Hydroxocobalamin dose escalation improves metabolic control in cblC.
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.
Carrillo-Carrasco
N
N
Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A18, Bethesda, MD, 20892, USA.
Sloan
J
J
Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A18, Bethesda, MD, 20892, USA.
Valle
D
D
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hamosh
A
A
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Venditti
C P
CP
Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Building 49, Room 4A18, Bethesda, MD, 20892, USA. venditti@mail.nih.gov.
D000293:Adolescent; D000592:Amino Acid Metabolism, Inborn Errors / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006879:Hydroxocobalamin / Q000008:administration & dosage*; D020138:Hyperhomocysteinemia / Q000150:complications / Q000188:drug therapy; D007273:Injections, Intramuscular; D008297:Male; D016896:Treatment Outcome; D014806:Vitamin B 12 Deficiency / Q000150:complications / Q000188:drug therapy
D006879:Hydroxocobalamin