Abstract：
Mutations in MMACHC cause cobalamin C disease (cblC, OMIM 277400), the commonest inborn error of vitamin B12 metabolism. In cblC, deficient activation of cobalamin results in methylcobalamin and adenosylcobalamin deficiency, elevating methylmalonic acid (MMA) and total plasma homocysteine (tHcy). We retrospectively reviewed the medical files of seven cblC patients: three compound heterozygotes for the MMACHC (NM_015506.3) missense variant c.158T>C p.(Leu53Pro) in trans with the common pathogenic mutation c.271dupA (p.(Arg91Lysfs*14), \"compounds\"), and four c.271dupA homozygotes (\"homozygotes\"). Compounds receiving hydroxocobalamin intramuscular injection monotherapy had age-appropriate psychomotor performance and normal ophthalmological examinations. In contrast, c.271dupA homozygotes showed marked psychomotor retardation, retinopathy and feeding problems despite penta-therapy (hydroxocobalamin, betaine, folinic acid, l-carnitine and acetylsalicylic acid). Pretreatment levels of plasma and urine MMA and tHcy were higher in c.271dupA homozygotes than in compounds. Under treatment, levels of the compounds approached or entered the reference range but not those of c.271dupA homozygotes (tHcy: compounds 9.8-32.9 μM, homozygotes 41.6-106.8 (normal (N) < 14); plasma MMA: compounds 0.14-0.81 μM, homozygotes, 10.4-61 (N < 0.4); urine MMA: compounds 1.75-48 mmol/mol creatinine, homozygotes 143-493 (N < 10)). Patient skin fibroblasts all had low cobalamin uptake, but this was milder in compound cells. Also, the distribution pattern of cobalamin species was qualitatively different between cells from compounds and from homozygotes. Compared to the classic cblC phenotype presented by c.271dupA homozygous patients, c.[158T>C];[271dupA] compounds had mild clinical and biochemical phenotypes and responded strikingly to hydroxocobalamin monotherapy.
摘要：
MMACHC中的突变导致钴胺素C病(cblC，OMIM277400),维生素B12代谢最常见的先天错误。在CBLC，缺乏钴胺激活导致甲基钴胺和腺苷钴胺缺乏，升高甲基丙二酸（MMA）和血浆总同型半胱氨酸（tHcy）。我们回顾性地回顾了7例cblC患者的医学档案：MMACHC（NM_015506.3）错义变体c.158T>Cp。（Leu53Pro）反式具有常见致病突变c.271dupA（p。（Arg91Lysfs*14），“化合物”)，和四个c.271dupA纯合子（“纯合子”）。接受羟钴胺素肌内注射单一疗法的化合物具有适合年龄的精神运动表现和正常的眼科检查。相比之下,c.271dupA纯合子显示出明显的精神运动迟钝，尽管五治疗，视网膜病变和喂养问题(羟钴胺，甜菜碱,亚叶酸,左旋肉碱和乙酰水杨酸）。c.271dupA纯合子的血浆和尿液MMA和tHcy的预处理水平高于化合物。在治疗中,化合物的水平接近或进入参考范围，但不是c.271dupA纯合子的水平（tHcy：化合物9.8-32.9μM，纯合子41.6-106.8（正常（N）<14）；血浆MMA：化合物0.14-0.81μM，纯合子，10.4-61（N<0.4）；尿液MMA：化合物1.75-48mmol/mol肌酐，纯合子143-493（N<10））。患者皮肤成纤维细胞都有低的钴胺素摄取，但这在复合细胞中更温和。此外，来自化合物和纯合子的细胞之间，钴胺素种类的分布模式在质量上是不同的。与c.271dupA纯合患者呈现的经典cblC表型相比，c.[158T>C];[271dupA]化合物具有轻度的临床和生化表型,并且对羟钴胺单药治疗反应显著。
