Hydroxocobalamin dose escalation improves metabolic control in cblC

Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Bethesda, MD 20892, USA.
Journal of Inherited Metabolic Disease (Impact Factor: 3.37). 10/2009; 32(6):728-31. DOI: 10.1007/s10545-009-1257-y
Source: PubMed


Cobalamin C (cblC), a combined form of methylmalonic acidaemia and hyperhomocysteinaemia, is recognized as the most frequent inborn error of intracellular cobalamin metabolism. This condition can be detected by expanded newborn screening and can have an acute neonatal presentation that is life-threatening if not suspected and promptly treated. Intramuscular (IM) hydroxocobalamin (OHCbl) is the main treatment for patients with cblC, but formal dosing guidelines do not exist. A clinical improvement and a decrease of plasma methylmalonic acid (MMA) and total homocysteine (tHcy) levels, and an increase in methionine are typically observed after its initiation. It is well recognized that despite treatment, long-term complications such as developmental delay and progressive visual loss, may still develop. We describe the biochemical response of a 13-year-old boy with worsening metabolic parameters despite strict adherence to a conventional treatment regimen. We progressively increased the OHCbl dose from 1 to 20 mg IM per day and observed a dose-dependent response with an 80% reduction of plasma MMA (25 to 5.14 micromol/L; normal range <0.27 micromol/L), a 55% reduction of tHcy (112 to 50 micromol/L; normal range: 0-13 micromol/L) and a greater than twofold increase in methionine (17 to 36 micromol/L; normal range: 7-47 micromol/L). This suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients, but it is unknown whether it may slow or eliminate other complications. Future clinical trials to determine the benefits of higher-dose OHCbl therapy in patients with cblC and other disorders of intracellular cobalamin metabolism should be planned.

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    • "Editor, I read the recent report by Carrillo-Carrasco et al. with a great interest (Carrillo-Carrasco et al. 2009). They reported a case of cobalamin C (CblC) and concluded that " higher hydroxocobalamin (OHCbl) doses might be required to achieve an optimal biochemical response in CblC patients, but it is unknown whether it may slow or eliminate other complications (Carrillo-Carrasco et al. 2009). " Indeed, the proper dosage of OHCbl in CblC patients is still a myth. "

    Journal of Inherited Metabolic Disease 03/2010; 33(4):453; author reply 455. DOI:10.1007/s10545-010-9068-8 · 3.37 Impact Factor
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    ABSTRACT: Derivatives of cobalamin (vitamin B(12)) are required for activity of two enzymes in humans. Adenosylcobalamin is required for activity of mitochondrial methylmalonylCoA mutase and methylcobalamin is required for activity of cytoplasmic methionine synthase. Deficiency in cobalamin, or inability to absorb cobalamin normally, can result in accumulation of methylmalonic acid and homocysteine in blood and urine. Methylmalonic acidemia can result in metabolic acidosis which in severe cases may be fatal. Hyperhomocysteinemia along with hypomethioninemia can result in hematologic (megaloblastic anemia, neutropenia, thrombocytopenia) and neurologic (subacute combined degeneration of the cord, dementia, psychosis) defects. Inborn errors affecting cobalamin absorption (inherited intrinsic factor deficiency, Imerslund–Gra¨ sbeck syndrome) and transport (transcobalamin deficiency) have been described. A series of inborn errors of intracellular cobalamin metabolism, designated cblA-cblG, have been differentiated by complementation analysis. These can give rise to isolated methylmalonic acidemia (cblA, cblB, cblD variant 2), isolated hyperhomocysteinemia (cblD variant 1, cblE, cblG) or combined methylmalonic acidemia and hyperhomocysteinemia (cblC, classic cblD, cblF). All these disorders are inherited as autosomal recessive traits. The genes underlying each of these disorders have been identified. Two other disorders, haptocorrin deficiency and transcobalamin receptor deficiency, have been described, but it is not clear that they have any consistent clinical phenotype.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 01/2001; 157(1):33-44. DOI:10.1002/ajmg.c.30288 · 3.91 Impact Factor
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    ABSTRACT: The most common inborn error of cobalamin (cbl) metabolism in China is the cblC type characterized by combined methylmalonic acidemia and hyperhomocysteinemia. The clinical presentation is relatively nonspecific, such as feeding difficulty, recurrent vomiting, hypotonia, lethargy, seizures, progressive developmental delay, and mental retardation, together with anemia and metabolic acidosis. More specific biochemical findings include high levels of propionylcarnitine (C3), free carnitine (C3/C0), and acetylcarnitine (C3/C2) measured by tandem mass spectrometry (MS/MS), elevation of methylmalonic acid (MMA) measured by gas chromatography-mass spectrometry (GC-MS), and increased total homocysteine with normal or decreased methionine. We report on 50 Chinese patients with combined methylmalonic acidemia and hyperhomocysteinemia. Forty-six belonged to the cblC complementation group. Mutation analysis of the MMACHC gene was performed to characterize the mutational spectrum of cblC deficiency, and 17 different mutations were found. Most were clustered in exons 3 and 4, accounting for 91.3% of all mutant alleles. Two mutations were novel, namely, c.315 C>G (p.Y105X) and c.470 G>C(p.W157S). In terms of genotype-phenotype correlation, the c.609 G>A mutation was associated with early-onset disease when homozygous. Unlike previous reports from other populations, c.609 G>A (p.W203X) was the most frequent cblC mutation detected in our study of Chinese patients, affecting 51 of 92 MMACHC alleles (55.4%). The high prevalence of this nonsense mutation could have potential therapeutic significance for Chinese cblC patients. Besides traditional approaches consisting of hydroxocobalamin injections, carnitine, betaine, and protein restriction, novel drugs that target premature termination codons may have a role in the future.
    Journal of Inherited Metabolic Disease 10/2010; 33(Suppl 3). DOI:10.1007/s10545-010-9217-0 · 3.37 Impact Factor
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