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.
Highlights
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
A protein restricted diet, defined by a natural protein intake below 100% of the World Health Organization (WHO) safe values r ecommendations[6], as well as depletion of branched-chain amino acids (BCAAs), the latter aggravated by the administration of P BA7, are thought to impair growth and weight development
To assess whether symptomatic individuals had a risk of postnatal weight and growth retardation, we evaluated 130 symptomatic individuals receiving conservative management during a mean individual observation period of 4.81 years
Summary
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. Based on a combined and comparative data analysis approach between large international multicenter registry studies from North America [Urea Cycle Disorders Consortium (UCDC; https://www.rarediseasesnetwork.org/ cms/ucdc)] and Europe [European registry and network for Intoxication type Metabolic Disease (E-IMD; https://www.eimd-registry.org/)], a new strategy for clinical outcome research in the field of rare diseases became lately available[11] This enabled us to evaluate the impact of long-term management on the cognitive outcome of individuals with UCDs, providing further evidence for future recommendations[12]. Due to the low clinical evidence with regard to the long-term (adverse) effects of medical treatment, we studied longitudinal data from the UCDC and E-IMD databases to address this shortcoming after two decades of systematic data collection To this end, we investigated whether individuals with UCDs suffer from intrauterine or postnatal weight and growth retardation, and whether medical management—as currently performed in symptomatic individuals with UCDs in North America and Europe—is safe or leads to an impaired development with regard to anthropometrical endpoints
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