Chen Chongfen, Zhang Yaodong, Ge Lili, Liu Lei, Zhang Xiaoman, Mei Shiyue, Luo Shuying
Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital); Henan Provincial Key Laboratory for Genetic and Metabolic Disease in Children, Zhengzhou, Henan 450018, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Sep 10;40(9):1086-1092. doi: 10.3760/cma.j.cn511374-20220621-00417.
To carry out Sanger sequencing for MMACHC gene variants among 65 Chinese pedigrees affected with combined methylmalonic aciduria and homocysteinemia, and summarize their genetic and clinical characteristics and prognosis.
Clinical characteristics of the 65 children identified with Methylmalonic acidemia and homocysteinemia at the Children's Hospital Affiliated to Zhengzhou University (Zhengzhou Children's Hospital) from April 2017 to April 2022 were selected as the study subjects. Potential variants of the MMACHC gene were detected by direct sequencing of the PCR products.
The median age of the 65 children was 3 months (14 days to 17 years old). These included 28 cases (43.08%) from neonatal screening, 11 cases (16.92%) with a history of jaundice, and 9 cases (13.85%) with various degrees of anemia. The main clinical symptoms included development delay, slow growth, epilepsy, hydrocephalus, lethargy, feeding difficulty, regression or decline in motor ability, recurrent respiratory infections, anemia, jaundice, respiratory and heart failures, hydrocephalus, limb weakness, and hypertension. Blood and urine tandem mass spectrometry screening has revealed increase of methylmalonic acid, propionyl carnitine, propionyl carnitine/acetylcarnitine ratio, and propionyl carnitine/free carnitine ratio to various extents, and blood homocysteine was increased in all patients. The detection rate of genetic variants was 98.46% (128/130), and in total 22 types of MMACHC gene variants were detected. The most common ones have included c.609G>A (W203X) (58/128), c.658-660del (K220del) (19/128), and c.80A>G (Q27A) (16/128). Two novel variants have been identified, namely c.565C>T (p.R189C) and c.624_ 625delTG (p.A208Afs), which were respectively predicted as likely pathogenic (PM2_Supporting+PM3+PP2+PP3) and pathogenic (PVS1+PM2_Supporting+PM3+PP2) based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Exon 4 had the highest frequency for the detection.
Identification of MMACHC gene variants has confirmed the diagnosis in the children, among which the c.609G>A variant has the highest frequency. Discovery of the new variants has enriched the mutational spectrum of the MMACHC gene.
对65个患有甲基丙二酸血症合并高同型半胱氨酸血症的中国家系进行MMACHC基因变异的桑格测序，总结其遗传、临床特征及预后情况。
选取2017年4月至2022年4月在郑州大学附属儿童医院（郑州市儿童医院）确诊为甲基丙二酸血症和高同型半胱氨酸血症的65例患儿的临床特征作为研究对象。通过对PCR产物直接测序检测MMACHC基因的潜在变异。
65例患儿的中位年龄为3个月（14天至17岁）。其中，新生儿筛查发现28例（43.08%），有黄疸病史的11例（16.92%），有不同程度贫血的9例（13.85%）。主要临床症状包括发育迟缓、生长缓慢、癫痫、脑积水、嗜睡、喂养困难、运动能力倒退或下降、反复呼吸道感染、贫血、黄疸、呼吸和心力衰竭、脑积水、肢体无力和高血压。血、尿串联质谱筛查显示甲基丙二酸、丙酰肉碱、丙酰肉碱/乙酰肉碱比值及丙酰肉碱/游离肉碱比值不同程度升高，所有患者血同型半胱氨酸均升高。基因变异检出率为98.46%（128/130），共检测到22种MMACHC基因变异。最常见的变异包括c.609G>A（W203X）（58/128）、c.658 - 660del（K220del）（19/128）和c.80A>G（Q27A）（16/128）。鉴定出两种新变异，即c.565C>T（p.R189C）和c.624_625delTG（p.A208Afs），根据美国医学遗传学与基因组学学会（ACMG）的指南，分别被预测为可能致病（PM2_Supporting + PM3 + PP2 + PP3）和致病（PVS1 + PM2_Supporting + PM3 + PP2）。外显子4的检测频率最高。
MMACHC基因变异的鉴定有助于确诊患儿，其中c.609G>A变异频率最高。新变异的发现丰富了MMACHC基因的突变谱。
