Abstract
Background
Cobalamin C (cblC), a vitamin B12 processing protein, plays a crucial role in metabolism for the conversion of homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA. CblC deficiency, an inborn error of cobalamin processing, is a rare cause of atypical hemolytic-uremic syndrome (aHUS) and results in hyperhomocysteinemia and methylmalonic aciduria. Both substances are thought to contribute to thrombotic microangiopathy (TMA) in cblC deficiency patients. However, the roles of homocysteine and methylmalonic acid (MMA) in these patients remain unclear. We want to shed more light on the contributions of homocysteine and MMA levels as contributing factors for thrombotic microangiopathy (TMA)/aHUS by a follow-up of a cblC deficiency patient over 6 years.
Case diagnosis
A 27-day-old Hispanic female presented with abnormal C3-carnitine on her newborn screen, poor feeding, decreased activity, and oligouria. She was diagnosed with cblC deficiency after laboratory results revealed elevated serum homocysteine, and serum MMA along with genetic testing showing a homozygous pathogenic frameshift variant in MMACHC. The patient developed aHUS and acute kidney injury (AKI), which resolved after appropriate therapy. Over 6 years, she continued to have normal kidney function with no thrombocytopenia despite persistently elevated homocysteine and MMA levels.
Conclusion
We question the roles of homocysteine and MMA as causative of aHUS/TMA in cblC deficiency as they remained elevated during follow-up but did not result in aHUS/TMA or AKI. Hyperhomocysteinemia and/or MMA caused by other metabolic diseases do not result in aHUS/TMA or AKI. This suggests that other nephrotoxic factors may trigger aHUS/TMA in cblC patients.
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References
Noris M, Remuzzi G (2005) Hemolytic uremic syndrome. J Am Soc Nephrol 16:1035–1050
Beck BB, van Spronson F, Diepstra A, Berger RMF et al (2017) Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity. Pediatr Nephrol 32:733–741
Sloan JL, Achilly NP, Arnold ML, Catlett JL et al (2020) The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth, and retinal morphology. Hum Mol Genet 29:2109–2123
Chern T, Achilleos A, Tong X, Hsu CW et al (2020) Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type. Dev Biol 468:1–13
van Guldener C, Stehouwer CD (2000) Hyperhomocysteinemia, vascular pathology, and endothelial dysfunction. Semin Thromb Hemost 26:281–289
Morath MA, Okun JG, Muller IB, Sauer SW et al (2008) Neurodegeneration and chronic renal failure in methylmalonic aciduria. J Inherit Metab Dis 31:35–43
Lerner-Ellis JP, Tirone JC, Pawelek PD, Dore C et al (2006) Identification of the gene responsible for methylmalonic aciduria and homocysteinuria, cblC type. Nat Genet 38:93–100
Sloan JL, Carrillo N, Adams D, Venditti CP et al (2008) Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA et al (eds). GeneReviews® [Internet]. University of Washington, Seattle; 1993–2021. Available from https://www.ncbi.nlm.nih.gov/books/NBK1328/
Bedin M, Boyer O, Servais A, Li Y et al (2020) Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J Clin Invest 130:335–344
Podder S, Cervates J, Dey BR (2015) Association of acquired thrombotic thrombocytopaenic purpura in a patient with pernicious anemia. BMJ Case Rep 2015:bcr2015211989. https://doi.org/10.1136/bcr-2015-211989
Labrune P, Zittoun J, Duvaltier I, Trioche P et al (1999) Haemolytic uraemic syndrome and pulmonary hypertension in a patient with methionine synthase deficiency. Eur J Pediatr 158:734–739
Paul EA, Guttenberg M, Kaplan P, Watkins D et al (2013) Atypical glomerulopathy associated with the cblE inborn error of vitamin B12 metabolism. Pediatr Nephrol 28:1135–1139
Frimat M, Boudhabhay I, Roumenina LT (2019) Hemolysis derived products toxicity and endothelium: model of the second hit. Toxins 11:660
Sonsino E, Ogier H, Mercier JC, Devictor D et al (1985) Congenital anomaly of the metabolism of vitamin B12. Histopathological study. Arch Anat Cytol Pathol 33:98–99
He R, Zhang H, Kang L, Li H et al (2020) Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency. Neurology 95:e3129–e3137
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The authors have no conflicts of interest to declare. MTW is supported by Children’s Clinical Research Advisory Committee (CCRAC), Department of Defense (W81XWH1910205), and the NIH (P30 DK079328-11, R01DK119631).
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Wood, W.D., Elmaghrabi, A., Gotway, G. et al. The roles of homocysteinemia and methylmalonic acidemia in kidney injury in atypical hemolytic uremic syndrome caused by cobalamin C deficiency. Pediatr Nephrol 37, 1415–1418 (2022). https://doi.org/10.1007/s00467-021-05372-6
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DOI: https://doi.org/10.1007/s00467-021-05372-6