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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
 

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