The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.

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.

Transcobalamin deficiency - a rare genetic defect in transportation of cobalamin; case report.

BACKGROUND: Vitamin B12 is primarily transported from plasma to cells by Transcobalamin. Deficiency of Transcobalamin is a rare autosomal recessive disorder that results in unavailability of cobalamin in cells and accumulation of homocysteine and methylmalonic acid. CASE REPORT: We report a case of a 2-year-old male child with persistent pancytopenia, recurrent infections, and megaloblastic anemia. Next-generation sequencing identified a novel variant in exon 8 of TCN2 gene. Substantial improvement has been observed following administration of high doses of parenteral methylcobalamin. CONCLUSION: In patients with unresolved pancytopenia and megaloblastic anemia, Transcobalamin deficiency should be investigated and treated promptly to prevent any irreversible and harmful outcome.

Case presentation: a severe case of cobalamin c deficiency presenting with nephrotic syndrome, malignant hypertension and hemolytic anemia.

BACKGROUND: The etiology of nephrotic syndrome can vary, with underlying metabolic diseases being a potential factor. Cobalamin C (cblC) defect is an autosomal recessive inborn error of metabolism caused by mutations in the MMACHC gene, resulting in impaired vitamin B12 processing. While cblC defect typically manifests with hematological and neurological symptoms, renal involvement is increasingly recognized but remains rare. CASE PRESENTATION: We describe a 7-month-old male patient presenting with fatigue and edema. His first laboratory findings showed anemia, thrombocytopenia, hypoalbuminemia and proteinuria and further examinations reveals hemolysis in peripheric blood smear. During his follow up respiratory distress due to pleural effusion in the right hemithorax was noticed. And fluid leakage to the third spaces supported nephrotic syndrome diagnosis. The patient's condition deteriorated, leading to intensive care admission due to, hypertensive crisis, and respiratory distress. High total plasma homocysteine and low methionine levels raised suspicion of cobalamin metabolism disorders. Genetic testing confirmed biallelic MMACHC gene mutations, establishing the diagnosis of cblC defect. Treatment with hydroxycobalamin, folic acid, and betaine led to remarkable clinical improvement. DISCUSSION/CONCLUSION: This case underscores the significance of recognizing metabolic disorders like cblC defect in atypical presentations of nephrotic syndrome. Early diagnosis and comprehensive management are vital to prevent irreversible renal damage. While cblC defects are more commonly associated with atypical hemolytic uremic syndrome, this case highlights the importance of considering cobalamin defects in the differential diagnosis of nephrotic syndrome, especially when associated with accompanying findings such as hemolysis. Our case, which has one of the highest homocysteine levels reported in the literature, emphasizes this situation again.

Generation of human pluripotent stem cell lines (WAe009-A) with THAP11F80L cobalamin disorder-associated mutation.

Recent studies reported that the mutation in the THAP11 gene (THAP11F80L) could be responsible for the inborn vitamin deficiency known as cobalamin disorder, by affecting the expression of the enzyme MMACHC, key in the cobalamin metabolism. However, the specifics of the molecular mechanism are largely unknown. In here we generated genetically modified human pluripotent stem cell lines with THAP11F80L mutation, providing a new research tool for futher exploring the molecular mechanism. The established hPSC lines remain pluripotent, showing expression of OCT3/4, differentiation capacity to the three germ layers and displaying normal karyotype.

New data supporting that early diagnosis and treatment are possible and necessary in intracellular cobalamin depletion: the case of transcobalamin II deficiency.

OBJECTIVES: Transcobalamin II (TC) promotes the cellular uptake of cobalamin (Cbl) through receptor-mediated endocytosis of the TC-cbl complex in peripheral tissues. TC deficiency is a rare disorder that causes intracellular Cbl depletion. It presents in early infancy with a failure to thrive, diarrhea, anemia, agammaglobulinemia, and pancytopenia. Data from five TC-deficient patients including clinical, biochemical, and molecular findings, as well as long-term outcomes, were collected. CASE PRESENTATION: Mutation analysis revealed one unreported pathogenic variant in the TCN2 gene. One patient had exocrine pancreatic insufficiency. We conducted a retrospective analysis of C3 and C3/C2 from dried blood samples, as this is implemented for newborn screening (NBS). We detected a marked increase in the C3/C2 ratio in two samples. Treatment was based on parenteral Cbl. Three patients treated before six months of age had an initial favorable outcome, whereas the two treated later or inadequately had neurological impairment. CONCLUSIONS: This is the first report of Argentinean patients with TC deficiency that detected a new variant in TCN2. NBS may be a tool for the early detection of TC deficiency. This data emphasizes that TC deficiency is a severe disorder that requires early detection and long-term, aggressive therapy. Accurate diagnosis is imperative, because early detection and treatment can be life-saving.

Expression of the cobalamin transporters cubam and MRP1 in the canine ileum-Upregulation in chronic inflammatory enteropathy.

Chronic inflammatory enteropathy (CIE) in dogs, a spontaneous model of human inflammatory bowel disease (IBD), is associated with a high rate of cobalamin deficiency. The etiology of hypocobalaminemia in human IBD and canine CIE remains unknown, and compromised intestinal uptake of cobalamin resulting from ileal cobalamin receptor deficiency has been proposed as a possible cause. Here, we evaluated the intestinal expression of the cobalamin receptor subunits, amnionless (AMN) and cubilin (CUBN), and the basolateral efflux transporter multi-drug resistance protein 1 (MRP1) in 22 dogs with CIE in comparison to healthy dogs. Epithelial CUBN and AMN levels were quantified by confocal laser scanning microscopy using immunohistochemistry in endoscopic ileal biopsies from dogs with (i) CIE and normocobalaminemia, (ii) CIE and suboptimal serum cobalamin status, (iii) CIE and severe hypocobalaminemia, and (iv) healthy controls. CUBN and MRP1 expression was quantified by RT-qPCR. Receptor expression was evaluated for correlation with clinical patient data. Ileal mucosal protein levels of AMN and CUBN as well as mRNA levels of CUBN and MRP1 were significantly increased in dogs with CIE compared to healthy controls. Ileal cobalamin receptor expression was positively correlated with age, clinical disease activity index (CCECAI) score, and lacteal dilation in the ileum, inversely correlated with serum folate concentrations, but was not associated with serum cobalamin concentrations. Cobalamin receptor downregulation does not appear to be the primary cause of hypocobalaminemia in canine CIE. In dogs of older age with severe clinical signs and/or microscopic intestinal lesions, intestinal cobalamin receptor upregulation is proposed as a mechanism to compensate for CIE-associated hypocobalaminemia. These results support oral supplementation strategies in hypocobalaminemic CIE patients.

Association between vitamin B12 deficiency and risk of Paediatric narcolepsy: Evidence from cross-sectional study and Mendelian randomization analysis.

BACKGROUND: Narcolepsy, a chronic neurologic sleep disorder, has sparked growing interest in the potential role of vitamin B12 in its pathogenic mechanism. However, research on this association has predominantly focused on adults. Our objective was to delineate the phenotypic and genetic connections between serum vitamin B12 levels and paediatric narcolepsy. METHODS: To investigate the causal relationship between vitamin B12 and paediatric narcolepsy, we conducted a retrospective analysis involving 60 narcolepsy patients and a matched control group. Univariate and multivariate logistic regression models were employed to identify independent factors influencing paediatric narcolepsy. Furthermore, a bidirectional two-sample Mendelian randomization (MR) analysis was performed to assess the causal connection between serum vitamin B12 levels and narcolepsy. RESULTS: Paediatric narcolepsy patients showed significantly lower serum levels of vitamin B12 and folate compared to the control group (P < 0.05). Multivariate logistic regression analysis identified serum vitamin B12 as the exclusive independent factor influencing paediatric narcolepsy (P < 0.001; OR = 0.96; 95%CI: 0.94-0.98). Additionally, IVW model results provided compelling evidence supporting a potential causal association between serum vitamin B12 levels and paediatric narcolepsy (OR: 0.958, 95% CI = 0.946-0.969, P = 0.001). CONCLUSION: This study establishes connections at both phenotypic and genetic levels, associating vitamin B12 deficiency with an increased risk of paediatric narcolepsy. These findings provide innovative perspectives for clinical strategies in the prevention and treatment of narcolepsy.

Déficit de cobalamina hereditario juvenil causado por mutaciones en el gen GIF / Hereditary juvenile cobalamin deficiency due to mutations in GIFgene

Los errores congénitos del metabolismo de la cobalamina afectan a su absorción, transporte o metabolismo intracelular. La anemia megaloblástica hereditaria juvenil por déficit de vitamina B12 está causada por una malabsorción de cobalamina. En la anemia perniciosa congénita por déficit de factor intrínseco, y en la anemia megaloblástica 1 por malabsorción de vitamina B12, causada por un defecto en el receptor vitamina B12/factor intrínseco o síndrome de Imerslund-Gräsbeck, existe un déficit de vitamina B12. El diagnóstico diferencial entre estas dos entidades no puede ser completado únicamente mediante la clínica y los datos de laboratorio. Presentamos un paciente español con anemia megaloblástica hereditaria juvenil por déficit de factor intrínseco, heterocigoto compuesto para dos mutaciones distintas en el gen GIF. La identificación de mutaciones causantes de la enfermedad en genes específicos ha mejorado nuestra capacidad de diagnóstico y tratamiento de estas situaciones (AU)

Inborn errors of cobalamin (Cbl) metabolism affect its absorption, transport, as well as its intracellular metabolism. Hereditary juvenile megaloblastic anaemia due to cobalamin deficiency, results from defects in Cbl absorption. There is a lack of vitamin B12 in congenital pernicious anaemia due to intrinsic factor deficiency and megaloblastic anaemia 1 due to selective intestinal malabsorption of vitamin B12 or Imerslund-Gräsbeck syndrome. Differential diagnosis can't be accomplished only by clinical and biochemical findings. We present a patient from Spain with a megaloblastic anaemia due to intrinsic factor deficiency (IFD). The patient is a compound heterozygous in GIF gene for a splice site mutation inherited from his mother and a missense change inherited from his father. The identification of disease-causing mutations in specific genes has improved our ability to diagnose many of these conditions (AU)