Predicting the Disease Severity in Male Individuals With Ornithine Transcarbamylase Deficiency

Authors

Svenja Scharre
Roland Posset
Sven F Garbade
Florian Gleich
Marie J Seidl
Ann-Catrin Druck
Jürgen G Okun
Andrea L Gropman
Sandesh C S Nagamani
Georg F Hoffmann
Stefan Kölker
Matthias Zielonka
Urea Cycle Disorders Consortium (UCDC) and the European registry and network for Intoxication type Metabolic Diseases (E-IMD) Consortia Study Group

Language

English

Publication Date

11-1-2022

Journal

Annals of Clinical and Translational Neurology

DOI

10.1002/acn3.51668

PMID

36217298

PMCID

PMC9639638

PubMedCentral® Posted Date

10-10-2022

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Male, Humans, Ornithine Carbamoyltransferase Deficiency Disease, Hyperammonemia, Phenotype, Severity of Illness Index

Published Open-Access

yes

Recommended Citation

Scharre, Svenja; Posset, Roland; Garbade, Sven F; et al., "Predicting the Disease Severity in Male Individuals With Ornithine Transcarbamylase Deficiency" (2022). Faculty and Staff Publications. 4388.
https://digitalcommons.library.tmc.edu/baylor_docs/4388