The challenge of understanding and predicting phenotypic diversity in urea cycle disorders

Abstract

The Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E‐IMD) are the worldwide largest databases for individuals with urea cycle disorders (UCDs) comprising longitudinal data from more than 1100 individuals with an overall long‐term follow‐up of approximately 25 years. However, heterogeneity of the clinical phenotype as well as different diagnostic and therapeutic strategies hamper our understanding on the predictors of phenotypic diversity and the impact of disease‐immanent and interventional variables (e.g., diagnostic and therapeutic interventions) on the long‐term outcome. A new strategy using combined and comparative data analyses helped overcome this challenge. This review presents the mechanisms and relevant principles that are necessary for the identification of meaningful clinical associations by combining data from different data sources, and serves as a blueprint for future analyses of rare disease registries.

Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice

“…The authors reap the benefits of the traditional use of ENS in Italy, which demonstrated that UCDs cannot be considered only in their acute forms and that late-onset cases can be detected in a relevant proportion of patients if suitable diagnostic processes are available. The relevance of ENS is confirmed by the recently published analysis of the two large databases gathered by the American and the European consortia [ 21 ]. Therefore, strategies to implement ENS with clinical observation and enzyme assessment to predict the patient’s evolution is of main importance [ 21 ].…”

“…The relevance of ENS is confirmed by the recently published analysis of the two large databases gathered by the American and the European consortia [ 21 ]. Therefore, strategies to implement ENS with clinical observation and enzyme assessment to predict the patient’s evolution is of main importance [ 21 ].…”

“…Due to the difficulty in generating high-level evidence-based guidelines, and in detecting the severity of the condition, even when enzyme-based tests are performed [ 21 ], the group of experts produced a protocol for treatment and follow-up based on their clinical practice. They are aware, nevertheless, that the impact of ENS on outcomes may be very variable and that counsels must be tailored to the local management capabilities.…”

“…The American Urea Cycle Disorders Consortium [ 40 ] and the European registry and network for Intoxication type Metabolic Diseases [ 41 ] aim to improve the knowledge of the natural history, treatment and clinical outcome of individuals with mild UCDs [ 24 ]. Both consortia focus on elucidating key physiopathology, early prediction of clinical severity, evaluating safety and efficacy of dietary treatment, pharmacological therapy, and liver transplantation, developing evidence-based consensus care recommendations, and empowering patients and their families [ 21 ].…”