Abstract
Cobalamin C is a rare inborn disorder of metabolism that results in multisystemic abnormalities, including progressive visual deficits. Although the cellular pathophysiology of cblC is a field of active study, little attention has been dedicated to documenting the cognitive consequences of the defect. The neuropsychological assessment of nine individuals aged between 23 months and 24 years was conducted to establish cognitive profiles. Results reveal a marked heterogeneity, with intellectual functioning ranging from extremely low to average, and cognitive difficulties (e.g., attention) evidenced even in those who are not intellectually disabled. Central nervous system abnormalities and multisystem disease are likely to be major contributing factors to the observed cognitive impairments, with the presence of visual deficits constituting an additional impediment to normal cognitive development. This study underscores the importance of conducting in-depth neuropsychological assessments in individuals with cblC, the results of which may be particularly helpful for clinical management, guidance toward rehabilitation services, and educational/vocational planning.
Competing interests: None declared
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References
Beauchamp MH, Anderson V, Boneh A (2009) Cognitive and social profiles in two patients with cobalamin C disease. J Inherit Metab Dis 32(Suppl 1):S327–S334
Biancheri R, Cerone R, Schiaffino MC et al (2001) Cobalamin (Cbl) C/D deficiency: clinical, neurophysiological and neuroradiologic findings in 14 cases. Neuropediatrics 32(1):14–22
Boxer AL, Kramer JH, Johnston K, Goldman J, Finley R, Miller BL (2005) Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology 64(8):1431–1434
De Bie I, Nizard SD, Mitchell GA (2009) Fetal dilated cardiomyopathy: an unsuspected presentation of methylmalonic aciduria and hyperhomocystinuria, cblC type. Prenat Diagn 29(3):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(4):329–330
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(5):831–840
Gizicki R, Robert MC, Gomez-Lopez L et al (2014) Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type. Ophthalmology 121(1):381–386
Iodice FG, Di Chiara L, Boenzi S et al (2013) Cobalamin C defect presenting with isolated pulmonary hypertension. Pediatrics 132(1):e248–e251
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(1):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(7):1072–1081
Lezak MD, Howieson DB, Loring DW (2004) Neuropsychological assessment, 4th edn. Oxford University Press, New York
Longo D, Fariello G, Dionisi-Vici C et al (2005) MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics 36(6):366–372
Manoli I, Myles JG, Sloan JL et al (2015) A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency. Genet Med. doi:10.1038/gim.2015.107
Martinelli D, Deodato F, Dionisi-Vici C (2011) Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34(1):127–135
McGuire PJ, Parikh A, Diaz GA (2009) Profiling of oxidative stress in patients with inborn errors of metabolism. Mol Genet Metab 98(1-2):173–180
Mitchell GA, Gauthier N, Lesimple A, Wang SP, Mamer O, Qureshi I (2008) Hereditary and acquired diseases of acyl-coenzyme A metabolism. Mol Genet Metab 94(1):4–15
Morel CF, Lerner-Ellis JP, Rosenblatt DS (2006) Combined methylmalonic aciduria and homocystinuria (cblC): phenotype–genotype correlations and ethnic-specific observations. Mol Genet Metab 88(4):315–321
Profitlich LE, Kirmse B, Wasserstein MP, Diaz GA, Srivastava S (2009) High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Mol Genet Metab 98(4):344–348
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(11):1558–1566
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(4):528–538
Rossi A, Cerone R, Biancheri R et al (2001) Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings. AJNR Am J Neuroradiol 22(3):554–563
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(7):451–454
Tsai AC, Morel CF, Scharer G et al (2007) Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. Am J Med Genet A 143A(20):2430–2434
Varvogli L, Repetto GM, Waisbren SE, Levy HL (2000) High cognitive outcome in an adolescent with mut-methylmalonic acidemia. Am J Med Genet 96(2):192–195
Weisfeld-Adams JD, Bender HA, Miley-Akerstedt 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(3):241–247
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(4):537–546
World Health Organization (2003) Consultation on development of standards for characterization of vision loss and visual functioning. WHO, Geneva, pp 4–5. WHO document WHO/ICD-10/H54
Acknowledgments
A special thank you to Ms. Martyne Gosselin, biochemical genetics nurse, who was of great help in the recruitment and the organization of the project. We would also like to thank the laboratory of David Rosenblatt for performing diagnostic complementation analysis on patient fibroblasts.
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Communicated by: Matthias Baumgartner
Synopsis
This article explores the heterogeneous nature of neuropsychological functioning in individuals with cobalamin C defect.
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Conflict of Interest
Jenny Bellerose, Mathilde Neugnot-Cerioli, Catherine Brunel-Guitton, Grant A. Mitchell, Luis H. Ospina, Karine Bédard, and Miriam H. Beauchamp declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.
Details on the Contribution of Individual Authors
Jenny Bellerose: Development of study protocol and methodology, ethics submissions, data collection, analyses, and interpretation, writing of manuscript.
Mathilde Neugnot-Cerioli: Development of study protocol and methodology, data collection and analyses, interpretation of findings, manuscript editing and review.
Luis H. Ospina: Consultant for ophthalmological aspects, interpretation of opthalmological data, manuscript review.
Grant A. Mitchell: Development of study protocol, recruitment of patients, consultant for medical aspects, writing of manuscript.
Catherine Brunel-Guitton: Recruitment of patients, manuscript review.
Miriam H. Beauchamp (principal investigator): Development of study protocol and methodology, funding, supervision of J.B. and M.N.C., interpretation of data, writing of manuscript.
Karine Bédard: Performance and interpretation of molecular sequencing data.
Appendix: Abbreviations and Details of Neuropsychological Tests Administered
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Bellerose, J. et al. (2015). A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect. In: Morava, E., Baumgartner, M., Patterson, M., Rahman, S., Zschocke, J., Peters, V. (eds) JIMD Reports, Volume 29. JIMD Reports, vol 29. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2015_517
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DOI: https://doi.org/10.1007/8904_2015_517
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