Skip to main content
SpringerLink
Log in

Clinical presentation and outcome in a series of 88 patients with the cblC defect

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

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.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Bartholomew DW, Batshaw ML, Allen RH et al (1998) Therapeutic approaches to cobalamin C methylmalonic acidemia and homocystinuria. J Pediatr 112:32–39

    Article  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Biancheri R, Cerone R, Rossi A et al (2002) Early-onset cobalamin C/D deficiency: epilepsy and electroenchephalographic features. Epilepsia 43:616–622

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  Google Scholar 

  • 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Fowler B (1998) Genetic defects in folate and cobalamin metabolism. Eur J Pediatr 157(Suppl):S60–S66

    Article  CAS  PubMed  Google Scholar 

  • Fowler B, Jakobs C (1998) Post- and Prenatal diagnostic methods for the homocystinurias. Eur J Pediatr 157:88–93

    Article  Google Scholar 

  • Geraghty MT, Perlman EJ, Martin LS et al (1992) Cobalamin C defect associated with hemolytic –uremic syndrome. J Pediatr 120:934–937

    Article  CAS  PubMed  Google Scholar 

  • Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291

    PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Iodice FG, Di Chiara L, Boenzi S et al (2013) Cobalamin C defect presenting with isolated pulmonary hypertension. Pediatrics 132:e248–e251

    Article  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • Kvittingen EA, Spangen S, Lindemans J, Fowler B (1997) Methionine synthase deficiency without megaloblastic anaemia. Eur J Pediatr 156:925–930

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Mamlock RJ, Isenberg JN, Rassin DN (1986) A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anaemia. Neuropediatrics 17:94–99

    Article  Google Scholar 

  • Martinelli D, Dotta A, Massella L et al (2011a) Cobalamin C defect presenting as severe neonatal hyperammonemia. Eur J Pediatr 170:887–890

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Ricci D, Pane M, Deodato F et al (2005) Assessment of visual function in children with methylmalonic aciduria and homocystinuria. Neuropediatrics 36:181–185

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • Roze E, Gervais D, Demeret S et al (2003) Neuropsychiatric disturbances in presumed late onset cobalamin C disease. Arch Neurol 60:1457–1462

    Google Scholar 

  • 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

    Google Scholar 

  • 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

    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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  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 

  • 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

    Google Scholar 

  • 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

    Article  CAS  PubMed  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 

Download references

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

  1. University Children’s Hospital Basel, Spitalstrasse 33, Basel, 4506, Switzerland

    Sabine Fischer & Brian Fowler

  2. Division of Metabolic Diseases and Children’s Research Center, University Children’s Hospital, Zürich, Switzerland

    Martina Huemer, Matthias Baumgartner, Johannes Häberle, Maren Tomaske & Brian Fowler

  3. Department of Pediatrics, Landeskrankenhaus Bregenz, Bregenz, Austria

    Martina Huemer

  4. Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Federica Deodato, Diego Martinelli & Carlo Dionisi-Vici

  5. Pédiatrie Moléculaire, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    Diana Ballhausen

  6. The Murdoch Children’s Research Institute and Royal Children’s Hospital, Melbourne, Australia

    Avihu Boneh

  7. Division of Inherited Metabolic Diseases, Department of Pediatrics, UniversityHospital, Padova, Italy

    Alberto B. Burlina

  8. Regional Center for Neonatal Screening and Diagnosis of Metabolic Diseases, University Department of Pediatrics-Istituto Giannina Gaslini, Genova, Italy

    Roberto Cerone

  9. Hospital Pediátrico do Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

    Paula Garcia

  10. Istanbul Medical Faculty, Children’s Hospital, Division, Nutrition and Metabolism, Istanbul University, Istanbul, Turkey

    Gülden Gökçay

  11. Metabolic Unit, Great Ormond Street Hospital and Clinical & Molecular Genetics Unit, UCL Institute of Child Health, London, UK

    Stephanie Grünewald

  12. Centre for Metabolic Disease, University Hospital Gasthuisberg, Leuven, Belgium

    Jaak Jaeken

  13. Metabolic Unit, SA Pathology at the Women’s & Children’s Hospital, North Adelaide, Australia

    David Ketteridge

  14. Division of Metabolic Diseases, University Children’s Hospital, Heidelberg, Germany

    Martin Lindner

  15. Metabolic Unit, Department of Pediatrics, Technion Faculty of Medicine, Rambam Medical Center, Haifa, Israel

    Hanna Mandel

  16. Unidade de Metabolismo, Centro Hospitalar do Porto, Porto, Portugal

    Esmeralda G. Martins

  17. Centre for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany

    Karl O. Schwab & Sarah C. Gruenert

  18. Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK

    Bernd C. Schwahn

  19. Department of Paediatrics, Division B, University of Szeged, Szeged, Hungary

    László Sztriha

  20. University Children’s Hospital Tübingen, Tübingen, Germany

    Maren Tomaske

  21. MVZ Kreiskliniken Reutlingen, Centre for Women, Children and Adolescents, Gammerting, Germany

    Friedrich Trefz

  22. Newborn Screening Unit, National Institute of Health, Porto, Portugal

    Laura Vilarinho

  23. Department of Human Genetics, Department of Medicine, McGill University, Montreal, Québec, Canada

    David S. Rosenblatt

Authors
  1. Sabine Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martina Huemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Baumgartner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Federica Deodato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Diana Ballhausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avihu Boneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alberto B. Burlina
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Roberto Cerone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paula Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gülden Gökçay
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stephanie Grünewald
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Johannes Häberle
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jaak Jaeken
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. David Ketteridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Martin Lindner
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hanna Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Diego Martinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Esmeralda G. Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Karl O. Schwab
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Sarah C. Gruenert
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Bernd C. Schwahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. László Sztriha
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Maren Tomaske
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Friedrich Trefz
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Laura Vilarinho
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. David S. Rosenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Brian Fowler
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Carlo Dionisi-Vici
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Brian Fowler.

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

Reprints 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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-014-9687-6

Keywords

Search

Navigation