Abstract
The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. Results: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with “overall impression” as judged by treating physicians. Physician’s impression of patient’s well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.
Similar content being viewed by others
References
Abeling NGGM, van Genip AH, Blom H et al (1999) Rapid diagnosis and methionine administration: basis for a favourable outcome in a patient with methylene-tetrahydrofolate reductase deficiency. J Inherit Metab Dis 22:240–242
Andersson HC (1998) Shapira. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with combined methylmalonic aciduria and homocystinuria (cblC). J Pediatr 132:121–124
Andersson HC, Merble M, Shapira E (1999) Long-term outcome in treated combined methylmalonic aciduria and homocystinuria. Genet Med 1:146–150
Bartholomew DW, Batshaw ML, Allen RH et al (1998) Therapeutic approaches to cobalamin C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39
Beauchamp MH, Anderson V, Boneh A (2009) Cognitive and social profiles in two patients with cobalamin C disease. J Inherit Metab Dis 32(1):S327–S334. doi:10.1007/s10545-009-1284-8
Bellini C, Cerone R, Bonacci W et al (1992) Biochemical diagnosis and outcome of 2 years treatment in a patient with combined methylmalonic aciduria and homocystinuria. Eur J Pediatr 151:818–820
Biancheri R, Cerone R, Schiaffino MC et al (2001) Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics 32:14–22
Biancheri R, Cerone R, Rossi A et al (2002) Early-onset cobalamin C/D deficiency: epilepsy and electroenchephalographic features. Epilepsia 43:616–622
Bodamer O, Fowler B (2004) Workshop CobalaminC/D. In Proceedings of 36th EMG Meeting Rimini, Italy May 14–16. Milupa, Uxbridge
Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL (2001) Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology 56:1113
Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Corpulmonale as a complication of methylmalonic acidemia and homocystinuria (Cbl-C type). Am J Med Genet 26:167–171
Carrillo-Carrasco N, Venditti CP (2012) Combined methylmalonic academia and homocystinuria, cblC type. II. Complications, pathophysiology and outcomes. J Inherit Metab Dis 35:103–114
Carrillo-Carrasco N, Chandler RJ, Venditti CP (2012) Combined methylmalonic academia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. J Inherit Metab Dis 35:91–102
Cerone R, Schiaffino MC, Caruso U, Lupino S, Gatti R (1999) Minor facial anomalies in combined methylmalonic aciduria and homocystinuria due to a defect in cobalamin metabolism. J Inherit Metab Dis 22:247–250
De Bie I, Nizard SD, Mitchell GA (2009) Fatal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type. Prenatal Diagn. 29:266–270
Dionisi-Vici C, Martinelli D, Ceravolo F, Boenzi S, Pastore A (2013) Optimizing the dose of hydroxocobalamin in cobalamin C (cblC) defect. Mol Genet Metab 109:329–330
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
Fowler B (1998) Genetic defects in folate and cobalamin metabolism. Eur J Pediatr 157(Suppl):S60–S66
Fowler B, Jakobs C (1998) Post- and Prenatal diagnostic methods for the homocystinurias. Eur J Pediatr 157:88–93
Geraghty MT, Perlman EJ, Martin LS et al (1992) Cobalamin C defect associated with hemolytic –uremic syndrome. J Pediatr 120:934–937
Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291
Grünert SC, Fowler B, Superti-Furga A, Sass JO, Schwab KO (2011) Hyperpyrexia resulting in encephalopathy in a 14-month-old patient with cblC disease. Brain Dev 33:432–436
Gutiérrez-Suárez R, Pistorio A, Cespedes Cruz A, Norambuena X, Flato B, Rumba I, Harjacek M, Nielsen S, Susic G, Mihaylova D, Huemer C, Melo-Gomes J, Andersson-Gare B, Balogh Z, De Cunto C, Vesely R, Pagava K, Romicka AM, Burgos-Vargas R, Martini A, Ruperto N (2007) Pediatric Rheumatology International Trials Organisation (PRINTO). Health-related quality of life of patients with juvenile idiopathic arthritis coming from 3 different geographic areas. The PRINTO multinational quality of life cohort study. Rheumatology 46:314–320
Heil SG, Hogeveen M, Kluijtmans LA et al (2007) Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (cblC type). J Inherit Metab Dis 30:811
Heinemann MK, Tomaske M, Trefz FK, Bosk A, Baden W, Ziemer G (2001) Ventricular septal defect closure in a neonate with combined methylmalonic aciduria/homocystinuria. Ann Thorac Surg 72:1391–1392
Huemer M, Simma B, Fowler B, Suormala T, \ OA, Sass JO (2005) Prenatal and postnatal treatment in cobalamin C defect. J Pediatr 147:469–472
Iodice FG, Di Chiara L, Boenzi S et al (2013) Cobalamin C defect presenting with isolated pulmonary hypertension. Pediatrics 132:e248–e251
Jorge-Finnigan A, Gámez A, Pérez B, Ugarte M, Richard E (2010) Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. Biochim Biophys Acta 1802:959–967
Kvittingen EA, Spangen S, Lindemans J, Fowler B (1997) Methionine synthase deficiency without megaloblastic anaemia. Eur J Pediatr 156:925–930
Lerner-Ellis JP, Tirone JC, Pawelek PD et al (2006) Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet 38:93–100
Lerner-Ellis JP, Anastasio N, Liu J et al (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations. Hum Mutat 30:1072–1081
Longo D, Fariello G, Dionisi-Vici C et al (2005) MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics 36:366–372
Mamlock RJ, Isenberg JN, Rassin DN (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anaemia. Neuropediatrics 17:94–99
Martinelli D, Dotta A, Massella L et al (2011a) Cobalamin C defect presenting as severe neonatal hyperammonemia. Eur J Pediatr 170:887–890
Martinelli D, Deodato F, Dionisi-Vici C (2011b) Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34:127–135
Mitchell BA, Watkins D, Melancon SB et al (1986) Clinical heterogeneity in cobalamin C variant of combined homocystinuria and methylmalonic aciduria. J Pediatr 108:410–415
Moat SJ, Bonham JR, Tanner MS, Allen JC, Powers HJ (1999) Recommended approaches for the laboratory measurement of homocysteine in the diagnosis and monitoring of patients with hyperhomocysteinaemia. Ann Clin Biochem 36:372–379
Morel CF, Lerner-Ellis JP, Rosenblatt DS (2006) Combined methylmalonicaciduria and homocystinuria (Cbl-C): phenotype genotype correlations and ethnic-specific observations. Mol Genet Metab 88:315–321
Nogueira C, Aiello C, Cerone R et al (2008) Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, Cbl-C type. Mol Genet Metab 93:475–480
Ogier de Baulny H, Gérard M, Saudubray JM, Zittoun J. Remethylation defects: guidelines for clinical diagnosis and treatment (1998) Eur J Pediatr 157:77–83
Pastore A, Martinelli D, Piemonte F, et al (2013) Glutathione metabolism in cobalamin deficiency type C (cblC). J Inherit Metat Dis. doi:10.1007/s10545-013-9605-3
Patton N, Beatty S, Lloyd IC, Wraith JE (2000) Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 21:151–154
Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S (2009) High prevalence of structural heart disease in children with Cbl-C-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98:344–348
Ribes A, Briones P, Vilaseca MA et al (1990) Methylmalonic aciduria with homocystinuria: biochemical studies, treatment, and clinical course of a Cbl-C patient. Eur J Pediatr 149:412–415
Ricci D, Pane M, Deodato F et al (2005) Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics 36:181–185
Richard E, Jorge-Finnigan A, Garcia-Villoria J et al (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
Robb RM, Dowton SB, Fulton AB, Levy HL (1984) Retinal degeneration in Vitamin B 12 disorder associated with methylmalonic aciduria and sulfur amino acid abnormaltities. Am J Ophthalmol 97:691–696
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
Roze E, Gervais D, Demeret S et al (2003) Neuropsychiatric disturbances in presumed late onset cobalamin C disease. Arch Neurol 60:1457–1462
Seid M, Huang B, Niehaus S, Brunner HI, Lovell DJ (2013) Determinants of health-related quality of life in children newly diagnosed with Juvenile Idiopathic Arthritis. Arthritis Care Res. doi:10.1002/acr.22117
Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (Cbl-C) disorder. Pediatr Nephrol 22:2097–2103
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
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
Thauvin-Robinet C, Roze E, Couvreur G et al (2008) The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 79:725–728
Tomaske M, Bosk A, Heinemann MK et al (2001) CblC/D defect combined with haemodynamically highly relevant VSD. J Inherit Metab Dis 24:511–512
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
Weintraub L, Tardo C, Rosenblatt D, Shapira E (1991) Hydrocephalus as a possible complication of the CblS type of methylmalonic aciduria (Abstract). Am J Hum Genet 49:108
Weisfeld-Adams JD, Bender HA, Miley-Åkerstedt A, Frempong T, Schrager NL, Patel K, Naidich TP, Stein V, Spat J, Towns S, Wasserstein MP, Peter I, Frank Y, Diaz GA (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
Wu S, Gonzalez-Gomez I, Coates T, Yano S (2005) Cobalamin C disease presenting with hemophagocytic lymphohistiocytosis. Pediatr Hematol Oncol 22:717–721
Acknowledgments
BF and MB were supported by the Swiss National Foundation, grant numbers 3200AO-109219/1 and 320000-122568/1. CD-V was supported by the grant “CCM 2010: Costruzione di percorsi diagnostico-assistenziali per le malattie oggetto di screening neonatale allargato” from the Italian Ministry of Health and by the grant R-12-92 from the “Fondazione Pierfranco e Luisa Mariani”. The clinical fellowship of DM was supported by the “Associazione la Vita è un Dono”.
Conflict of interest
Sabine Fischer, Martina Huemer, Federica Deodato, Diana Ballhausen, Avihu Boneh, Alberto B. Burlina, Roberto Cerone, Paula Garcia, Gülden Gökçay, Stephanie Grünewald, Johannes Häberle, Jaak Jaeken, David Ketteridge, Martin Lindner, Hanna Mandel, Esmeralda G. Martins, Karl O. Schwab, Sarah C. Gruenert, Bernd C. Schwahn, László Sztriha, Maren Tomaske, Friedrich Trefz, Laura Vilarinho and David S. Rosenblatt declare that they have no conflict of interest
Brian Fowler, Carlo Dionisi-Vici and Matthias Baumgartner and Diego Martinelli have received grants as listed in the acknowledgements.
Author information
Authors and Affiliations
Corresponding author
Additional information
Communicated by: John H. Walter
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Fig. 1
(DOC 51 kb)
Supplementary Table 1
(DOC 43 kb)
Supplementary Table 2
(DOC 82.5 kb)
Supplementary Table 3
(DOC 68 kb)
Rights and permissions
About this article
Cite this article
Fischer, S., Huemer, M., Baumgartner, M. et al. Clinical presentation and outcome in a series of 88 patients with the cblC defect. J Inherit Metab Dis 37, 831–840 (2014). https://doi.org/10.1007/s10545-014-9687-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10545-014-9687-6