Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders.

Abstract

BACKGROUND:

Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation.

AIMS:

Determining the effect of diagnostic and therapeutic interventions on the neurological outcome.

METHODS:

Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry.

RESULTS:

About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 μmol/L) best predicted the neurological outcome.

CONCLUSIONS:

Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.

• Authors: Roland Posset, Angeles Garcia-Cazorla, Vassili Valayannopoulos, Elisa Leão Teles, Carlo Dionisi-Vici, Anaïs Brassier, Alberto B Burlina, Peter Burgard, Elisenda Cortès-Saladelafont, Dries Dobbelaere, Maria L Couce, Jolanta Sykut-Cegielska, Johannes Häberle, Allan M Lund, Anupam Chakrapani, Manuel Schiff, John H Walter, Jiri Zeman, Roshni Vara, Stefan Kölker, Additional individual contributors of the E-IMD consortium
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 39 Issue 5 Pg. 661-672 (09 2016) ISSN: 1573-2665 [Electronic] United States
• PMID: 27106216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ammonium Compounds
• Urea
• Argininosuccinate Synthase

Topics

• Adolescent
• Amino Acid Metabolism, Inborn Errors (diagnosis, metabolism)
• Ammonium Compounds (metabolism)
• Argininosuccinate Synthase (metabolism)
• Child
• Citrullinemia (diagnosis, metabolism)
• Female
• Humans
• Hyperammonemia (diagnosis, metabolism)
• Infant, Newborn
• Late Onset Disorders (diagnosis, metabolism)
• Male
• Neonatal Screening (methods)
• Nervous System Diseases (diagnosis, metabolism)
• Prospective Studies
• Urea (metabolism)
• Urea Cycle Disorders, Inborn (diagnosis, metabolism)