Journal Article

Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort

Xu, Peng, Shuai, Rui-Xue, Gong, Zhu-Wen, Qiu, Wen-Juan, Zou, Hui, Chen, Xi-Gui, Han, Lian-Shu, Zhang, Hui-Wen, Chen, Yong-Xing, Wu, Sheng-Nan, E, Hui-Shu, Zhang, Kai-Chuang, Yang, Chi-Ju, Yu, Yue, Hu, Hai-Li, Liang, Li-Li, Zhan, Xia, Ling, Shi-Ying, Feng, Ji-Zhen, Gu, Xue-Fan, Wei, Hai-Yan, Ji, Wen-Jun, Lu, De-Yun, Niu, Ting-Ting

2024

Overview

Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene ( MMACHC ) c.482G > A mutation in 195 Chinese cases with CblC disease. Methods We carried out a national, retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G > A variant either in a homozygous or compound heterozygous state. The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G > A mutation. Clinical features, including disease onset, symptoms, biochemical metabolites, gene mutation, and follow-up outcomes were reviewed and analyzed in detail. The median follow-up period spanned 3 years and 8 months, with a range of 1 year and 2 months to 12 years and 10 months. Results Among 195 patients carrying the c.482G > A variant, 125 (64.1%) cases were diagnosed by newborn screening (NBS), 60 (30.8%) cases were detected due to disease onset, and 10 (5.1%) cases were identified from sibling diagnoses. One hundred and seventeen (93.6%) individuals who were diagnosed by NBS, and nine patients who came from sibling diagnoses remained asymptomatic in this study. From 69 symptomatic patients of the c.482G > A group, more patients presented with later onset, and the top six common clinical symptoms at disease onset were developmental delay (59.4%), lower limb weakness and poor exercise tolerance (50.7%), cognitive decline (37.7%), gait instability and abnormal posture (36.2%), seizures (26.1%), and psychiatric and behavioral disturbances (24.6%). In the 159 symptomatic patients lacking c.482G > A variants, the most frequently observed clinical manifestations at disease onset included developmental delay (81.8%), lethargy and feeding difficulty (62.9%), lower limb weakness and poor exercise tolerance (54.7%), prolonged neonatal jaundice (51.6%), vomiting (47.2%), and seizures (32.7%). Before treatment, the levels of blood propionylcarnitine, propionylcarnitine/acetylcarnitine ratio, and homocysteine in the c.482G > A group were significantly lower ( P  < 0.05) than those in the non-c.482G > A group, while the concentration of urinary methylmalonic acid was slightly lower ( P  > 0.05). The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels ( P  < 0.05). In patients carrying the c.482G > A variant compared with the non-c.428G > A group, there were markedly lower rates of mortality (0.5% vs. 2.0%) and developmental delay (20.5% vs. 65.5%). When compared with individuals diagnosed due to disease onset, those identified through NBS in either group exhibited a reduced proportion of disease onset (6.7% vs. 100% in the c.482G > A group, 54.4% vs. 100% in the non-c.482G > A group), lower mortality (0.0% vs. 1.7% in the c.482G > A group, 0.0% vs. 3.6% in the non-c.482G > A group), and had a higher percentage of patients exhibiting normal psychomotor and language development (99.3% vs. 33.3% in the c.482G > A group, 58.9% vs. 10.9% in the non-c.482G > A group). Conclusions The c.482G > A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease. Patients with this mutation tend to have a relatively better response to hydroxocobalamin, better metabolic control, and more favorable neurological outcomes. NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis, resulting in favorable clinical outcomes. CNU96JjhPhuCQHh9ViZTVJ Video Abstract (MP4 136794 kb)

• Publisher: Springer Nature Singapore,Springer Nature B.V
• Subject: Age / Asymptomatic / Critical Care Medicine / Genetic testing / Homocysteine / Imaging / Intensive / Mass spectrometry / Maternal and Child Health / Medical screening / Medicine / Medicine & Public Health / Metabolites / Mortality / Mutation / Original / Original Article / Patients / Pediatric Surgery / Pediatrics / Radiology / Scientific imaging / Surgery