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

Abstract

Urea Cycle Disorders Consortium (UCDC) * & European registry and network for Intoxication type Metabolic Diseases (E-IMD) * 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.

Thirty-Year Lessons from the Newborn Screening for Congenital Adrenal Hyperplasia (CAH) in Japan

“…Despite not covering 21OHD patients, the introduction of several registry systems for rare congenital diseases has encouraged us. In the EU, some international collaborationbased registry systems for rare congenital diseases, such as the European Registry and Network for Intoxication type Metabolic Diseases (E-IMD) and the European Registry and Network for Homocystinurias and Methylation Defects (E-HOD), have been established [25,[72][73][74][75]. Further, the Japanese Society for Inherited Metabolic Disease has successfully introduced the registry system, "JaSMIn", for patients with inherited metabolic disease (https://www.jasmin-mcbank.com/, visited 23 April 2021).…”

Long‐term anthropometric development of individuals with inherited metabolic diseases identified by newborn screening

“…However, the results of this study reflect real‐world data on anthropometrics in screened IMD patients followed up in specialized metabolic centers following the latest recommendations. Our findings are pointing at the need for evaluations of bigger single‐disease study cohorts for all screened IMDs as done before in PKU, 4,24,25 GA1 6 and Gal, 7 or other IMDs, as urea cycle disorders 29 …”

“…Our findings are pointing at the need for evaluations of bigger single-disease study cohorts for all screened IMDs as done before in PKU, 4,24,25 GA1 6 and Gal, 7 or other IMDs, as urea cycle disorders. 29 Due to the study design, a distinction or proof that the findings on anthropometric parameters in individuals with IMDs identified by NBS are caused by the type of diet, disease-specific factors (e.g., metabolic impairment, neurotoxins), or an amplification of both cannot be given. Here, single-disease analyses in bigger study cohorts are necessary.…”

Physical, cognitive, and social status of patients with urea cycle disorders in Japan

“…Of note, the restriction of protein intake was related to growth impairment in UCD patients because treatment intensification is required in neonatal-onset patients with severe types of UCDs, such as neonatal-onset OTCD and CPS1D [ 34 ]. Posset et al [ 35 ] suggested that growth impairment was determined by disease severity and associated with diminished or borderline plasma BCAA concentrations, regardless of the degree of natural protein intake. Moreover, patients with neonatal-onset UCDs exhibited severe growth impairment over time.…”

“…Even patients with late-onset UCDs are likely to present growth impairment over time. However, LT could contribute to catch-up growth [ 35 ]. Unfortunately, our study did not demonstrate an association between the height and plasma BCAA levels of patients with UCDs.…”