Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency. Issue 11 (10th October 2022)

• Record Type: Journal Article
• Authors: Scharre, Svenja; Posset, Roland; Garbade, Sven F.; Gleich, Florian; Seidl, Marie J.; Druck, Ann‐Catrin; Okun, Jürgen G.; Gropman, Andrea L.; Nagamani, Sandesh C. S.; Hoffmann, Georg F.; Kölker, Stefan; Zielonka, Matthias
• Other Names: Ah Mew Nicholas investigator.; Baumgartner Matthias R. investigator.; Berry Gerard T. investigator.; Berry Susan A. investigator.; Burrage Lindsay investigator.; Diaz George A. investigator.; Ficicioglu Can investigator.; Kisin Genya investigator.; Konczal Laura investigator.; Lam Christina investigator.; McCandless Shawn E. investigator.; Merritt J. Lawrence investigator.; Schulze Andreas investigator.; Walter Magdalena E. investigator.; Wilson Ashley investigator.; Wong Derek investigator.; Arnaudo Florence investigator.; Augoustides‐Savvopoulou Persephone investigator.; Barić Ivo investigator.; Bosch Annet M. investigator.; Cano Aline investigator.; Chien Yin‐Hsiu investigator.; Dionisi‐Vici Carlo investigator.; Dobbelaere Dries investigator.; Eyskens Francois investigator.; Freisinger Peter investigator.; Garcia‐Cazorla Angeles investigator.; Honzik Tomas investigator.; Karall Daniela investigator.; Lund Allan M. investigator.; Murphy Elaine investigator.; Santer René investigator.; Schiff Manuel investigator.; Skouma Anastasia investigator.; Sykut‐Cegielska Jolanta investigator.; Wijburg Frits A. investigator.; Zeman Jiri investigator.;
• Is Part Of: Annals of clinical and translational neurology. Volume 9:Issue 11(2022)
• Page Start: 1715
• Page End: 1726
• Publication Date: 2022-10-10
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.51668
• Languages: English
• ISSNs: 2328-9503

Abstract

Abstract: Objective: Ornithine transcarbamylase deficiency (OTC‐D) is an X‐linked metabolic disease and the most common urea cycle disorder. Due to high phenotypic heterogeneity, ranging from lethal neonatal hyperammonemic events to moderate symptoms and even asymptomatic individuals, the prediction of the disease course at an early disease stage is very important to individually adjust therapies such as medical treatment or liver transplantation. In this translational study, we developed a severity‐adjusted classification system based on in vitro residual enzymatic OTC activity. Methods: Applying a cell‐based expression system, residual enzymatic OTC activities of 71 pathogenic OTC variants were spectrophotometrically determined and subsequently correlated with clinical and biochemical outcome parameters of 119 male individuals with OTC‐D (mOTC‐D) as reported in the UCDC and E‐IMD registries. Results: Integration of multiple data sources enabled the establishment of a robust disease prediction model for mOTC‐D. Residual enzymatic OTC activity not only correlates with age at first symptoms, initial peak plasma ammonium concentration and frequency of metabolic decompensations but also predicts mortality. The critical threshold of 4.3% residual enzymatic activity distinguishes a severe from an attenuated phenotype. Interpretation: Residual enzymatic OTC activity reliably predicts the disease severity in mOTC‐D and could thus serve as a tool for severity‐adjusted evaluation of therapeutic strategies and counselling patients and parents.