Combined methylmalonic aciduria with homocystinuria (cblC type) is a rare disease caused by mutations in the MMACHC gene. MMACHC encodes an enzyme crucial for intracellular vitamin B₁₂ metabolism, leading to the accumulation of toxic metabolites e.g. methylmalonic acid (MMA) and homocysteine (Hcy), and secondary disturbances in folate and one-carbon metabolism when not fully functional. Patients with cblC deficiency often present in the neonatal or early childhood period with a severe multisystem pathology, which comprises a broad spectrum of treatment-resistant ophthalmological phenotypes, including retinal degeneration, impaired vision, and vascular changes. To examine the potential function of MMACHC in the retina and how its loss may impact disease, we performed gene expression studies in human and mouse, which showed that local expression of MMACHC in the retina and retinal pigment epithelium is relatively stable over time. To study whether functional MMACHC is required for retinal function and tissue integrity, we generated a transgenic mouse lacking Mmachc expression in cells of the peripheral retina. Characterization of this mouse revealed accumulation of cblC disease related metabolites, including MMA and the folate-dependent purine synthesis intermediates AICA-riboside and SAICA-riboside in the retina. Nevertheless, fundus appearance, morphology, vasculature, and cellular composition of the retina, as well as ocular function, remained normal in mice up to 6 or 12 months of age. Our data indicates that peripheral retinal neurons do not require intrinsic expression of Mmachc for survival and function and questions whether a local MMACHC deficiency is responsible for the retinal phenotypes in patients.

甲基丙二酸尿症合并高胱氨酸尿症（cblC 型）是一种由MMACHC基因突变引起的罕见疾病。MMACHC编码一种对细胞内维生素 B ₁₂代谢至关重要的酶，导致有毒代谢物的积累，例如甲基丙二酸 (MMA) 和同型半胱氨酸 (Hcy)，以及叶酸和一碳代谢在功能不完全时的继发性干扰。cblC 缺乏症患者通常在新生儿或儿童早期出现严重的多系统病理，包括广泛的抗治疗眼科表型，包括视网膜变性、视力受损和血管变化。为了检查 MMACHC 在视网膜中的潜在功能以及它的缺失如何影响疾病，我们在人和小鼠中进行了基因表达研究，结果表明MMACHC 的局部表达在视网膜和视网膜色素上皮随着时间的推移相对稳定。为了研究视网膜功能和组织完整性是否需要功能性 MMACHC，我们生成了一种在外周视网膜细胞中缺乏Mmachc表达的转基因小鼠。这只小鼠的特征揭示了 cblC 疾病相关代谢物的积累，包括 MMA 和叶酸依赖性嘌呤合成中间体 AICA-核糖苷和 SAICA-核糖苷在视网膜中。尽管如此，在 6 或 12 个月大的小鼠中，眼底外观、形态学、脉管系统和视网膜细胞组成以及眼部功能仍然正常。我们的数据表明外周视网膜神经元不需要Mmachc 的内在表达 生存和功能，并质疑局部 MMACHC 缺乏是否是导致患者视网膜表型的原因。