Efficacy of early treatment in patients with cobalamin C disease identified by newborn screening: a 16-year experience

Abstract

Purpose Despite implementation of newborn screening (NBS), outcomes in cobalamin C disease (cblC) remain poor. Therapy with hydroxycobalamin and betaine is widely used, but dietary recommendations vary among metabolic centers. We present a longitudinal analysis of the relationship between metabolic control, diet, and outcomes in a cohort of cblC patients. Methods We completed a retrospective analysis of 12 patients with cblC referred for abnormal NBS results and followed in our center between 1999 and 2015. Results Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had one episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. We found no relationship between diet and cognitive outcomes. Conclusions Although dietary therapy for cblC patients improves metabolic control, few patients experience metabolic decompensation regardless of diet. Increased incomplete protein intake is not correlated with improvements in outcomes. Overall, outcomes are poor despite early initiation of therapy and regardless of the dietary strategy used.

Phenotype, treatment practice and outcome in the cobalamin‐dependent remethylation disorders and MTHFR deficiency: Data from the E‐HOD registry

“…Early diagnosis by means of NBS is associated with decreased mortality and less severe organ damage. 24,25 Furthermore, the diagnostic delay for clinically presenting cases was relatively short in our sample. The widespread availability of tHcy measurement and the growing familiarity with MMA as a parameter in acquired vitamin B12 deficiency 26 probably contributed to this, as well as the increased awareness for rare diseases in general and remethylation disorders in particular.…”

“…Our observation that 43 patients were treated with protein restriction with or without additional supplementation of amino acid products requires further exploration given the results of Manoli et al and Ahrens‐Nicklas et al . While our study could neither identify nor confirm the unintended lowering of branched chain amino acids or methionine, this effect may well have been missed given the non‐experimental, retrospective design of this study.…”

“…Early diagnosis by pre‐clinical screening may be one reason for this observation. Early diagnosis by means of NBS is associated with decreased mortality and less severe organ damage . Furthermore, the diagnostic delay for clinically presenting cases was relatively short in our sample.…”

“…As first reported by Manoli et al, our data show that 19 of 47 European and US centres apply dietary treatment despite convincing evidence against this approach. Ahrens‐Nicklas et al reported that the intake of medical foods improved metabolic control but resulted in perturbations of essential amino acids ratios and lower z‐scores for head circumference in their cblC cohort. A protein‐reduced diet would be expected to decrease Met and, consequently, methylation capacity even further.…”

Treatable Inherited Movement Disorders in Children: Spotlight on Clinical and Biochemical Features

“…Severe forms of propionic acidemia, methylmalonic acidemia, and maple syrup urine disease are candidates for early liver transplantation to prevent severe and irreversible neurological impairment. In cobalamin C patients, presymptomatic treatment prevents or limits metabolic decompensations, Globus pallidus (GP) lesions, and related MDs …”