Long-term effects of medical management on growth and weight in individuals with urea cycle disorders

Abstract

Low protein diet and sodium or glycerol phenylbutyrate, two pillars of recommended long-term therapy of individuals with urea cycle disorders (UCDs), involve the risk of iatrogenic growth failure. Limited evidence-based studies hamper our knowledge on the long-term effects of the proposed medical management in individuals with UCDs. We studied the impact of medical management on growth and weight development in 307 individuals longitudinally followed by the Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD). Intrauterine growth of all investigated UCDs and postnatal linear growth of asymptomatic individuals remained unaffected. Symptomatic individuals were at risk of progressive growth retardation independent from the underlying disease and the degree of natural protein restriction. Growth impairment was determined by disease severity and associated with reduced or borderline plasma branched-chain amino acid (BCAA) concentrations. Liver transplantation appeared to have a beneficial effect on growth. Weight development remained unaffected both in asymptomatic and symptomatic individuals. Progressive growth impairment depends on disease severity and plasma BCAA concentrations, but cannot be predicted by the amount of natural protein intake alone. Future clinical trials are necessary to evaluate whether supplementation with BCAAs might improve growth in UCDs.

Figure 1

Intrauterine development of 205 individuals with UCDs is unaffected. Z-scores of weight (A), length (B), and head circumference (C) of 205 individuals with UCDs at birth. Mean z-scores for weight (z-score: − 0.24), length (z-score: 0.14) and head circumference (z-score: − 0.13) are overall within the normal range. Various diseases do not differ with regard to weight (p = 0.20; ANOVA), length (p = 0.26; ANOVA), and head circumference (p = 0.11; ANOVA). Data are shown as median (black line) and mean (triangle), length of the box corresponds to interquartile range (IQR), upper and lower whiskers correspond to max. 1.5 × IQR, each point represents an outlier. Descriptive characteristics are presented separately in Supplementary Table S1. ASL-D, argininosuccinate lyase deficiency; ASS1-D, argininosuccinate synthetase 1 deficiency; fOTC-D, female ornithine transcarbamylase deficiency; mOTC-D, male ornithine transcarbamylase deficiency.

Figure 2

Postnatal weight development and linear growth of 11 asymptomatic UCDs is normal. Preschool children were observed during a period of approximately 3 years and both weight (A) and height (B) did not differ between the first [mean z-score (weight): 0.09; mean z-score (height): 0.02] and last [mean z-score (weight): 0.65; mean z-score (height): 0.62] observation (each p > 0.05; t-test). Moreover, weight and height were within the normal range. Data are shown as median (black line) and mean (triangle), length of the box corresponds to IQR, upper and lower whiskers correspond to max. 1.5 × IQR. Descriptive characteristics are presented separately in Supplementary Table S1.

Figure 3

Symptomatic individuals (n = 130) have normal weight development but abnormal linear growth. Prepubertal children were observed during a period of approximately 5 years. Weight (A) was not affected neither by age (p = 0.41; LME ANOVA), nor by disease onset (p = 0.77; LME ANOVA) or specific diseases (p = 0.71; LME ANOVA). β-Coefficients did not differ between EO (β = − 0.01) and LO (β = 0.02; p = 0.23, LME) individuals. Height (B) however, was affected by age (p < 0.001; LME ANOVA), disease onset (p = 0.03; LME ANOVA) and interaction of both (p < 0.001; LME ANOVA), suggesting that disease severity—as reflected by EO individuals—is associated with impaired growth over time. In line, β-coefficients differed between EO (β = − 0.11) and LO (β = − 0.02; p < 0.001, LME) individuals. Accordingly, BMI (C) was determined by age (p < 0.001; LME ANOVA) and interaction between age and disease onset (p = 0.02; LME ANOVA), indicating that BMI increases with age for the EO but not the LO group. Gray lines are fitted weight, height, and BMI values from the LME model; the gray shaded area corresponds to 95% confidence interval. Descriptive characteristics are presented separately in Supplementary Table S1. BMI, body mass index; EO, early onset; LO, late onset.

Figure 4

Impaired growth is not associated with the use of protein restricted diet as part of medical management in 46 symptomatic UCDs. Preschool children receiving a protein restricted diet were similarly restricted (p = 0.28; ANOVA) with regard to their mean natural protein intake. Data are shown as median (black line) and mean (triangle), length of the box corresponds to IQR, upper and lower whiskers correspond to max. 1.5 × IQR (A). During an observation period of approximately 3 years individuals with (n = 23) or without (n = 23) a protein restricted diet did not differ (each p > 0.05; LME ANOVA) with regard to their normal weight development (B) and impaired linear growth (C). β-coefficients did not differ between individuals with or without a protein restricted diet neither for weight development (protein restricted diet: β = − 0.01, no protein restricted diet: β = − 0.01; p = 0.98, LME; B) nor for linear growth (protein restricted diet: β = − 0.03; no protein restricted diet: β = − 0.06; p = 0.28; LME; C). Gray lines are fitted weight and height values from the LME model; the gray shaded area corresponds to 95% confidence interval (B, C). Descriptive characteristics are presented separately in Supplementary Table S1. ASL-D, argininosuccinate lyase deficiency; ASS1-D, argininosuccinate synthetase 1 deficiency; fOTC-D, female ornithine transcarbamylase deficiency; mOTC-D, male ornithine transcarbamylase deficiency.

Figure 5

Liver transplantation appears to have a beneficial effect on growth of 19 individuals with UCDs. Individuals with UCDs (n = 19) have normal weight gain (A) over time pre- and post-transplantation (p = 0.48; LME ANOVA), but suffer from impaired growth (B) prior to transplantation [mean z-score at first observation: 0.53, mean z-sore at last observation prior to LTx: − 0.75; p < 0.001; contrast t-test). However, growth retardation does not further aggravate after transplantation (mean z-score at last observation prior to LTx: − 0.75, mean z-score at last observation after LTx: − 0.17; p = 0.13; contrast t-test). Data are shown as median (black line) and mean (triangle), length of the box corresponds to IQR, upper and lower whiskers correspond to max. 1.5 × IQR, each point represents an outlier. Descriptive characteristics are presented separately in Supplementary Table S1. LTx, liver transplantation.