Skip to main content

Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review

Abstract

Inherited disorders of cobalamin (cbl) metabolism (cblA-J) result in accumulation of methylmalonic acid (MMA) and/or homocystinuria (HCU). Clinical presentation includes ophthalmological manifestations related to retina, optic nerve and posterior visual alterations, mainly reported in cblC and sporadically in other cbl inborn errors.

We searched MEDLINE EMBASE and Cochrane Library, and analyzed articles reporting ocular manifestations in cbl inborn errors. Out of 166 studies a total of 52 studies reporting 163 cbl and 24 mut cases were included. Ocular manifestations were found in all cbl defects except for cblB and cblD-MMA; cblC was the most frequent disorder affecting 137 (84.0%) patients. The c.271dupA was the most common pathogenic variant, accounting for 70/105 (66.7%) cases. One hundred and thirty-seven out of 154 (88.9%) patients presented with early-onset disease (0–12 months). Nystagmus and strabismus were observed in all groups with the exception of MMA patients while maculopathy and peripheral retinal degeneration were almost exclusively found in MMA-HCU patients. Optic nerve damage ranging from mild temporal disc pallor to complete atrophy was prevalent in MMA-HCU.and MMA groups. Nystagmus was frequent in early-onset patients. Retinal and macular degeneration worsened despite early treatment and stabilized systemic function in these patients. The functional prognosis remains poor with final visual acuity < 20/200 in 55.6% (25/45) of cases. In conclusion, the spectrum of eye disease in Cbl patients depends on metabolic severity and age of onset. The development of visual manifestations over time despite early metabolic treatment point out the need for specific innovative therapies.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Availability of data

All analyzed data are included in this article and the supplementary data files.

References

  1. Abu-El-Haija A, Mendelsohn BA, Duncan JL et al (2018) Cobalamin D Deficiency Identified Through Newborn Screening. In: Morava E, Baumgartner M, Patterson M et al (eds) JIMD Reports, vol 44. Springer. Berlin Heidelberg, Berlin, Heidelberg, pp 73–77

    Google Scholar 

  2. Ahrens-Nicklas RC, Serdaroglu E, Muraresku C, Ficicioglu C (2015) Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level. In: Zschocke J, Baumgartner M, Morava E et al (eds) JIMD Reports, vol 23. Springer. Berlin Heidelberg, Berlin, Heidelberg, pp 71–75

    Google Scholar 

  3. Aleman TS, Cideciyan AV, Sumaroka A et al (2007) Inner retinal abnormalities in X-linked retinitis pigmentosa with RPGR mutations. Invest Ophthalmol vis Sci 48:4759. https://doi.org/10.1167/iovs.07-0453

    Article  PubMed  PubMed Central  Google Scholar 

  4. Aleman TS, Soumittra N, Cideciyan AV et al (2009) CERKL mutations cause an autosomal recessive cone-rod dystrophy with inner retinopathy. Invest Ophthalmol vis Sci 50:5944. https://doi.org/10.1167/iovs.09-3982

    Article  PubMed  Google Scholar 

  5. Aleman TS, Brodie F, Garvin C et al (2015) Retinal structure in cobalamin C disease: mechanistic and therapeutic implications. Ophthalmic Genet 36:339–348. https://doi.org/10.3109/13816810.2014.885059

    CAS  Article  PubMed  Google Scholar 

  6. AlOwain M, Khalifa OA, Al Sahlawi Z et al (2019) Optic neuropathy in classical methylmalonic acidemia. Ophthalmic Genet 40:313–322. https://doi.org/10.1080/13816810.2019.1634740

    CAS  Article  PubMed  Google Scholar 

  7. Bacci GM, Donati MA, Pasquini E et al (2017) Optical coherence tomography morphology and evolution in cblC disease-related maculopathy in a case series of very young patients. Acta Ophthalmol 95:e776–e782. https://doi.org/10.1111/aos.13441

    CAS  Article  PubMed  Google Scholar 

  8. Bailey LB, Gregory JF (1999) Folate metabolism and requirements. J Nutr 129:779–782. https://doi.org/10.1093/jn/129.4.779

    CAS  Article  PubMed  Google Scholar 

  9. Bertsch M, Floyd M, Kehoe T et al (2017) The clinical evaluation of infantile nystagmus: what to do first and why. Ophthalmic Genet 38:22–33. https://doi.org/10.1080/13816810.2016.1266667

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bonafede L, Ficicioglu CH, Serrano L et al (2015) Cobalamin C deficiency shows a rapidly progressing maculopathy with severe photoreceptor and ganglion cell loss. Invest Ophthalmol vis Sci 56:7875. https://doi.org/10.1167/iovs.15-17857

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Bourque DK, Mellin-Sanchez LE, Bullivant G et al (2021) Outcomes of patients with cobalamin C deficiency: a single center experience. JIMD Reports 57:102–114. https://doi.org/10.1002/jmd2.12179

    Article  PubMed  Google Scholar 

  12. Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cb1-C type). Am J Med Genet 36:167–171. https://doi.org/10.1002/ajmg.1320360208

    CAS  Article  PubMed  Google Scholar 

  13. Brooks BP, Thompson AH, Sloan JL et al (2016) Ophthalmic manifestations and long-term visual outcomes in patients with cobalamin C deficiency. Ophthalmology 123:571–582. https://doi.org/10.1016/j.ophtha.2015.10.041

    Article  PubMed  Google Scholar 

  14. Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A, Venditti CP (2009) Hydroxocobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis 32:728–731. https://doi.org/10.1007/s10545-009-1257-y

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Caterino M, Pastore A, Strozziero MG et al (2015) The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. J Inherit Metab Dis 38:969–979. https://doi.org/10.1007/s10545-014-9806-4

    CAS  Article  PubMed  Google Scholar 

  16. Chung Y-R, Lee SY, Kim YH et al (2020) Hyperreflective foci in diabetic macular edema with serous retinal detachment: association with dyslipidemia. Acta Diabetol. https://doi.org/10.1007/s00592-020-01495-8

    Article  PubMed  Google Scholar 

  17. Collison FT, Xie Y, (Angela), Gambin T, et al (2015) Whole exome sequencing identifies an adult-onset case of methylmalonic aciduria and homocystinuria type C (cblC) with non-syndromic bull’s eye maculopathy. Ophthalmic Genet 36:270–275. https://doi.org/10.3109/13816810.2015.1010736

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Constantinou P, D’’Alessandro M, Lochhead P, et al (2015) A new, atypical case of cobalamin F disorder diagnosed by whole exome sequencing. Mol Syndromol 6:254–258. https://doi.org/10.1159/000441134

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Curcio CA, Zanzottera EC, Ach T, Balaratnasingam C, Freund KB (2017) Activated retinal pigment epithelium, an optical coherence tomography biomarker for progression in age-related macular degeneration. Invest Ophthalmol vis Sci 58(6):BIO211–BIO226. https://doi.org/10.1167/iovs.17-21872

    Article  PubMed  PubMed Central  Google Scholar 

  20. De Las M, Casas C, Epeldegui M, Tudela C et al (2003) High exogenous homocysteine modifies eye development in early chick embryos: Homocysteine Modifies Eye Development in Chicks. Birth Defects Res A 67:35–40. https://doi.org/10.1002/bdra.10014

    CAS  Article  Google Scholar 

  21. Devi S, Pasanna RM, Shamshuddin Z, Bhat K, Sivadas A, Mandal AK, Kurpad AV (2020) Measuring vitamin B-12 bioavailability with [13C]-cyanocobalamin in humans. Am J Clin Nutr 112(6):1504–1515. https://doi.org/10.1093/ajcn/nqaa221

    Article  PubMed  Google Scholar 

  22. Fettelschoss V, Burda P, Sagné C et al (2017) Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B 12 -trafficking proteins ABCD4 and LMBD1. J Biol Chem 292:11980–11991. https://doi.org/10.1074/jbc.M117.784819

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Fischer S, Huemer M, Baumgartner M et al (2014) Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 37:831–840. https://doi.org/10.1007/s10545-014-9687-6

    CAS  Article  PubMed  Google Scholar 

  24. Fishman GA, Chappelow AV, Anderson RJ et al (2005) Short-term intervisit variability of ERG amplitudes in normal subjects and patients with retinitis pigmentosa. Retina 25:1014–1021. https://doi.org/10.1097/00006982-200512000-00010

    Article  PubMed  Google Scholar 

  25. Fofou-Caillierez MB, Mrabet NT, Chéry C et al (2013) Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Hum Mol Genet 22:4591–4601. https://doi.org/10.1093/hmg/ddt308

    CAS  Article  PubMed  Google Scholar 

  26. Froese DS, Gravel RA (2010) Genetic disorders of vitamin B 12 metabolism: eight complementation groups – eight genes. Expert Rev Mol Med 12:e37. https://doi.org/10.1017/S1462399410001651

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Fuchs LR, Robert M, Ingster-Moati I et al (2012) Ocular manifestations of cobalamin C type methylmalonic aciduria with homocystinuria. J Am Assoc Pediatr Ophthalmol Strabismus 16:370–375. https://doi.org/10.1016/j.jaapos.2012.02.019

    Article  Google Scholar 

  28. Gaillard M-C, Matthieu J-M, Borruat F-X (2008) Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders. Klin Monatsbl Augenheilkd 225:491–494. https://doi.org/10.1055/s-2008-1027310

    Article  PubMed  Google Scholar 

  29. George S (2008) Retinopathy in inherited transcobalamin II deficiency. Arch Ophthalmol 126:142. https://doi.org/10.1001/archophthalmol.2007.20

    Article  Google Scholar 

  30. Gerth C, Morel CF, Feigenbaum A, Levin AV (2008) Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J Am Assoc Pediatr Ophthalmol Strabismus 12:591–596. https://doi.org/10.1016/j.jaapos.2008.06.008

    Article  Google Scholar 

  31. Gizicki R, Robert M-C, Gómez-López L et al (2014) Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type. Ophthalmology 121:381–386. https://doi.org/10.1016/j.ophtha.2013.08.034

    Article  PubMed  Google Scholar 

  32. Grant LW, McCandless SE, Traboulsi EI (2010) Maculopathy due to cobalamin C (cb1C) disease in an amish child. J Pediatr Ophthalmol Strabismus. https://doi.org/10.3928/01913913-20090918-10

    Article  Google Scholar 

  33. Guéant J-L, Namour F, Guéant-Rodriguez R-M, Daval J-L (2013) Folate and fetal programming: a play in epigenomics? Trends Endocrinol Metab 24:279–289. https://doi.org/10.1016/j.tem.2013.01.010

    CAS  Article  PubMed  Google Scholar 

  34. Guéant J-L, Coelho D, Nicolas J-P (2014) La vitamine B12 et les maladies génétiques associées. Bulletin De L’académie Nationale De Médecine 198:1141–1156. https://doi.org/10.1016/S0001-4079(19)31264-6

    Article  PubMed  Google Scholar 

  35. Guo J, Ni S, Li Q et al (2019) Folate/vitamin B alleviates hyperhomocysteinemia-induced alzheimer-like pathologies in rat retina. Neurosci Bull 35:325–335. https://doi.org/10.1007/s12264-018-0293-8

    CAS  Article  PubMed  Google Scholar 

  36. Hannibal L, Kim J, Brasch NE et al (2009) Processing of alkylcobalamins in mammalian cells: a role for the MMACHC (cblC) gene product. Mol Genet Metab 97:260–266. https://doi.org/10.1016/j.ymgme.2009.04.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Higashimoto T, Kim AY, Ogawa JT et al (2019) High-dose hydroxocobalamin achieves biochemical correction and improvement of neuropsychiatric deficits in adults with late onset cobalamin C deficiency. JIMD Rep 51:17–24. https://doi.org/10.1002/jmd2.12087

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hörster F, Tuncel AT, Gleich F, Plessl T, Froese SD, Garbade SF, Kölker S, Baumgartner MR (2021) Additional contributors from E-IMD. Delineating the clinical spectrum of isolated methylmalonic acidurias: cblA and mut. J Inherit Metab Dis 44(1):193–214. https://doi.org/10.1002/jimd.12297

    CAS  Article  PubMed  Google Scholar 

  39. Huemer M, Scholl-Bürgi S, Hadaya K et al (2014) Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis 9:161. https://doi.org/10.1186/s13023-014-0161-1

    Article  PubMed  PubMed Central  Google Scholar 

  40. Huemer M, Bürer C, Ješina P et al (2015) Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data. J Inherit Metab Dis 38:957–967. https://doi.org/10.1007/s10545-014-9803-7

    CAS  Article  PubMed  Google Scholar 

  41. Huemer M, Diodato D, Schwahn B et al (2017) Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. J Inherit Metab Dis 40:21–48. https://doi.org/10.1007/s10545-016-9991-4

    CAS  Article  PubMed  Google Scholar 

  42. Huemer M, Diodato D, Martinelli D et al (2019) Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry. J Inherit Metab Dis 42:333–352. https://doi.org/10.1002/jimd.12041

    CAS  Article  PubMed  Google Scholar 

  43. Kandula T, Peters H, Fahey M (2014) Cobalamin E defect, a rare inborn error of vitamin B12 metabolism: value of early diagnosis and treatment. J Clin Neurosci 21:1815–1817. https://doi.org/10.1016/j.jocn.2013.12.030

    CAS  Article  PubMed  Google Scholar 

  44. Kim DJ, Koh J-M, Lee O et al (2006) Homocysteine enhances apoptosis in human bone marrow stromal cells. Bone 39:582–590. https://doi.org/10.1016/j.bone.2006.03.004

    CAS  Article  PubMed  Google Scholar 

  45. Kind T, Levy J, Lee M et al (2002) Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 24:327–329. https://doi.org/10.1097/00043426-200205000-00023

    Article  PubMed  Google Scholar 

  46. Kon Y, Iida T, Maruko I, Saito M (2008) THE OPTICAL COHERENCE TOMOGRAPHY–OPHTHALMOSCOPE FOR EXAMINATION OF CENTRAL SEROUS CHORIORETINOPATHY WITH PRECIPITATES. Retina 28:864–869. https://doi.org/10.1097/IAE.0b013e3181669795

    Article  PubMed  Google Scholar 

  47. Ku CA, Ng JK, Karr DJ et al (2016) Spectrum of ocular manifestations in cobalamin C and cobalamin A types of methylmalonic acidemia. Ophthalmic Genet 37:404–414. https://doi.org/10.3109/13816810.2015.1121500

    CAS  Article  PubMed  Google Scholar 

  48. Kvittingen EA, Spangen S, Lindemans J, Fowler B (1997) Methionine synthase deficiency without megaloblastic anaemia. Eur J Pediatr 156(12):925–930. https://doi.org/10.1007/s004310050744

    CAS  Article  PubMed  Google Scholar 

  49. Lattanzio R, Sampietro F, Ramoni A et al (2006) Moderate hyperhomocysteinemia and early-onset central retinal vein occlusion. Retina 26:65–70. https://doi.org/10.1097/00006982-200601000-00011

    Article  PubMed  Google Scholar 

  50. Martinez Alvarez L, Jameson E, Parry NRA et al (2016) Optic neuropathy in methylmalonic acidemia and propionic acidemia. Br J Ophthalmol 100:98–104. https://doi.org/10.1136/bjophthalmol-2015-306798

    Article  PubMed  Google Scholar 

  51. Mascarenhas R, Li Z, Gherasim C et al (2020) The human B 12 trafficking protein CblC processes nitrocobalamin. J Biol Chem 295:9630–9640. https://doi.org/10.1074/jbc.RA120.014094

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Matos IV, Castejón E, Meavilla S et al (2013) Clinical and biochemical outcome after hydroxocobalamin dose escalation in a series of patients with cobalamin C deficiency. Mol Genet Metab 109:360–365. https://doi.org/10.1016/j.ymgme.2013.05.007

    CAS  Article  PubMed  Google Scholar 

  53. Mitchell GA, Watkins D, Melançon SB et al (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415. https://doi.org/10.1016/S0022-3476(86)80882-4

    CAS  Article  PubMed  Google Scholar 

  54. Müller P, Horneff G, Hennermann J (2007) A rare inborn error of intracellular processing of cobalamine presenting with microcephalus and megaloblastic anemia: a report of 3 children. Klin Padiatr 219:361–367. https://doi.org/10.1055/s-2007-973067

    Article  PubMed  Google Scholar 

  55. Nogueira C, Aiello C, Cerone R et al (2008) Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Mol Genet Metab 93:475–480. https://doi.org/10.1016/j.ymgme.2007.11.005

    CAS  Article  PubMed  Google Scholar 

  56. Outteryck O, de Seze J, Stojkovic T et al (2012) Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy. Neurology 79:386–388. https://doi.org/10.1212/WNL.0b013e318260451b

    Article  PubMed  Google Scholar 

  57. Pastore A, Martinelli D, Piemonte F et al (2014) Glutathione metabolism in cobalamin deficiency type C (cblC). J Inherit Metab Dis 37:125–129. https://doi.org/10.1007/s10545-013-9605-3

    CAS  Article  PubMed  Google Scholar 

  58. Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154. https://doi.org/10.1076/1381-6810(200009)2131-ZFT151

    CAS  Article  PubMed  Google Scholar 

  59. Perna AF, Ingrosso D, Lombardi C et al (2003) Possible mechanisms of homocysteine toxicity. Kidney Int 63:S137–S140. https://doi.org/10.1046/j.1523-1755.63.s84.33.x

    Article  Google Scholar 

  60. Pinar-Sueiro S, Martínez-Fernández R, Lage-Medina S, Aldamiz-Echevarria L, Vecino E (2010) Optic neuropathy in methylmalonic acidemia: the role of neuroprotection. J Inherit Metab Dis 33(Suppl 3):S199-203. https://doi.org/10.1007/s10545-010-9084-8

    Article  PubMed  Google Scholar 

  61. Poloschek CM, Fowler B, Unsold R, Lorenz B (2005) Disturbed visual system function in methionine synthase deficiency. Graefe’s Arch Clin Exp Ophthalmol 243:497–500. https://doi.org/10.1007/s00417-004-1044-2

    CAS  Article  Google Scholar 

  62. Powers JM, Rosenblatt DS, Schmidt RE et al (2001) Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 49:396–400. https://doi.org/10.1002/ana.78

    CAS  Article  PubMed  Google Scholar 

  63. Profitlich LE, Kirmse B, Wasserstein MP et al (2009) High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98:344–348. https://doi.org/10.1016/j.ymgme.2009.07.017

    CAS  Article  PubMed  Google Scholar 

  64. Quigley HA (1999) Neuronal death in glaucoma. Prog Retin Eye Res 18:39–57. https://doi.org/10.1016/S1350-9462(98)00014-7

    CAS  Article  PubMed  Google Scholar 

  65. Ricci D, Pane M, Deodato F et al (2005) Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics 36:181–185. https://doi.org/10.1055/s-2005-865609

    CAS  Article  PubMed  Google Scholar 

  66. Ricci D, Martinelli D, Ferrantini G et al (2020) Early neurodevelopmental characterization in children with cobalamin C/defect. Jrnl of Inher Metab Disea 43:367–374. https://doi.org/10.1002/jimd.12171

    CAS  Article  Google Scholar 

  67. Rosenblatt DS, Aspler AL, Shevell MI et al (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538. https://doi.org/10.1023/A:1005353530303

    CAS  Article  PubMed  Google Scholar 

  68. Schimel AM, Mets MB (2006) The natural history of retinal degeneration in association with cobalamin C (cbl C) disease. Ophthalmic Genet 27:9–14. https://doi.org/10.1080/13816810500481758

    CAS  Article  PubMed  Google Scholar 

  69. Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103. https://doi.org/10.1007/s00467-007-0604-1

    Article  PubMed  Google Scholar 

  70. Shinnar S (1984) Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence: a treatable cause of dementia and myelopathy. N Engl J Med 311(7):451–454

    CAS  Article  Google Scholar 

  71. Stabler SP (2013) Vitamin B 12 deficiency. N Engl J Med 368:149–160. https://doi.org/10.1056/NEJMcp1113996

    CAS  Article  PubMed  Google Scholar 

  72. Suormala T, Baumgartner MR, Coelho D et al (2004) The cblD defect causes either isolated or combined deficiency of methylcobalamin and adenosylcobalamin synthesis. J Biol Chem 279:42742–42749. https://doi.org/10.1074/jbc.M407733200

    CAS  Article  PubMed  Google Scholar 

  73. Thauvin-Robinet C, Roze E, Couvreur G et al (2007) The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 79:725–728. https://doi.org/10.1136/jnnp.2007.133025

    Article  Google Scholar 

  74. Ticho B, Feist R, Fishman G (1992) Nondetectable electroretinogram in combined methylmalonic aciduria and homocystinuria. Ann Ophthalmol 24(5):180–181

    CAS  PubMed  Google Scholar 

  75. Traber G, Baumgartner MR, Schwarz U, Pangalu A, Donath MY, Landau K (2011) Subacute bilateral visual loss in methylmalonic acidemia. J Neuroophthalmol 31(4):344–346. https://doi.org/10.1097/WNO.0b013e31822db480

    Article  PubMed  Google Scholar 

  76. Traboulsi EI, Silva JC, Geraghty MT et al (1992) Ocular histopathologic characteristics of cobalamin C type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 113:269–280. https://doi.org/10.1016/S0002-9394(14)71578-8

    CAS  Article  PubMed  Google Scholar 

  77. Trakadis YJ, Alfares A, Bodamer OA et al (2014) Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis 37:461–473. https://doi.org/10.1007/s10545-013-9664-5

    CAS  Article  PubMed  Google Scholar 

  78. Tsina EK (2005) Maculopathy and retinal degeneration in cobalamin C methylmalonic aciduria and homocystinuria. Arch Ophthalmol 123:1143. https://doi.org/10.1001/archopht.123.8.1143

    Article  PubMed  Google Scholar 

  79. Valayannopoulos V, Hubert L, Benoist JF et al (2009) Multiple OXPHOS deficiency in the liver of a patient with CblA methylmalonic aciduria sensitive to vitamin B12. J Inherit Metab Dis 32:159–162. https://doi.org/10.1007/s10545-009-1023-1

    CAS  Article  PubMed  Google Scholar 

  80. Wang X, Yang Y, Li X et al (2019) Distinct clinical, neuroimaging and genetic profiles of late-onset cobalamin C defects (cb1C): a report of 16 Chinese cases. Orphanet J Rare Dis 14:109. https://doi.org/10.1186/s13023-019-1058-9

    Article  PubMed  PubMed Central  Google Scholar 

  81. Watkin D, Rosenblatt DS (1989) Functional methionine synthase deficiency (cblE and cblG): clinical and biochemical heterogeneity. Am J Med Genet 34:427–434. https://doi.org/10.1002/ajmg.1320340320

    Article  Google Scholar 

  82. Watkins D, Rosenblatt DS (2011) Inborn errors of cobalamin absorption and metabolism. Am J Med Genet 157:33–44. https://doi.org/10.1002/ajmg.c.30288

    CAS  Article  Google Scholar 

  83. Watkins D, Rosenblatt DS (2013) Lessons in biology from patients with inborn errors of vitamin B12 metabolism. Biochimie 95:1019–1022. https://doi.org/10.1016/j.biochi.2013.01.013

    CAS  Article  PubMed  Google Scholar 

  84. Weisfeld-Adams JD, Bender HA, Miley-Åkerstedt A et al (2013) Neurologic and neurodevelopmental phenotypes in young children with early-treated combined methylmalonic acidemia and homocystinuria, cobalamin C type. Mol Genet Metab 110:241–247. https://doi.org/10.1016/j.ymgme.2013.07.018

    CAS  Article  PubMed  Google Scholar 

  85. Weisfeld-Adams JD, McCourt EA, Diaz GA, Oliver SC (2015) Ocular disease in the cobalamin C defect: a review of the literature and a suggested framework for clinical surveillance. Mol Genet Metab 114:537–546. https://doi.org/10.1016/j.ymgme.2015.01.012

    CAS  Article  PubMed  Google Scholar 

  86. Williams ZR, Hurley PE, Altiparmak UE et al (2009) Late Onset Optic Neuropathy in Methylmalonic and Propionic Acidemia. Am J Ophthalmol 147:929–933. https://doi.org/10.1016/j.ajo.2008.12.024

    CAS  Article  PubMed  Google Scholar 

  87. Wilson A, Leclerc D, Saberi F et al (1998) Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency. Am J Hum Genet 63:409–414. https://doi.org/10.1086/301976

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Wingert V, Mukherjee S, Esser AJ et al (2020) Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC. Biochimie. https://doi.org/10.1016/j.biochi.2020.10.006

    Article  PubMed  Google Scholar 

  89. Wu L-Y, An H, Liu J et al (2017) Manic-depressive psychosis as the initial symptom in adult siblings with late-onset combined methylmalonic aciduria and homocystinemia. Cobalamin C Type: Chin Med J 130:492–494. https://doi.org/10.4103/0366-6999.199826

    Article  PubMed Central  Google Scholar 

  90. Zava P, Fowler B, Zeman J, Suormala T (2002) CblE type of homocystinuria due to methionine synthase reductase de¢ciency: Clinical and molecular studies and prenatal diagnosis in two families. J Inherit Metab Dis 16

Download references

Funding

The study was funded by the research project FHU ARRIMAGE and the French PIA project “Lorraine Université d’Excellence”, reference ANR-15-IDEX-04-LUE.

Author information

Affiliations

Authors

Contributions

KM, JBC, RMGR performed literature search, KM, JBC wrote manuscript, RMGR, AO, AWF, CDV, DC, JLG revised manuscript. All authors approved the final version of the manuscript and were accountable for all aspects of the work.

Corresponding authors

Correspondence to Rosa-Maria Guéant-Rodriguez or Jean-Baptiste Conart.

Ethics declarations

Conflict of interest

None to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 143 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Matmat, K., Guéant-Rodriguez, RM., Oussalah, A. et al. Ocular manifestations in patients with inborn errors of intracellular cobalamin metabolism: a systematic review. Hum Genet (2021). https://doi.org/10.1007/s00439-021-02350-8

Download citation