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Journal of Pediatric Biochemistry 2016; 06(01): 025-029
DOI: 10.1055/s-0036-1582251
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Pathobiological Insights into Neurological Involvement in Cobalamin C Deficiency

Ferdinando Ceravolo
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Michele Grisolia
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Angela Nicolettti
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Simona Sestito
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Vincenzo Salpietro
2   Department of Pediatrics, University of Messina, Messina, Italy
3   Institute of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom
,
Agata Polizzi
4   National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
,
Martino Ruggieri
5   Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Giuseppe Bonapace
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Elisa Pascale
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
,
Daniela Concolino
1   Department of Medical and Surgical Science, Pediatric Unit, University “Magna Graecia”, Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

15 December 2015

28 January 2016

Publication Date:
26 April 2016 (online)

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Abstract

Cobalamin C (Cbl-C) defects are inherited autosomal recessive disorders of vitamin B12 (or cyanocobalamin [CNCbl]) metabolism. These defects are caused by mutations in the methylmalonic aciduria and homocystinuria Cbl-C type (MMACHC; MIM # 609831) gene located on chromosome 1p34.1, which catalyzes the reductive decyanation of CNCbl, thus impairing the biosynthesis of 5′-deoxyadenosylcobalamin, adenosylcobalamin, and methylcobalamin. This impairment results in methylmalonic acidemia [MMA; MIM # 277400] combined with hyperhomocysteinemia and hypomethioninemia. Clinically, Cbl-C defects are characterized by a constellation of systemic signs and symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy, are common in the early-onset form of the disease, but are rare in its adult-onset counterpart. Administration of hydroxocobalamin (OHCbl), betaine, and folinic acid represents main therapeutic approaches. No proven efficacy has been demonstrated for carnitine and dietary protein restrictions. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adjustment exist. Despite these measures, the long-term outcome is unsatisfactory especially in patients with early onset, who experience frequent progression of their neurological and ocular impairment. The unfavorable outcome suggests that a better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.

Keywords

cobalamin C - vitamin B12 - MMACHC gene
 

  • References

  • 1 Caterino M, Pastore A, Strozziero MG , et al. The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. J Inherit Metab Dis 2015; 38 (5) 969-979
    CrossrefPubMedGoogle Scholar
  • 2 Biancheri R, Cerone R, Rossi A , et al. Early-onset cobalamin C/D deficiency: epilepsy and electroencephalographic features. Epilepsia 2002; 43 (6) 616-622
    CrossrefPubMedGoogle Scholar
  • 3 Pavone P, Spalice A, Polizzi A, Parisi P, Ruggieri M. Ohtahara syndrome with emphasis on recent genetic discovery. Brain Dev 2012; 34 (6) 459-468
    CrossrefPubMedGoogle Scholar
  • 4 Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev 2014; 36 (9) 739-751
    CrossrefPubMedGoogle Scholar
  • 5 Longo D, Fariello G, Dionisi-Vici C , et al. MRI and 1H-MRS findings in early-onset cobalamin C/D defect. Neuropediatrics 2005; 36 (6) 366-372
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Van der Knaap M, Valk J. Magnetic Resonance of Myelination and Myelin Disorders. 3rd ed. Berlin: Springer-Verlag; 2005
    CrossrefGoogle Scholar
  • 7 Patton N, Beatty S, Lloyd IC, Wraith JE. Optic atrophy in association with cobalamin C (cblC) disease. Ophthalmic Genet 2000; 21 (3) 151-154
    CrossrefPubMedGoogle Scholar
  • 8 Traboulsi EI, Silva JC, Geraghty MT, Maumenee IH, Valle D, Green WR. Ocular histopathologic characteristics of cobalamin C type vitamin B12 defect with methylmalonic aciduria and homocystinuria. Am J Ophthalmol 1992; 113 (3) 269-280
    CrossrefPubMedGoogle Scholar
  • 9 Thauvin-Robinet C, Roze E, Couvreur G , et al. The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum. J Neurol Neurosurg Psychiatry 2008; 79 (6) 725-728
    PubMedGoogle Scholar
  • 10 Smith SE, Kinney HC, Swoboda KJ, Levy HL. Subacute combined degeneration of the spinal cord in cblC disorder despite treatment with B12. Mol Genet Metab 2006; 88 (2) 138-145
    CrossrefPubMedGoogle Scholar
  • 11 Martinelli D, Deodato F, Dionisi-Vici C. Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 2011; 34 (1) 127-135
    CrossrefPubMedGoogle Scholar
  • 12 Wong A, Mok V, Fan YH, Lam WW, Liang KS, Wong KS. Hyperhomocysteinemia is associated with volumetric white matter change in patients with small vessel disease. J Neurol 2006; 253 (4) 441-447
    CrossrefPubMedGoogle Scholar
  • 13 Kölker S, Sauer SW, Hoffmann GF, Müller I, Morath MA, Okun JG. Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 2008; 31 (2) 194-204
    CrossrefPubMedGoogle Scholar
  • 14 Scott JM, Dinn JJ, Wilson P, Weir DG. Pathogenesis of subacute combined degeneration: a result of methyl group deficiency. Lancet 1981; 2 (8242) 334-337
    PubMedGoogle Scholar
  • 15 Lee CC, Surtees R, Duchen LW. Distal motor axonopathy and central nervous system myelin vacuolation caused by cycloleucine, an inhibitor of methionine adenosyltransferase. Brain 1992; 115 (Pt 3) 935-955
    CrossrefPubMedGoogle Scholar
  • 16 Kruman II, Culmsee C, Chan SL , et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000; 20 (18) 6920-6926
    PubMedGoogle Scholar
  • 17 Di Rocco A, Bottiglieri T, Werner P , et al. Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy. Neurology 2002; 58 (5) 730-735
    CrossrefPubMedGoogle Scholar
  • 18 Longo N, Ardon O, Vanzo R, Schwartz E, Pasquali M. Disorders of creatine transport and metabolism. Am J Med Genet C Semin Med Genet 2011; 157C (1) 72-78
    PubMedGoogle Scholar
  • 19 Bodamer OA, Sahoo T, Beaudet AL , et al. Creatine metabolism in combined methylmalonic aciduria and homocystinuria. Ann Neurol 2005; 57 (4) 557-560
    CrossrefPubMedGoogle Scholar
  • 20 Maestro de las Casas C, Epeldegui M, Tudela C, Varela-Moreiras G, Pérez-Miguelsanz J. High exogenous homocysteine modifies eye development in early chick embryos. Birth Defects Res A Clin Mol Teratol 2003; 67 (1) 35-40
    CrossrefPubMedGoogle Scholar
  • 21 Kikuchi M, Kashii S, Honda Y, Tamura Y, Kaneda K, Akaike A. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthalmol Vis Sci 1997; 38 (5) 848-854
    PubMedGoogle Scholar
  • 22 Vidal-Alaball J, Butler CC, Cannings-John R , et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev 2005; 20 (3) CD004655
    PubMedGoogle Scholar
  • 23 Dionisi-Vici C, Martinelli D, Ceravolo F, Boenzi S, Pastore A. Optimizing the dose of hydroxocobalamin in cobalamin C (cblC) defect. Mol Genet Metab 2013; 109 (4) 329-330
    CrossrefPubMedGoogle Scholar
  • 24 Spector R. Cerebrospinal fluid folate and the blood brain barrier. In: Botez M, Reynolds E, eds. Folic Acid in Neurology, Psychiatry, and Internal Medicine. New York, NY: Reven Press; 1979: 187-194
    Google Scholar
  • 25 Smulders YM, Smith DE, Kok RM , et al. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. Br J Haematol 2006; 132 (5) 623-629
    CrossrefPubMedGoogle Scholar
  • 26 Bartholomew DW, Batshaw ML, Allen RH , et al. Therapeutic approaches to cobalamin-C methylmalonic acidemia and homocystinuria. J Pediatr 1988; 112 (1) 32-39
    CrossrefPubMedGoogle Scholar
  • 27 Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR. Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 1997; 20 (4) 528-538
    CrossrefPubMedGoogle Scholar
  • 28 Andersson HC, Marble M, Shapira E. Long-term outcome in treated combined methylmalonic acidemia and homocystinemia. Genet Med 1999; 1 (4) 146-150
    CrossrefPubMedGoogle Scholar