Cobalamin C defect is caused by pathogenic variants in the MMACHC gene leading to impaired conversion of dietary vitamin B₁₂ into methylcobalamin and adenosylcobalamin. Variants in the MMACHC gene cause accumulation of methylmalonic acid and homocysteine along with decreased methionine synthesis. The spectrum of MMACHC gene variants differs in various populations. A total of 19 North Indian children (age 0–18 years) with elevated methylmalonic acid and homocysteine were included in the study, and their DNA samples were subjected to Sanger sequencing of coding exons with flanking intronic regions of MMACHC gene. The genetic analysis resulted in the identification of a common pathogenic nonsense mutation, c.394C > T (R132*) in 85.7% of the unrelated cases with suspected cobalamin C defect. Two other known mutations c.347T > C (7%) and c.316G > A were also detected. Plasma homocysteine was significantly elevated (> 100 µmol/L) in 75% of the cases and methionine was decreased in 81% of the cases. Propionyl (C3)-carnitine, the primary marker for cobalamin C defect, was found to be elevated in only 43.75% of cases. However, the secondary markers such as C3/C2 and C3/C16 ratios were elevated in 87.5% and 100% of the cases, respectively. Neurological manifestations were the most common in our cohort. Our findings of the high frequency of a single MMACHC R132* mutation in cases with combined homocystinuria and methylmalonic aciduria may be proven helpful in designing a cost-effective and time-saving diagnostic strategy for resource-constraint settings. Since the R132* mutation is located near the last exon–exon junction, this is a potential target for the read-through therapeutics.

钴胺素 C 缺陷是由MMACHC 基因中的致病变异引起的，导致膳食维生素 B ₁₂ 向甲基钴胺素和腺苷钴胺素的转化受损。变体在MMACHC 甲基丙二酸和高半胱氨酸的基因积累的原因具有降低的甲硫氨酸合成沿。MMACHC基因变异的谱在不同的人群中有所不同。共有 19 名甲基丙二酸和同型半胱氨酸升高的北印度儿童（0-18 岁）被纳入研究，并对他们的 DNA 样本进行 Sanger 测序，对编码外显子与MMACHC 的侧翼内含子区域进行测序基因。遗传分析导致在 85.7% 的疑似钴胺素 C 缺陷的无关病例中鉴定出常见的致病性无义突变 c.394C > T (R132*)。还检测到另外两个已知突变 c.347T > C (7%) 和 c.316G > A。在 75% 的病例中血浆同型半胱氨酸显着升高 (> 100 µmol/L)，在 81% 的病例中蛋氨酸降低。丙酰 (C3)-肉碱是钴胺素 C 缺陷的主要标志物，仅在 43.75% 的病例中升高。然而，在 87.5% 和 100% 的病例中，次要标志物如 C3/C2 和 C3/C16 比率分别升高。神经系统表现是我们队列中最常见的。我们对单个MMACHC高频的发现R132* 突变在合并高胱氨酸尿症和甲基丙二酸尿症的情况下可能被证明有助于为资源受限环境设计一种具有成本效益和节省时间的诊断策略。由于 R132* 突变位于最后一个外显子-外显子连接点附近，因此这是通读疗法的潜在目标。