Division of Medical Genetics, Department of Medicine, Centre Hospitalier de l'Université de Montréal (CHUM) and Université de Montréal, Tour Viger, 900 rue St-Denis, R07-462, Montreal, Quebec H2X 0A9, Canada.
Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine and Université de Montréal, 3175 Côte-Sainte-Catherine, Montreal, Quebec H3T 1C5, Canada.
J Inherit Metab Dis. 2019 Jan;42(1):107-116. doi: 10.1002/jimd.12032.
The clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints.
Using a cross-sectional multicenter retrospective natural history study, we describe the course of all known CMAMMA individuals in the province of Quebec.
We identified 25 CMAMMA patients (6 months to 30 years old) with a favorable outcome regardless of treatment. All but one came to clinical attention through the Provincial Neonatal Urine Screening Program (screening on day 21 of life). Median methylmalonic acid (MMA) levels ranged from 107 to 857 mmol/mol creatinine in urine (<10) and from 8 to 42 μmol/L in plasma (<0.4); median urine malonic acid (MA) levels ranged from 9 to 280 mmol/mol creatinine (<5). MMA was consistently higher than MA. These findings are comparable to those previously reported in CMAMMA. Causal ACSF3 mutations were identified in all patients for whom genotyping was performed (76% of cases). The most common ACSF3 mutations in our cohort were c.1075G > A (p.E359K) and c.1672C > T (p.R558W), representing 38.2 and 20.6% of alleles in genotyped families, respectively; we also report several novel mutations.
Because our province still performs urine newborn screening, our patient cohort is the only one free of selection bias. Therefore, the favorable clinical course observed suggests that CMAMMA is probably a benign condition, although we cannot exclude the possibility that a small minority of patients may present symptoms attributable to CMAMMA, perhaps as a result of interactions with other genetic or environmental factors.
由于 ACSF3 缺乏导致的丙二酸和甲基丙二酸尿症（CMAMMA）的临床意义存在争议。在大多数出版物中，受影响的患者是在调查各种疾病时被发现的。
我们使用了一项横断面多中心回顾性自然史研究，描述了魁北克省所有已知的 CMAMMA 个体的病程。
我们发现了 25 名 CMAMMA 患者（6 个月至 30 岁），无论治疗与否，他们的预后都较好。除了一名患者外，所有人都是通过省级新生儿尿液筛查计划（在出生后第 21 天进行筛查）引起临床关注的。尿中甲基丙二酸（MMA）的中位数水平范围为 107 至 857mmol/mol 肌酐（<10），血浆中 MMA 的中位数水平范围为 8 至 42μmol/L（<0.4）；尿中丙二酸（MA）的中位数水平范围为 9 至 280mmol/mol 肌酐（<5）。MMA 始终高于 MA。这些发现与以前报道的 CMAMMA 结果相当。对所有进行基因分型的患者（76%的病例）都鉴定出了导致 ACSF3 突变的原因。我们的队列中最常见的 ACSF3 突变是 c.1075G>A（p.E359K）和 c.1672C>T（p.R558W），分别代表了基因分型家族中 38.2%和 20.6%的等位基因；我们还报告了几个新的突变。
由于我们省仍在进行新生儿尿液筛查，因此我们的患者队列是唯一没有选择偏差的队列。因此，观察到的有利临床病程表明，CMAMMA 可能是一种良性疾病，尽管我们不能排除一小部分患者可能会出现归因于 CMAMMA 的症状，这可能是由于与其他遗传或环境因素的相互作用所致。
