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Cbl\u2010C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The gene responsible for the Cbl\u2010C defect has been recently identified, and more than 40 mutations have been reported. <jats:italic>MMACHC<\/jats:italic> gene is located on chromosome 1p and catalyzes the reductive decyanation of CNCbl. Cbl\u2010C patients present with a heterogeneous clinical picture and, based on their age at onset, can be categorized into two distinct clinical forms. Early\u2010onset patients, presenting symptoms within the first year, show a multisystem disease with severe neurological, ocular, haematological, renal, gastrointestinal, cardiac, and pulmonary manifestations. Late\u2010onset patients present a milder clinical phenotype with acute or slowly progressive neurological symptoms and behavioral disturbances. To improve clinical course and metabolic abnormalities, treatment of Cbl\u2010C defect usually consists of a combined approach that utilizes vitamin B12 to increase intracellular cobalamin and to maximize deficient enzyme activities, betaine to provide a substrate for the conversion of homocysteine into methionine through betaine\u2010homocysteine methyltransferase, and folic acid to enhance remethylation pathway. No proven efficacy has been demonstrated for carnitine and dietary protein restriction. Despite these measures, the long\u2010term follow\u2010up is unsatisfactory especially in patients with early onset, with frequent progression of neurological and ocular impairment. The unfavorable outcome suggests that better understanding of the pathophysiology of the disease is needed to improve treatment protocols and to develop new therapeutic approaches.<\/jats:p>","DOI":"10.1007\/s10545-010-9161-z","type":"journal-article","created":{"date-parts":[[2010,7,14]],"date-time":"2010-07-14T15:31:21Z","timestamp":1279121481000},"page":"127-135","source":"Crossref","is-referenced-by-count":141,"title":["Cobalamin C defect: natural history, pathophysiology, and treatment"],"prefix":"10.1002","volume":"34","author":[{"given":"Diego","family":"Martinelli","sequence":"first","affiliation":[{"name":"Division of Metabolism Bambino Ges\u00f9 Children's Hospital Piazza S. Onofrio 4 Rome 00165 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Deodato","sequence":"additional","affiliation":[{"name":"Division of Metabolism Bambino Ges\u00f9 Children's Hospital Piazza S. 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