title: Clinical and biochemical outcome after hydroxocobalamin dose escalation in a series of patients with cobalamin C deficiency.
abstract: BACKGROUND
  CblC deficiency produces a combination of methylmalonic aciduria (MMA) and homocystinuria (HCU), and is the most common error of cobalamin metabolism. Patients present a wide spectrum of symptoms, ranging from early severe multisystemic forms, to milder late-onset phenotypes. Cognitive and visual impairment are nearly constant. Hydroxocobalamin (OHCbl), betaine, folinic acid, levocarnitine and eventually dietary protein restriction are the main therapeutic approaches. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adaptation exist. No reports on long-term outcomes after high doses of this vitamin have been published.
  
  
  METHODS
  In this study five patients with CblC deficiency (early severe forms) were treated with high doses of OHCbl for 18 to 30months. Clinical examinations, neurological assessment, and biochemical studies (plasma total homocysteine (tHcy), amino acids, hydroxocobalamin, and methylmalonic acid in urine) were periodically performed.
  
  
  RESULTS
  Variable clinical and biochemical outcomes were observed in patients treated with high doses of OHCbl. The best biochemical response was observed in those children with the worse metabolic control. By contrast, those patients with a concentration of tHcy around 50μmol/l or less showed only minor changes. Clinically, a considerable improvement was observed in those patients with severe problems in communication, expressive language and behavior.
  
  
  CONCLUSIONS
  According to our study, high OHCbl doses in CblC deficiency could have a greater benefit in those children with a prior history of suboptimal metabolic control, and also in those with severe neurological phenotypes. More specifically, we observed improvements in communication skills and behavior. These results should encourage further prospective trials to determine the optimal OHCbl regimen and to generate protocols and guidelines in this rare disorder.
authors.affiliation: Department of Neurology, Hospital Sant Joan de Déu (HSJD), Barcelona, Spain.
authors.forename: I Vaz
authors.initials: IV
authors.lastname: Matos
authors.forename: E
authors.initials: E
authors.lastname: Castejón
authors.forename: S
authors.initials: S
authors.lastname: Meavilla
authors.forename: M
authors.initials: M
authors.lastname: O'Callaghan
authors.forename: J
authors.initials: J
authors.lastname: Garcia-Villoria
authors.forename: A
authors.initials: A
authors.lastname: López-Sala
authors.forename: A
authors.initials: A
authors.lastname: Ribes
authors.forename: R
authors.initials: R
authors.lastname: Artuch
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Cazorla
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006712:Homocystinuria / Q000175:diagnosis; D006801:Humans; D006879:Hydroxocobalamin / Q000008:administration & dosage*; D008297:Male; D016896:Treatment Outcome; D014805:Vitamin B 12 / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000188:drug therapy* / Q000473:pathology
chemical_list: D014805:Vitamin B 12; D006879:Hydroxocobalamin
keywords: Behavioral disturbances; Cobalamin C; Expressive language disorder; Homocysteine; Hydroxocobalamin treatment; Methylmalonic acid