme A carboxylase deficiency: an analysis of six cases

摘要:

目的 探讨3-甲基巴豆酰辅酶A羧化酶缺乏症（3-methylcrotonyl-coenzyme A carboxylase deficiency, MCCD）患儿的临床及遗传学特征。方法 回顾性分析2018年1月—2023年10月就诊于郑州大学附属儿童医院的6例MCCD患儿的临床表现及基因检测结果。结果 6例MCCD患儿中，男性4例，女性2例，平均就诊年龄为7 d，平均确诊年龄为45 d。1例小便气味异常，5例无临床症状。6例患儿血3-羟基异戊酰肉碱、尿3-羟基异戊酸、3-甲基巴豆酰甘氨酸均增高，5例伴游离肉碱降低。共检出MCCC1基因变异6个：c.1630del(p.R544Dfs*2)、c.269A>G(p.D90G)、c.1609T>A(p.F537I)、c.639+2T>A、c.761+1G>T、c.1331G>A(p.R444H)，以及MCCC2基因变异3个：c.838G>T(p.D280Y)、c.592C>T(p.Q198*, 366)、c.1342G>A(p.G448A)，其中MCCC1基因c.269A>G(p.D90G)、c.1609T>A(p.F537I)未见文献报道。1例为母源性MCCD，患儿携带来自母亲的一个杂合变异。5例伴游离肉碱降低患儿予补充左卡尼汀，末次随访时游离肉碱均恢复至正常水平。结论 MCCC1基因c.269A>G(p.D90G)、c.1609T>A(p.F537I)为新发现的变异，丰富了MCCC1基因变异谱。血氨基酸及酰基肉碱谱和尿有机酸谱联合基因检测有助于MCCD早期诊断和治疗，并为遗传咨询提供参考。

Abstract:

Objective To investigate the clinical and genetic features of children with 3-methylcrotonyl-coenzyme A carboxylase deficiency (MCCD).Methods A retrospective analysis was conducted on the clinical manifestations and genetic testing results of six children with MCCD who attended Children's Hospital Affiliated to Zhengzhou University from January 2018 to October 2023.Results Among the six children with MCCD, there were 4 boys and 2 girls, with a mean age of 7 days at the time of attending the hospital and 45 days at the time of confirmed diagnosis. Of all children, one had abnormal urine odor and five had no clinical symptoms. All six children had increases in blood 3-hydroxyisovaleryl carnitine and urinary 3-hydroxyisovaleric acid and 3-methylcrotonoylglycine, and five of them had a reduction in free carnitine. A total of six mutations were identified in the MCCC1 gene, i.e., c.1630del(p.R544Dfs*2), c.269A>G(p.D90G), c.1609T>A(p.F537I), c.639+2T>A, c.761+1G>T, and c.1331G>A(p.R444H), and three mutations were identified in the MCCC2 gene, i.e., c.838G>T(p.D280Y), c.592C>T(p.Q198*,366), and c.1342G>A(p.G448A). Among these mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I) had not been previously reported in the literature. There was one case of maternal MCCD, and the child carried a heterozygous mutation from her mother. Five children with a reduction in free carnitine were given supplementation of L-carnitine, and free carnitine was restored to the normal level at the last follow-up visit.Conclusions This study identifies two new mutations, c.269A>G(p.D90G) and c.1609T>A(p.F537I), thereby expanding the mutation spectrum of the MCCC1 gene. A combination of blood amino acid and acylcarnitine profiles, urine organic acid analysis, and genetic testing can facilitate early diagnosis and treatment of MCCD, and provide essential data for genetic counseling.