Objective: To analyze regional differences in MMACHC gene variations among patients with cblC-type methylmalonic acidemia (MMA) in China and to explore the relationship between these variations and neonatal screening, biochemical markers and prognosis. Methods: Retrospective case summary. Clinical and laboratory data, including general condition, biochemical markers and genetic analysis, were collected from 1 859 cblC MMA patients from 2005 to 2023. Patients were divided into 7 groups according to their regions: north China, northeast China, east China, central China, south China, southwest China and northwest China. They were also classified into neonatal screening and non-neonatal screening groups. Mann-Whitney U and Kruskal-Wallis tests were used to compare biochemical marker levels. In contrast, the Chi-square test was applied to compare MMACHC gene variant frequencies, neonatal screening proportion, onset age and prognosis between groups. Results: Among 1 859 cases of cblC MMA, 1 019 were male and 840 were female, with a consultation age of 1.0 (0.1, 5.0) month. A total of 1 787 cases carried compound heterozygous or homozygous variants and only 1 variant site was identified in 72 cases. The 10 most frequent variants were c.609G>A (1 238 cases), c.658_660delAAG (343 cases), c.80A>G (284 cases), c.482G>A (239 cases), c.567dupT (191 cases), c.656_658delAGA (131 cases), c.217C>T (109 cases), c.394C>T (105 cases), c.445_446delTG (51 cases) and c.1A>G (50 cases). The frequency of the c.609G>A was the lowest in northwest China (28.8% (44/154), χ²=-18.42, P<0.05). The frequency of the c.567dupT was the most common in southwest China (25.0% (20/80), χ²=71.70, P<0.001) and c.656_658delAGA had the highest frequency in northeast China (9.3% (19/205), χ²=32.08, P<0.001). Non-missense variants (91.2% (62/68), 88.5% (46/52)) and early-onset patients (90.0% (36/40), 94.4% (34/36)) were both more prevalent in southwest and south China (χ²=14.95, 31.69, both P<0.05). The proportion of neonatal screening was the lowest in south China (22.2% (8/36), χ²=98.48, P<0.05), where the mortality rate was the highest (19.1% (4/21), χ²=38.98, P<0.001). East China exhibited the highest frequency of missense variants (21.5% (339/1 579)), the highest proportion of patients identified through neonatal screening (54.5% (465/853)), and a more significant proportion of patients with good prognosis (36.6% (227/621), χ²=14.57, 93.49, 38.98, all P<0.05). In addition, the c.482G>A variant was more frequent in patients diagnosed by neonatal screening compared to those diagnosed by other methods (8.3% (132/1 586) vs. 5.9% (122/2 060), χ²=7.97, P<0.05). Conclusions: The frequency of MMACHC gene variation varies across different regions. The c.609G>A was least frequent in northwest China, c.567dupT was most common in southwest China, and c.656_658delAGA was most prevalent in northeast China. South China had the lowest neonatal screening rate and the highest mortality. At the same time, east China exhibited the highest frequency of missense variants, the highest proportion of patients identified through neonatal screening and the best prognosis. The c.482G>A variant was more frequent in patients diagnosed by neonatal screening compared to those diagnosed by other methods.
目的： 了解中国各地区cblC型甲基丙二酸血症（MMA）患儿MMACHC基因变异特点，探究MMACHC基因变异与新生儿筛查（简称为新筛）、生化标志物水平及预后的关系。 方法： 回顾性病例总结。收集2005至2023年就诊于上海交通大学医学院附属新华医院的1 859例cblC型MMA患儿的一般情况、实验室检查、基因检测等临床资料，根据患儿籍贯分为华北、东北、华东、华中、华南、西南、西北7组，根据新筛情况将患儿分为新筛组和非新筛组，采用Mann-Whitney U检验及Kruskal-Wallis检验对生化标志物水平进行组间比较，采用χ²检验对MMACHC基因变异频率、新筛占比、发病年龄及预后情况进行组间比较。 结果： 1 859例cblC型MMA患儿中男1 019例、女840例，就诊时年龄1.0（0.1，5.0）月龄。其中1 787例为复合杂合或纯合变异，另72例患儿中仅发现1个变异位点，前10位变异位点分别为c.609G>A（1 238例）、c.658_660delAAG（343例）、c.80A>G（284例）、c.482G>A（239例）、c.567dupT（191例）、c.656_658delAGA（131例）、c.217C>T（109例）、c.394C>T（105例）、c.445_446delTG（51例）、c.1A>G（50例）。c.609G>A在西北地区的变异频率最低［28.8%（44/154），χ²=-18.42，P<0.05］。c.567dupT在西南地区的变异频率最高［25.0%（20/80），χ²=71.70，P<0.001］。c.656_658delAGA在东北地区的变异频率最高［9.3%（19/205），χ²=32.08，P<0.001］。西南和华南地区非错义变异频率［91.2%（62/68）、88.5%（46/52）］和早发型患儿占比［90.0%（36/40）、94.4%（34/36）］均更高（χ²=14.57、31.69，均P<0.05）。华南地区新筛患儿占比最低［22.2%（8/36），χ²=98.48，P<0.05］，患儿病死率最高［19.1%（4/21），χ²=38.98，P<0.001］。华东地区错义变异频率［21.5%（339/1 579）］、新筛患儿［54.5%（465/853）］和预后良好［36.6%（227/621）］占比均最高（χ²=14.57、93.49、38.98，均P<0.05）。新筛组患儿c.482G>A变异频率高于非新筛组［8.3%（132/1 586）比5.9%（122/2 060），χ²=7.97，P<0.05］。 结论： MMACHC基因变异位点在不同地域的变异频率不同，c.609G>A在西北地区的变异频率最低，c.567dupT在西南地区的变异频率最高，c.656_658delAGA在东北地区的变异频率最高。华南地区非错义变异频率较高，新筛患儿占比最低，患儿病死率最高，华东地区错义变异、新筛患儿和预后良好占比均最高，c.482G>A在新筛组患儿中的变异频率高于非新筛组患儿。.