There have been several advances in the understanding of the molecular basis of cblC disease. Diagnostic approaches have improved considerably, and cblC can be diagnosed early in life through expanded newborn screening (Fearing and Marsden 2003
). However, the management and outcome of patients with cblC disease have not changed significantly, and there is a need to perform clinical trials. One of the limiting factors in planning such studies is the lack of information regarding the natural history and factors associated with the outcome of patients with cblC disease. The present review attempts to compile the knowledge on the clinical manifestations and pathophysiology since cblC disease was identified in 1969 (Mudd et al. 1969
). It also systematically reviews the literature to understand the factors associated with the outcome in cblC disease.
We found that most publications related to cblC disease are case reports; we only found a few case series and small longitudinal studies; no controlled trials were identified. The clinical evaluation, biochemical parameters, monitoring strategies, and management of patients differed significantly among studies, and most did not include genotype data. The heterogeneity among publications and the lack of classification tools complicated the analysis and comparison of the data obtained.
Although cblC disease was identified more than 40 years ago, the management strategies have remained largely unchanged. Parenteral OHCbl remains the treatment of choice, and its use has likely decreased the infantile mortality rate in cblC disease considerably (Rosenblatt et al. 1997
). However, the treatment of cblC disease appears to be based on expert opinion rather than clinical trial results, similar to other rare disorders (Vockley and Vockley 2010
). Our review of the literature also showed that the treatment of cblC disease varies significantly, and patients receive different formulations, doses, and routes of administration of cobalamin. Not all patients are treated with betaine, and the supplementation of folic acid and carnitine is varied. The use of low-protein diets, which have the possibility to reduce methionine intake, is common. These therapeutic strategies are based on very limited evidence, and there have been no clinical trials to evaluate their efficacy.
When comparing the different therapeutic strategies reported in the literature, we found that the combination of daily doses of parenteral OHCbl with betaine provides a better outcome than other therapeutic strategies. An intermediate response was seen in patients given parenteral OHCbl less frequently or in those not receiving betaine. The review of published case reports discourages the use of CNCbl and oral OHCbl alone in the treatment of cblC, as they were associated consistently with a poor outcome in the cases reviewed (, Supplementary Table 2
Although infantile mortality has decreased considerably, there is a growing population of children and young adults with cblC disease who develop complications despite treatment. Patients with early-onset disease have a progressive visual loss leading to blindness in the first decade of life. None of the current interventions seem to slow the progression to blindness, although optimized therapy with OHCbl and betaine and early prenatal therapy could play a role. Patients with late-onset cblC disease have variable visual alterations, suggesting the severity of the disease correlates with the progression of eye disease.
There are few reports describing prenatal treatment in patients with cblC, but this strategy seems to improve the outcome of patients (Patton et al. 2000
; Huemer et al. 2005
). No cases of prenatal treatment before the third trimester of pregnancy have been reported. Since cblC is a developmental disorder, the initiation of prenatal interventions at the beginning of pregnancy may have a more significant impact.
Vascular complications are a major cause or morbidity and mortality in patients with early- and late-onset cblC disease (). Hyperhomocysteinemia is a recognized risk factor for vascular complications. Although tHcy levels improve with appropriate treatment in cblC disease, they are rarely reduced to safe levels. In our review of the literature, most patients remain in the moderate (26–50 µM) or severe (>50 µM) range, and several have levels above 100 µM. Interestingly, we found tHcy levels above 45 µM have been reported to be associated with the development of vascular complications in several patients. Whether these metabolite levels represent a goal for treatment is uncertain, but it is possible that if tHcy concentrations in cblC could be decreased below this range with optimized OHCbl and betaine doses, outcomes could be affected.
In conclusion, controlled studies are needed to provide appropriate evidence to guide clinical decisions in cblC disease, as has been suggested for other inborn errors of metabolism (Steiner 2005
; Vockley and Vockley 2010
). These include longitudinal studies to better define the natural history, progression, and factors associated with outcome in cblC disease. The information provided by such studies can be used to create appropriate classification tools to monitor patients and guide the choice of outcomes in controlled studies. Clinical trials are needed to determine whether higher doses of OHCbl, prenatal treatment, or other therapies could improve the management and outcome of patients with cblC disease.