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DOI: 10.1055/s-0039-1698232
Urea Cycle Disorders in the US and Europe – Evidence-based Clinical Outcomes Derived from Two Decades of Experience with Prospective Registry Studies
Publication History
Publication Date:
11 September 2019 (online)
Background: Urea cycle disorders (UCDs) are a group of rare inherited neurometabolic diseases with an estimated cumulative prevalence of 1 in 35,000 to 52,000 newborns presenting with life-threatening symptoms within the first 28 days of life or with heterogeneous symptoms (e.g. developmental, neurological and intellectual disabilities) any time after the newborn period. Growing clinical awareness for UCDs, development of diagnostic and therapeutic recommendations, and the implementation of national newborn screening programs hold out the potential for improved clinical outcome.
Aim: To evaluate the impact of current diagnostic and therapeutic strategies on the neurocognitive outcome of individuals with UCDs.
Materials and Methods: This prospective, observational, transatlantic, multicentre study includes data from 1,095 individuals from the two largest registries for UCDs, i.e. the North American Urea Cycle Disorders Consortium (UCDC) and the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). 503 individuals with a cumulative follow-up of 702 patient-years received comprehensive cognitive testing. z-scores were calculated using the normative data of each psychological test
Results: Non-interventional variables, such as UCD subtype, early disease onset and height of initial peak plasma ammonium concentration are predictors of intellectual disability (z < -2.0). Protection of cognitive abilities is related to early detection by newborn screening and timely liver transplantation. Importantly, none of the currently used nitrogen scavengers (sodium-/glycerol-phenylbutyrate or sodium benzoate) appeared superior with regard to long-term neurocognitive outcome of specific individuals with UCDs.
Discussion: Combining data from registry studies (UCDC and E-IMD) is a powerful tool to provide evidence-based information in the field of rare neurometabolic disorders. Moreover, it is a prerequisite to identify important indicators of neuroprotection and thus, to analyze the impact of current treatment principles. Confirmation in a longitudinal manner will provide evidence-based recommendations that can be translated to patient care. Future clinical trials in the field of rare neurometabolic disoders would benefit from evaluation against clinical outcome variables instead of biochemical surrogate parameters and must be carefully matched against variables that have a known impact on the clinical outcome.
References
1. Posset R, Gropman AL, Nagamani SCS, et al; Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases Consortia Study Group. Impact of diagnosis and therapy on cognitive function in urea cycle disorders. Ann Neurol 2019;86(1):116–128; [Epub ahead of print] 10.1002/ana.25492
2. Posset R, Garbade SF, Boy N, et al; Additional individual contributors of the UCDC and the E-IMD consortium. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-a successful strategy for clinical research of rare diseases. J Inherit Metab Dis 2019;42(1):93–106