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.Genet Med advance online publication 02 February 2017.

Figure 1. Neurodevelopmental outcomes are correlated with the lowest lifetime methionine and highest peak homocysteine levels and mean lifetime total homocysteine levels

(a) Mean (±SD) values for each developmental domain tested are shown. Not all subjects were able to participate in all tests. Closed circles represent each individual for each domain. (b) An impairment score, the percentage of neuropsychological domains that were severely impaired, was calculated for each of the eight individuals who underwent neuropsychological evaluation. Pearson correlation coefficient and multiple linear regression analyses were used to evaluate correlations between variables. Statistically significant relationships (P < 0.05) are indicated in bold with an asterisk. (c, d) Lowest methionine level and highest total homocysteine level correlated with more neuropsychological impairment; 100% of the lowest methionine levels occurred in the neonatal period and 75% of the peak homocysteine levels occurred in the neonatal period. (e) Higher mean homocysteine levels were also correlated with poorer neuropsychological test scores. MMA, methylmalonic acid.

Figure 2. Increased intake of incomplete protein and decreased intake of complete protein is associated with mild improvements in metabolic control, but these dietary interventions are also associated with perturbations of essential amino acid ratios

Retrospective dietary information and serum metabolite values were evaluated for all patients in the study who were at least 18 months old at the last evaluation. Information from the visit closest to selected standardized ages (2, 3, 6, 9, 12, 18, and 24 months) was reviewed. (a–d) Pearson correlation coefficient and multiple linear regression analyses were used to evaluate correlations between variables. Statistically significant relationships (P < 0.05) are indicated in red. Increased incomplete protein intake was statistically significantly correlated with lower methylmalonic acid (MMA) levels, and there was a nonsignificant trend toward higher MMA levels with higher complete protein intake. Increased incomplete protein and decreased complete protein were associated with higher leucine-to-valine ratios. (e–h) Heat map analysis demonstrates differences between individuals in their sensitivity to dietary manipulations as measured by the leucine-to-valine ratio and plasma MMA levels. For incomplete protein (e), leucine-to valine-ratio (f), and MMA (h), the lowest value of the heat map is indicated in green, the highest is in red, and the 50th percentile is in yellow. For complete protein, the lowest value is indicated in red and the highest is indicated in green.

Figure 3. Long-term increased medical food consumption is correlated with lower head circumference measurements, but no other outcomes are correlated with diet in this population

Pearson correlation coefficient and multiple linear regression analyses were used to evaluate correlations between protein intake and growth parameters measured at the standardized time points shown in Figure 2. (a) Higher consumption of incomplete protein was correlated with small head circumferences. (b) No other growth parameters were correlated with either complete or incomplete protein intake. OFC, occipital frontal circumference.