Skip to main content

Advertisement

SpringerLink
Log in

Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Combined methylmalonic acidemia and homocystinuria, cblC type, is stated to be the most common inborn error of intracellular cobalamin metabolism. The disorder can display a wide spectrum of clinical manifestations, spanning the prenatal period through late adulthood. While increased homocysteine concentrations and impaired methyl group metabolism may contribute to disease-related complications, the characteristic macular and retinal degeneration seen in many affected patients appears to be unique to cblC disease. The early detection of cblC disease by newborn screening mandates a careful assessment of therapeutic approaches and provides a new opportunity to improve the outcome of affected patients. The following article reviews the current knowledge on the complications, pathophysiology, and outcome of cblC disease in an effort to better guide clinical practice and future therapeutic trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

cblC:

Cobalamin C disease

CBS:

Cystathionine beta synthase

CNCbl:

Cyanocobalamin

IM:

Intramuscular

MeCbl:

Methylcobalamin

MMA:

Methylmalonic acid

MTHFR:

Methylenetetrahydrofolate reductase

OHCbl:

Hydroxocobalamin

SAM:

S-Adenosylmethionine

SCD:

Subacute combined degeneration of the spinal cord

tHcy:

Total plasma homocysteine

HcyTL:

Homocysteine thiolactone

References

  • Akdal G, Yener GG, Kurt P (2008) Treatment responsive executive and behavioral dysfunction associated with vitamin B12 deficiency. Neurocase 14:147–150

    Article  PubMed  Google Scholar 

  • Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E, Buring JE, Manson JE (2008) Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 299:2027–2036

    Article  PubMed  CAS  Google Scholar 

  • Andersson HC, Marble M, Shapira E (1999) Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med 1:146–150

    Article  PubMed  CAS  Google Scholar 

  • Armitage JM, Bowman L, Clarke RJ, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, Parish S, Sleight P, Peto R, Collins R (2010) Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 303:2486–2494

    Article  PubMed  CAS  Google Scholar 

  • Augoustides-Savvopoulou P, Mylonas I, Sewell AC, Rosenblatt DS (1999) Reversible dementia in an adolescent with cblC disease: clinical heterogeneity within the same family. J Inherit Metab Dis 22:756–758

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner ER, Wick H, Linnell JC, Gaull GE, Bachmann C, Steinmann B (1979a) Congenital defect in intracellular cobalamin metabolism resulting in homocystinuria and methylmalonic aciduria. II. Biochemical investigations. Helv Paediatr Acta 34:483–496

    PubMed  CAS  Google Scholar 

  • Baumgartner ER, Wick H, Maurer R, Egli N, Steinmann B (1979b) Congenital defect in intracellular cobalamin metabolism resulting in homocysteinuria and methylmalonic aciduria. I. Case report and histopathology. Helv Paediatr Acta 34:465–482

    PubMed  CAS  Google Scholar 

  • Beauchamp MH, Anderson V, Boneh A (2009) Cognitive and social profiles in two patients with cobalamin C disease. J Inherit Metab Dis

  • Ben-Omran TI, Wong H, Blaser S, Feigenbaum A (2007) Late-onset cobalamin-C disorder: a challenging diagnosis. Am J Med Genet A 143A:979–984

    Article  PubMed  CAS  Google Scholar 

  • Biancheri R, Cerone R, Rossi A, Schiaffino MC, Caruso U, Minniti G, Perrone MV, Tortori-Donati P, Veneselli E (2002) Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia 43:616–622

    Article  PubMed  Google Scholar 

  • Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL (2001) Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56:1113

    PubMed  CAS  Google Scholar 

  • Bodamer OA, Sahoo T, Beaudet AL, O'Brien WE, Bottiglieri T, Stockler-Ipsiroglu S, Wagner C, Scaglia F (2005) Creatine metabolism in combined methylmalonic aciduria and homocystinuria. Ann Neurol 57:557–560

    Article  PubMed  CAS  Google Scholar 

  • Boxer AL, Kramer JH, Johnston K, Goldman J, Finley R, Miller BL (2005) Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology 64:1431–1434

    Article  PubMed  CAS  Google Scholar 

  • Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type). Am J Med Genet 36:167–171

    Article  PubMed  CAS  Google Scholar 

  • Brosnan JT, da Silva RP, Brosnan ME (2011) The metabolic burden of creatine synthesis. Amino Acids 40:1325–1331

    Article  PubMed  CAS  Google Scholar 

  • Brunelli SM, Meyers KE, Guttenberg M, Kaplan P, Kaplan BS (2002) Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 17:800–803

    Article  PubMed  Google Scholar 

  • Carmel R, Bedros AA, Mace JW, Goodman SI (1980) Congenital methylmalonic aciduria–homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test. Blood 55:570–579

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Chenel C, Wood C, Gourrier E, Zittoun J, Casadevall I, Ogier H (1993) Neonatal hemolytic-uremic syndrome, methylmalonic aciduria and homocystinuria caused by intracellular vitamin B 12 deficiency. Value of etiological diagnosis. Arch Fr Pediatr 50:749–754

    PubMed  CAS  Google Scholar 

  • Chwatko G, Boers GH, Strauss KA, Shih DM, Jakubowski H (2007) Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J 21:1707–1713

    Article  PubMed  CAS  Google Scholar 

  • Cogan DG, Schulman J, Porter RJ, Mudd SH (1980) Epileptiform ocular movements with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 90:251–253

    PubMed  CAS  Google Scholar 

  • Colucci M, Cattaneo M, Martinelli I, Semeraro F, Binetti BM, Semeraro N (2008) Mild hyperhomocysteinemia is associated with increased TAFI levels and reduced plasma fibrinolytic potential. J Thromb Haemost 6:1571–1577

    PubMed  CAS  Google Scholar 

  • Cusmano-Ozog K, Levine S, Martin M, Nicholas E, Packman S, Rosenblatt D, Cederbaum S, Cowan T, Enns G (2007) Cobalamin C disease identified by newborn screening: The California experience. In: Program and abstracts for the SIMD annual meeting. Mol Genet Metab 90:227–265

  • Dayal S, Lentz SR (2007) Role of redox reactions in the vascular phenotype of hyperhomocysteinemic animals. Antioxid Redox Signal 9:1899–1909

    Article  PubMed  CAS  Google Scholar 

  • Dayal S, Lentz SR (2008) Murine models of hyperhomocysteinemia and their vascular phenotypes. Arterioscler Thromb Vasc Biol 28:1596–1605

    Article  PubMed  CAS  Google Scholar 

  • Dayal S, Wilson KM, Leo L, Arning E, Bottiglieri T, Lentz SR (2006) Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood 108:2237–2243

    Article  PubMed  CAS  Google Scholar 

  • Dayan AD, Ramsey RB (1974) An inborn error of vitamin B12 metabolism associated with cellular deficiency of coenzyme forms of the vitamin. Pathological and neurochemical findings in one case. J Neurol Sci 23:117–128

    Article  PubMed  CAS  Google Scholar 

  • De Bie I, Nizard SD, Mitchell GA (2009) Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type. Prenat Diagn 29:266–270

    Article  PubMed  CAS  Google Scholar 

  • Debray FG, Boulanger Y, Khiat A, Decarie JC, Orquin J, Roy MS, Lortie A, Ramos F, Verhoeven NM, Struys E, Blom HJ, Jakobs C, Levy E, Mitchell GA, Lambert M (2008) Reduced brain choline in homocystinuria due to remethylation defects. Neurology 71:44–49

    Article  PubMed  CAS  Google Scholar 

  • Dharmasena A, Calcagni A, Kerr AR (2008) Retinopathy in inherited transcobalamin II deficiency. Arch Ophthalmol 126:141–142

    Article  PubMed  Google Scholar 

  • Eberhardt RT, Forgione MA, Cap A, Leopold JA, Rudd MA, Trolliet M, Heydrick S, Stark R, Klings ES, Moldovan NI, Yaghoubi M, Goldschmidt-Clermont PJ, Farber HW, Cohen R, Loscalzo J (2000) Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 106:483–491

    Article  PubMed  CAS  Google Scholar 

  • Ellaway C, Christodoulou J, Kamath R, Carpenter K, Wilcken B (1998) The association of protein-losing enteropathy with cobalamin C defect. J Inherit Metab Dis 21:17–22

    Article  PubMed  CAS  Google Scholar 

  • Enns GM, Barkovich AJ, Rosenblatt DS, Fredrick DR, Weisiger K, Ohnstad C, Packman S (1999) Progressive neurological deterioration and MRI changes in cblC methylmalonic acidaemia treated with hydroxocobalamin. J Inherit Metab Dis 22:599–607

    Article  PubMed  CAS  Google Scholar 

  • Fearing MK, Marsden D (2003) Expanded newborn screening. Pediatr Ann 32:509–515

    PubMed  Google Scholar 

  • Finsterer J (2009) Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol 30:659–681

    Article  PubMed  Google Scholar 

  • Flott-Rahmel B, Schurmann M, Schluff P, Fingerhut R, Musshoff U, Fowler B, Ullrich K (1998) Homocysteic and homocysteine sulphinic acid exhibit excitotoxicity in organotypic cultures from rat brain. Eur J Pediatr 157(Suppl 2):S112–S117

    Article  PubMed  CAS  Google Scholar 

  • Folbergrova J (1997) Anticonvulsant action of both NMDA and non-NMDA receptor antagonists against seizures induced by homocysteine in immature rats. Exp Neurol 145:442–450

    Article  PubMed  CAS  Google Scholar 

  • Frattini D, Fusco C, Ucchino V, Tavazzi B, Della Giustina E (2010) Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. Pediatr Neurol 43:135–138

    Article  PubMed  Google Scholar 

  • Gaillard MC, Matthieu JM, Borruat FX (2008) Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders. Klin Monbl Augenheilkd 225:491–494

    Article  PubMed  Google Scholar 

  • Gaull GE, Von Berg W, Raiha NC, Sturman JA (1973) Development of methyltransferase activities of human fetal tissues. Pediatr Res 7:527–533

    PubMed  CAS  Google Scholar 

  • Geiman TM, Muegge K (2010) DNA methylation in early development. Mol Reprod Dev 77:105–113

    PubMed  CAS  Google Scholar 

  • Geraghty MT, Perlman EJ, Martin LS, Hayflick SJ, Casella JF, Rosenblatt DS, Valle D (1992) Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr 120:934–937

    Article  PubMed  CAS  Google Scholar 

  • Gerth C, Morel CF, Feigenbaum A, Levin AV (2008) Ocular phenotype in patients with methylmalonic aciduria and homocystinuria, cobalamin C type. J AAPOS 12:591–596

    Article  PubMed  Google Scholar 

  • Gold R, Bogdahn U, Kappos L, Toyka KV, Baumgartner ER, Fowler B, Wendel U (1996) Hereditary defect of cobalamin metabolism (homocystinuria and methylmalonic aciduria) of juvenile onset. J Neurol Neurosurg Psychiatry 60:107–108

    Article  PubMed  CAS  Google Scholar 

  • Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, Mougenot B, Rosenblatt DS, Deschenes G (2005) Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 45:588–595

    Article  PubMed  CAS  Google Scholar 

  • Hajjar KA, Mauri L, Jacovina AT, Zhong F, Mirza UA, Padovan JC, Chait BT (1998) Tissue plasminogen activator binding to the annexin II tail domain. Direct modulation by homocysteine. J Biol Chem 273:9987–9993

    Article  PubMed  CAS  Google Scholar 

  • Handy DE, Zhang Y, Loscalzo J (2005) Homocysteine down-regulates cellular glutathione peroxidase (GPx1) by decreasing translation. J Biol Chem 280:15518–15525

    Article  PubMed  CAS  Google Scholar 

  • Harding CO, Pillers DA, Steiner RD, Bottiglieri T, Rosenblatt DS, Debley J, Michael Gibson K (2003) Potential for misdiagnosis due to lack of metabolic derangement in combined methylmalonic aciduria/hyperhomocysteinemia (cblC) in the neonate. J Perinatol 23:384–386

    Article  PubMed  Google Scholar 

  • Heydrick SJ, Weiss N, Thomas SR, Cap AP, Pimentel DR, Loscalzo J, Keaney JF Jr (2004) L-Homocysteine and L-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med 36:632–640

    Article  PubMed  CAS  Google Scholar 

  • Hofmann MA, Lalla E, Lu Y, Gleason MR, Wolf BM, Tanji N, Ferran LJ Jr, Kohl B, Rao V, Kisiel W, Stern DM, Schmidt AM (2001) Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107:675–683

    Article  PubMed  CAS  Google Scholar 

  • Horster F, Surtees R, Hoffmann GF (2005) Disorders of intermediary metabolism: toxic leukoencephalopathies. J Inherit Metab Dis 28:345–356

    Article  PubMed  CAS  Google Scholar 

  • Howard R, Frieden IJ, Crawford D, McCalmont T, Levy ML, Rosenblatt DS, Sweetman L, Goodman SI, Ohnstad C, Hart K, Berrios M, Packman S (1997) Methylmalonic acidemia, cobalamin C type, presenting with cutaneous manifestations. Arch Dermatol 133:1563–1566

    Article  PubMed  CAS  Google Scholar 

  • Huemer M, Simma B, Fowler B, Suormala T, Bodamer OA, Sass JO (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472

    Article  PubMed  CAS  Google Scholar 

  • Jacovina AT, Deora AB, Ling Q, Broekman MJ, Almeida D, Greenberg CB, Marcus AJ, Smith JD, Hajjar KA (2009) Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis. J Clin Invest 119:3384–3394

    PubMed  CAS  Google Scholar 

  • Jakubowski H (1997) Metabolism of homocysteine thiolactone in human cell cultures. Possible mechanism for pathological consequences of elevated homocysteine levels. J Biol Chem 272:1935–1942

    PubMed  CAS  Google Scholar 

  • Jakubowski H (1999) Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J 13:2277–2283

    PubMed  CAS  Google Scholar 

  • Jakubowski H (2000) Homocysteine thiolactone: metabolic origin and protein homocysteinylation in humans. J Nutr 130:377S–381S

    PubMed  CAS  Google Scholar 

  • Jakubowski H (2002) Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease. J Biol Chem 277:30425–30428

    Article  PubMed  CAS  Google Scholar 

  • Kamath AF, Chauhan AK, Kisucka J, Dole VS, Loscalzo J, Handy DE, Wagner DD (2006) Elevated levels of homocysteine compromise blood-brain barrier integrity in mice. Blood 107:591–593

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi M, Kashii S, Honda Y, Tamura Y, Kaneda K, Akaike A (1997) Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci 38:848–854

    PubMed  CAS  Google Scholar 

  • Kind T, Levy J, Lee M, Kaicker S, Nicholson JF, Kane SA (2002) Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period. J Pediatr Hematol Oncol 24:327–329

    Article  PubMed  Google Scholar 

  • Kubova H, Folbergrova J, Mares P (1995) Seizures induced by homocysteine in rats during ontogenesis. Epilepsia 36:750–756

    Article  PubMed  CAS  Google Scholar 

  • Lee CC, Surtees R, Duchen LW (1992) Distal motor axonopathy and central nervous system myelin vacuolation caused by cycloleucine, an inhibitor of methionine adenosyltransferase. Brain 115(Pt 3):935–955

    Article  PubMed  Google Scholar 

  • Loland KH, Bleie O, Blix AJ, Strand E, Ueland PM, Refsum H, Ebbing M, Nordrehaug JE, Nygard O (2010) Effect of homocysteine-lowering B vitamin treatment on angiographic progression of coronary artery disease: a Western Norway B Vitamin Intervention Trial (WENBIT) substudy. Am J Cardiol 105:1577–1584

    Article  PubMed  CAS  Google Scholar 

  • Longo D, Fariello G, Dionisi-Vici C, Cannata V, Boenzi S, Genovese E, Deodato F (2005) MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics 36:366–372

    Article  PubMed  CAS  Google Scholar 

  • Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M (2011) Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet 157:72–78

    Article  PubMed  CAS  Google Scholar 

  • Maestro de las Casas C, Epeldegui M, Tudela C, Varela-Moreiras G, Perez-Miguelsanz J (2003) High exogenous homocysteine modifies eye development in early chick embryos. Birth Defects Res A Clin Mol Teratol 67:35–40

    Article  PubMed  CAS  Google Scholar 

  • Mamlok RJ, Isenberg JN, Rassin DK, Norcross K, Tallan HH (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia. Neuropediatrics 17:94–99

    Article  PubMed  CAS  Google Scholar 

  • Mares P, Folbergrova J, Kubova H (2004) Excitatory aminoacids and epileptic seizures in immature brain. Physiol Res 53(Suppl 1):S115–S124

    PubMed  CAS  Google Scholar 

  • Martinelli D, Deodato F, Dionisi-Vici C (2011) Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34:127–135

    Article  PubMed  CAS  Google Scholar 

  • Mc Guire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98:173–180

    Article  PubMed  CAS  Google Scholar 

  • McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111–128

    PubMed  CAS  Google Scholar 

  • McCully KS (1996) Homocysteine and vascular disease. Nat Med 2:386–389

    Article  PubMed  CAS  Google Scholar 

  • Mikael LG, Wang XL, Wu Q, Jiang H, Maclean KN, Rozen R (2009) Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 98:187–194

    Article  PubMed  CAS  Google Scholar 

  • Mitchell GA, Watkins D, Melancon SB, Rosenblatt DS, Geoffroy G, Orquin J, Homsy MB, Dallaire L (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415

    Article  PubMed  CAS  Google Scholar 

  • Mudd SH, Levy HL, Abeles RH, Jennedy JP Jr (1969) A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun 35:121–126

    Article  PubMed  CAS  Google Scholar 

  • Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154

    PubMed  CAS  Google Scholar 

  • Pinar-Sueiro S, Martinez-Fernandez R, Lage-Medina S, Aldamiz-Echevarria L, Vecino E (2010) Optic neuropathy in methylmalonic acidemia: the role of neuroprotection. J Inherit Metab Dis (in press)

  • Poloschek CM, Fowler B, Unsold R, Lorenz B (2005) Disturbed visual system function in methionine synthase deficiency. Graefes Arch Clin Exp Ophthalmol 243:497–500

    Article  PubMed  CAS  Google Scholar 

  • Powers JM, Rosenblatt DS, Schmidt RE, Cross AH, Black JT, Moser AB, Moser HW, Morgan DJ (2001) Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency. Ann Neurol 49:396–400

    Article  PubMed  CAS  Google Scholar 

  • Profitlich L, Kirmse B, Wasserstein MP, Diaz G, Srivastava S (2009a) Resolution of cor pulmonale after medical management in a patient with cblC-type methylmalonic aciduria and homocystinuria: a case report. Cases J 2:8603

    Article  PubMed  Google Scholar 

  • Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S (2009b) High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98:344–348

    Article  PubMed  CAS  Google Scholar 

  • Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Perez-Cerda C, Ribes A, Ugarte M, Perez B (2009) Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum Mutat 30:1558–1566

    Article  PubMed  CAS  Google Scholar 

  • Robb RM, Dowton SB, Fulton AB, Levy HL (1984) Retinal degeneration in vitamin B12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormalities. Am J Ophthalmol 97:691–696

    PubMed  CAS  Google Scholar 

  • Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538

    Article  PubMed  CAS  Google Scholar 

  • Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P (2001) Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol 22:554–563

    PubMed  CAS  Google Scholar 

  • Roze E, Gervais D, Demeret S, Ogier de Baulny H, Zittoun J, Benoist JF, Said G, Pierrot-Deseilligny C, Bolgert F (2003) Neuropsychiatric disturbances in presumed late-onset cobalamin C disease. Arch Neurol 60:1457–1462

    Article  PubMed  Google Scholar 

  • Russo P, Doyon J, Sonsino E, Ogier H, Saudubray JM (1992) A congenital anomaly of vitamin B12 metabolism: a study of three cases. Hum Pathol 23:504–512

    Article  PubMed  CAS  Google Scholar 

  • Sauls DL, Lockhart E, Warren ME, Lenkowski A, Wilhelm SE, Hoffman M (2006) Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia. Biochemistry 45:2480–2487

    Article  PubMed  CAS  Google Scholar 

  • Schimel AM, Mets MB (2006) The natural history of retinal degeneration in association with cobalamin C (cbl C) disease. Ophthalmic Genet 27:9–14

    Article  PubMed  CAS  Google Scholar 

  • Scott JM, Dinn JJ, Wilson P, Weir DG (1981) Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 2:334–337

    Article  PubMed  CAS  Google Scholar 

  • Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103

    Article  PubMed  Google Scholar 

  • Shinnar S, Singer HS (1984) Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. A treatable cause of dementia and myelopathy. N Engl J Med 311:451–454

    Article  PubMed  CAS  Google Scholar 

  • Smith SE, Kinney HC, Swoboda KJ, Levy HL (2006) Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 88:138–145

    Article  PubMed  CAS  Google Scholar 

  • Steiner RD (2005) Evidence based medicine in inborn errors of metabolism: is there any and how to find it. Am J Med Genet A 134A:192–197

    Article  PubMed  Google Scholar 

  • Surtees R (1998) Demyelination and inborn errors of the single carbon transfer pathway. Eur J Pediatr 157(Suppl 2):S118–S121

    Article  PubMed  CAS  Google Scholar 

  • Tangney CC, Tang Y, Evans DA, Morris MC (2009) Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology 72:361–367

    Article  PubMed  CAS  Google Scholar 

  • Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L (2008) The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 79:725–728

    Article  PubMed  CAS  Google Scholar 

  • Topal G, Brunet A, Millanvoye E, Boucher JL, Rendu F, Devynck MA, David-Dufilho M (2004) Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med 36:1532–1541

    Article  PubMed  CAS  Google Scholar 

  • Traboulsi EI, Silva JC, Geraghty MT, Maumenee IH, Valle D, Green WR (1992) Ocular histopathologic characteristics of cobalamin C type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 113:269–280

    PubMed  CAS  Google Scholar 

  • Tsai AC, Morel CF, Scharer G, Yang M, Lerner-Ellis JP, Rosenblatt DS, Thomas JA (2007) Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. Am J Med Genet A 143A:2430–2434

    Article  PubMed  CAS  Google Scholar 

  • Tsina EK, Marsden DL, Hansen RM, Fulton AB (2005) Maculopathy and retinal degeneration in cobalamin C methylmalonic aciduria and homocystinuria. Arch Ophthalmol 123:1143–1146

    Article  PubMed  Google Scholar 

  • Undas A, Brozek J, Szczeklik A (2005) Homocysteine and thrombosis: from basic science to clinical evidence. Thromb Haemost 94:907–915

    PubMed  CAS  Google Scholar 

  • Ungvari Z, Csiszar A, Edwards JG, Kaminski PM, Wolin MS, Kaley G, Koller A (2003) Increased superoxide production in coronary arteries in hyperhomocysteinemia: role of tumor necrosis factor-alpha, NAD(P)H oxidase, and inducible nitric oxide synthase. Arterioscler Thromb Vasc Biol 23:418–424

    Article  PubMed  CAS  Google Scholar 

  • Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J (1997) Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem 272:17012–17017

    Article  PubMed  CAS  Google Scholar 

  • Van Hove JL, Van Damme-Lombaerts R, Grunewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B (2002) Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet 111:195–201

    Article  PubMed  Google Scholar 

  • Vitvitsky V, Dayal S, Stabler S, Zhou Y, Wang H, Lentz SR, Banerjee R (2004) Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol 287:R39–R46

    Article  PubMed  CAS  Google Scholar 

  • Vockley J, Vockley CM (2010) Clinical trials: curing a critical deficiency in metabolic medicine. Mol Genet Metab 99:244–245

    Article  PubMed  CAS  Google Scholar 

  • Wall RT, Harlan JM, Harker LA, Striker GE (1980) Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 18:113–121

    Article  PubMed  CAS  Google Scholar 

  • Weir DG, Keating S, Molloy A, McPartlin J, Kennedy S, Blanchflower J, Kennedy DG, Rice D, Scott JM (1988) Methylation deficiency causes vitamin B12-associated neuropathy in the pig. J Neurochem 51:1949–1952

    Article  PubMed  CAS  Google Scholar 

  • Weisfeld-Adams JD, Morrissey MA, Kirmse BM, Salveson BR, Wasserstein MP, McGuire PJ, Sunny S, Cohen-Pfeffer JL, Yu C, Caggana M, Diaz GA (2010) Newborn screening and early biochemical follow-up in combined methylmalonic aciduria and homocystinuria, cblC type, and utility of methionine as a secondary screening analyte. Mol Genet Metab 99:116–123

    Article  PubMed  CAS  Google Scholar 

  • Weiss N, Zhang YY, Heydrick S, Bierl C, Loscalzo J (2001) Overexpression of cellular glutathione peroxidase rescues homocyst(e)ine-induced endothelial dysfunction. Proc Natl Acad Sci U S A 98:12503–12508

    Article  PubMed  CAS  Google Scholar 

  • Williams ZR, Hurley PE, Altiparmak UE, Feldon SE, Arnold GL, Eggenberger E, Mejico LJ (2009) Late onset optic neuropathy in methylmalonic and propionic acidemia. Am J Ophthalmol 147:929–933

    Article  PubMed  CAS  Google Scholar 

  • Wu S, Gonzalez-Gomez I, Coates T, Yano S (2005) Cobalamin C disease presenting with hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol 22:717–721

    Article  PubMed  Google Scholar 

  • Younessi D, Moseley K, Yano S (2009) Creatine metabolism in combined methylmalonic aciduria and homocystinuria disease revisited. Ann Neurol 65:481–482, author reply 482–3

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A18, Bethesda, MD, 20892, USA

    Nuria Carrillo-Carrasco & Charles P. Venditti

Authors
  1. Nuria Carrillo-Carrasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles P. Venditti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles P. Venditti.

Additional information

Communicated by: Johan Lodewijk Karel Van Hove

References to electronic databases: Methylmalonic aciduria and homocystinuria cblC type: OMIM #277400.

MMACHC gene: OMIM *609831.

Methionine synthase: EC 1.16.1.8.

Methylmalonyl-CoA mutase: EC 5.4.99.2.

Competing interests: None declared

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Ophthalmologic complications in patients with cblC disease (DOCX 191 kb)

Supplementary Table 2

Outcome of patients with cblC disease and their therapeutic regimens (DOCX 159 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carrillo-Carrasco, N., Venditti, C.P. Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes. J Inherit Metab Dis 35, 103–114 (2012). https://doi.org/10.1007/s10545-011-9365-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-011-9365-x

Keywords

Search

Navigation