A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency

Abstract

PURPOSE Cobalamin C (cblC) deficiency impairs the biosynthesis of adenosyl- and methylcobalamin resulting in methylmalonic acidemia combined with hyperhomocysteinemia and hypomethioninemia. However, some patients with cblC deficiency are treated with medical foods, devoid of methionine and high in leucine content, that are formulated for patients with isolated propionate oxidative defects. We examined the effects of imbalanced branched-chain amino acid intake on growth outcomes in cblC patients. METHODS Dietary intake was correlated with biochemical, anthropometric, body composition measurements and other disease parameters in a cohort of 28 early-onset cblC patients. RESULTS Protein restricted diets were followed by 21% of the patients, while 32% received medical foods. Patients on protein-restricted diets had lower height-for-age Z-score (P=0.034), while patients consuming medical foods had lower head-circumference Z-scores (P=0.037), plasma methionine concentrations (P=0.001) and predicted methionine influx through the blood brain barrier Z-score (−1.29 vs. −0.0617, P=0.007). The combination of age of diagnosis, a history of seizures and the leucine/valine dietary intake ratio best predicted head circumference Z-score based on multiple regression modeling (R2= 0.945). CONCLUSIONS Patients with cblC deficiency treated with medical foods designed for isolated methylmalonic acidemia are at risk for iatrogenic methionine deficiency that could adversely affect brain growth and development. TRIAL REGISTRATION This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078

Milder clinical and biochemical phenotypes associated with the c.482G > A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening

“…The high frequency of the c.482G>A(p.Arg161Gln) pathogenic variant in our cohort contributes to this observation as 13/27 (48%) of our individuals are compound heterozygous for this variant compared to 4/86 (5%) individuals in these published studies (combined) 8, 9, 14–18 .…”

“…Other agents like betaine, folic acid, and carnitine may also be prescribed. A special diet, including protein restriction, is not necessary and not recommended 8,9 . The long term outlook of cobalamin C disease in the era of newborn screening is yet to be comprehensively explored.…”

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

“…Patients on protein-restricted diets had lower height-for-age z-score. Patients consuming medical foods with presumably low Met supply had lower head circumference and lower plasma Met concentrations (Manoli et al 2015). For these reasons, methionine-free formulas and protein restriction leading to low methionine plasma levels is contraindicated in cblC patients (Ogier de Baulny et al 1998; Manoli et al 2015).…”

A Highly Diverse Portrait: Heterogeneity of Neuropsychological Profiles in cblC Defect

“…Although patients with cblC were traditionally restricted in protein intake, in a recent survey, none of 88 European patients received protein restriction (Fischer et al 2014). Furthermore, recent studies of treatment in cblC found no benefit in restricting protein access and a possibly deleterious effect of using low-methionine medical foods (Manoli et al 2015). Hyperhomocystinuria is a known risk factor for thrombosis.…”