Cobalamin C defect: natural history, pathophysiology, and treatment

Abstract

Cobalamin C (Cbl-C) defect is the most common inborn cobalamin metabolism error; it causes impaired conversion of dietary vitamin B12 into its two metabolically active forms, methylcobalamin and adenosylcobalamin. Cbl-C defect causes the accumulation of methylmalonic acid and homocysteine and decreased methionine synthesis. The gene responsible for the Cbl-C defect has been recently identified, and more than 40 mutations have been reported. MMACHC gene is located on chromosome 1p and catalyzes the reductive decyanation of CNCbl. Cbl-C patients present with a heterogeneous clinical picture and, based on their age at onset, can be categorized into two distinct clinical forms. Early-onset patients, presenting symptoms within the first year, show a multisystem disease with severe neurological, ocular, haematological, renal, gastrointestinal, cardiac, and pulmonary manifestations. Late-onset 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-C 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-homocysteine 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-term follow-up 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.

Cobalamin C Disease Missed by Newborn Screening in a Patient with Low Carnitine Level

“…Early diagnosis and treatment can improve outcomes but cannot prevent all complications of CblC disease (Rosenblatt et al 1997;Andersson et al 1999;Boxer et al 2005;Smith et al 2006;Thauvin-Robinet et al 2007;Martinelli et al 2011;Aleman et al 2014). Early therapy may be particularly beneficial for late-onset patients, as it can be started prior to the development of any organ damage .…”

“…He was also initially started on a lowprotein diet that was subsequently liberalized. Hydroxycobalamin, rather than dietary therapy, is the definitive treatment for CblC (Martinelli et al 2011).…”

“…Methylcobalamin is required for the conversion of homocysteine to methionine by methionine synthase. Adenosylcobalamin is required for the conversion of methylmalonyl-CoA to succinyl-CoA by methylmalonyl-CoA mutase (Martinelli et al 2011). Therefore, CblC disease is characterized by elevated levels of homocysteine, low methionine level, and elevated methylmalonic acid (MMA).…”

Cobalamin C Deficiency in an Adolescent With Altered Mental Status and Anorexia

“…2 Cbl undergoes a series of modifications into its active forms: adenosylcobalamin, the cofactor for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA, and methylcobalamin, the cofactor for methionine synthase, which converts homocysteine to methionine. [3][4][5] Disorders of cbl metabolism are classified into several complementation classes, some of which (cblC, 6 cblD, 7 cblF, 8 cblJ, 9 and cblX 10 deficiencies) result in dysfunction of both methylmalonyl-CoA mutase and methionine synthase, and subsequent hyperhomocysteinemia and methylmalonic aciduria. [3][4][5] The most commonly affected complementation class is cblC, the incidence of which is estimated to be 1 in 100 000.…”

“…[3][4][5] Disorders of cbl metabolism are classified into several complementation classes, some of which (cblC, 6 cblD, 7 cblF, 8 cblJ, 9 and cblX 10 deficiencies) result in dysfunction of both methylmalonyl-CoA mutase and methionine synthase, and subsequent hyperhomocysteinemia and methylmalonic aciduria. [3][4][5] The most commonly affected complementation class is cblC, the incidence of which is estimated to be 1 in 100 000. 3,11 Approximately 400 patients with cblC deficiency have been described, with only 10% presenting in adolescence or adulthood.…”