A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias

Abstract

Purpose: Medical foods for methylmalonic acidemias (MMAs) and propionic acidemias 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 patients with MMA ascertained via a natural history study.

Methods: Cross-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).

Results: Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut(0): 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent 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-to-valine intake ratio (r = -0.453; P = 0.014; R(2) = 0.209 and r = -0.341; P = 0.05; R(2) = 0.123, respectively).

Conclusion: Increased 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.Genet Med 18 4, 386-395.

Conflict of interest statement

Disclosures: All authors have no conflicts of interest to declare.

Figures

Figure 1

A. Height-, weight- and BMI-for-age Z-scores for patients 20 y and under (N=28 mut0, 3 mut−, 5 cblA, 2 cblB) are depicted in a box plot. The box represents the middle 50% of all cases per variable, while the remaining 50% is contained between the box and whiskers on each side. The single line inside the box represents the median of the entire data set. The location of this line suggests the skewness in the distribution, when noticeably shifted away from the center, as is the case for the BMI-for-age Z-score in the mut0 subgroup. As evidenced by the Z-scores, mut0 patients were short and overweight or obese. B. Head circumference Z-score was lower in the mut0 group, −1.66 ± 1.63 (mean ± SD, N=22). C. Percent fat and fat-free (lean) mass are depicted by MMA subtype for non-transplanted patients in a box plot (N=28 mut0, 3 mut−, 7 cblA and 5 cblB). Percent fat mass was significantly higher in the muto subtype compared to the milder cblA subtype (one-way ANOVA between groups P=0.01, Bonferroni post-hoc correction between mut0 and cblA, *P=0.042 for %fat and *P=0.037 for %lean).

Figure 2

A. Daily protein intake (g/kg/day) is provided per patient sorted by age and MMA subtype (mut, cblA and cblB). A number of mut patients (N=7) required additional valine and/or isoleucine supplementation because of persistently low plasma amino acid levels during their follow-up monitoring by their home metabolic clinics (labeled with a star). Four of these patients had a complete protein intake at or above the RDA (recommended dietary allowance) for age (solid stars), while three were on a low complete protein diet (clear stars). Age-adjusted RDA is depicted as a dotted line. B. The mean daily complete protein intake is depicted as %RDA for protein for healthy children in a box plot. The box represents the middle 50% of all cases per variable, while the remaining 50% is contained between the box and whiskers on each side. The single line inside the box represents the median of the entire data set. Patients with the mut0 subtype consumed 99.45 ± 32.05% RDA complete protein (mean ± SD), mut− 119.0 ± 10.00%, cblA 139.6 ± 66.37 and cblB 68.83 ± 18.19% (N=31, 6, 8, and 6, respectively). Transplant recipients were excluded. Although adjusting for the high versus low biological value of dietary protein source might decrease slightly the aforementioned percentage, this analysis was not feasible based on existing dietary records. On the other hand, calculations are provided for the actual and not ideal weight of the patients, suggesting that protein intake would be more generous if expressed per gram of their decreased lean mass. C. The ratios of incomplete/complete protein intakes in the subset of patients consuming medical foods are provided per MMA subtype in a box-plot. Patients with mut0 MMA had a ratio of 1.16 ± 0.13 (mean ± SD), mut− 0.68 ± 0.20, cblA 0.63 ± 0.13 and cblB 1.53 ± 0.24 (N=24, 4, 3, and 4, respectively). 13/37 or 35.0% of mut patients on medical foods exceeded the current treatment guidelines of 1:1 ratio of complete to deficient protein intake. D and E. Daily intake of leucine, valine and isoleucine (mg/kg/day by age group) is provided for patients with the mut subtype of MMA in a box plot. Leucine intake was 222.0 ± 24.9 in the 2–9y olds, 173.33 ± 55.6 in the 10–18y olds, and 60.0 ± 20.8 in the >18y olds. The younger patients consumed amounts four to five times higher than the recommended DRI based on the 2007 FAO/WHO guidelines (DRI of 44–50 mg/kg/day, dotted line). High daily consumption was recorded even for the two propiogenic amino acids, valine and isoleucine, in the younger age groups.

Figure 3

A. Ratios of leucine over valine or isoleucine dietary intake are compared between patients on and off medical foods. Normal BCAA ratios with very narrow distribution were observed in patients who consumed no medical foods, (Leu/Val mean intake ratio was 1.54 ± 0.07, while Leu/Ile intake ratio was 1.73 ± 0.10, N=16, bars represent mean with 95%CI), in contrast to significantly higher ratios recorded in patients taking medical foods (Leu/Val of 3.82 ± 1.82 and Leu/Ile of 3.99 ± 1.65, N=34, independent t-test ****P<0.001 for both Leu/Val and Leu/Ile) as a result of the high leucine content in these formulations. B. Higher leucine over valine and isoleucine dietary intake ratios translated in reversed or higher ratios, respectively, in their relative plasma amino acids concentrations. Patients on medical foods had a reversed plasma Leu/Val ratio of 1.25 ± 0.74 and a close to two-fold increased ratio of Leu/Ile 3.58 ± 2.4, compared to patients on no medical foods (***P=0.003 and ****P<0.001 for Leu/Val and Leu/Ile). C. Amount of deficient protein intake (g/kg/day) was inversely related to the plasma valine (solid circles) and isoleucine (clear circles) concentrations. Although a range of plasma concentrations were observed in patients without medical food intake – depicted on the left aspect of the graph, the lowest plasma Val and Ile values were observed in patients consuming the highest amounts of medical food. D. Dietary leucine/valine intake showed a negative correlation to height-for-age (solid squares) and weight-for-age Z-scores (clear squares) in the subgroup of mut0 MMA patients, supporting that increased consumption of deficient protein administered at the expense of complete protein may adversely affect the growth parameters. Patients of comparable severity (age of onset, frequency and severity of metabolic crises/hospitalizations, renal disease, among other disease complications) are present at each end of the regression curve.