PURPOSEMedical foods for methylmalonic and propionic acidemias (MMA/PA) contain minimal valine, isoleucine, methionine and threonine, but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of MMA patients ascertained via a natural history study.METHODSCross-sectional anthropometric and body composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA and 6 cblB).RESULTSPatients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut0: 99.45 ± 32.05% RDA). However, 85% received medical foods, the protein-equivalent in which often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight and height–for age Z-scores correlated negatively with the leucine/valine intake ratio (r=−0.453, P=0.014, R2=0.209 and r=−0.341, P=0.05, R2=0.123, respectively).CONCLUSIONIncreased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively, to ensure efficacy and safety.TRIAL REGISTRATIONThis clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078

Purpose-Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. Methods-Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the NIH (ClinicalTrials.gov identifier: NCT02890342). Results-Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P <0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m 2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared to serum cystatin C (P <0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P <0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. Conclusions-CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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

Investigations into the optimal composition of medical foods for MMA and propionic acidemia, and potential scenarios in which Leu supplementation may be beneficial are needed. Until then, MMA/propionic acidemia medical foods should be used judiciously in the dietary management of these patients and avoided altogether in cblC deficiency.

Purpose To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. Methods Data from a clinically diverse PA patient population (https://clinicaltrials.gov/ct2/show/NCT02890342) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. Results Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. Conclusion Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.