Predicting the disease severity in male individuals with ornithine transcarbamylase deficiency
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, Nicholas Ah Mew, Matthias R Baumgartner, Gerard T Berry, Susan A Berry, Lindsay Burrage, George A Diaz, Can Ficicioglu, Genya Kisin, Laura Konczal, Christina Lam, Shawn E McCandless, J Lawrence Merritt, Andreas Schulze, Magdalena E Walter, Ashley Wilson, Derek Wong, Florence Arnaudo, Persephone Augoustides-Savvopoulou, Ivo Barić, Annet M Bosch, Aline Cano, Yin-Hsiu Chien, Carlo Dionisi-Vici, Dries Dobbelaere, Francois Eyskens, Peter Freisinger, Angeles Garcia-Cazorla, Tomas Honzik, Daniela Karall, Allan M Lund, Elaine Murphy, René Santer, Manuel Schiff, Anastasia Skouma, Jolanta Sykut-Cegielska, Frits A Wijburg, Jiri Zeman, 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, Nicholas Ah Mew, Matthias R Baumgartner, Gerard T Berry, Susan A Berry, Lindsay Burrage, George A Diaz, Can Ficicioglu, Genya Kisin, Laura Konczal, Christina Lam, Shawn E McCandless, J Lawrence Merritt, Andreas Schulze, Magdalena E Walter, Ashley Wilson, Derek Wong, Florence Arnaudo, Persephone Augoustides-Savvopoulou, Ivo Barić, Annet M Bosch, Aline Cano, Yin-Hsiu Chien, Carlo Dionisi-Vici, Dries Dobbelaere, Francois Eyskens, Peter Freisinger, Angeles Garcia-Cazorla, Tomas Honzik, Daniela Karall, Allan M Lund, Elaine Murphy, René Santer, Manuel Schiff, Anastasia Skouma, Jolanta Sykut-Cegielska, Frits A Wijburg, Jiri Zeman
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.
Conflict of interest statement
SK received EU funding for the European registry and network for Intoxication type Metabolic Diseases (E‐IMD; CHAFEA agreement no. 2010 12 01). SK receives funding from Immedica Pharma AB for the European Post‐Authorization Registry for Ravicti® (glycerol phenylbutyrate) oral liquid in partnership with the E‐IMD (RRPE) (EU PAS Register no. EUPAS17267; http://www.encepp.eu/). SK and GFH receive funding from the Dietmar Hopp Foundation (St. Leon‐Rot, Germany) for a pilot study on extended newborn screening evaluating the technical feasibility, diagnostic process quality and health benefits for 28 inherited metabolic diseases including UCDs (NBS 2025, project no. 1DH1911376, 1DH2011117). GFH received lecture fees from Swedish Orphan Biovitrum GmbH. RP receives consultancy fees from Immedica Pharma AB. The sponsors have in no way influenced the design, conductance, analysis and report of the present study. All other authors declare that they have no conflict of interest.
© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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References
- Batshaw ML, Tuchman M, Summar M, Seminara J, Members of the urea cycle disorders C . A longitudinal study of urea cycle disorders. Mol Genet Metab. 2014;113(1‐2):127‐130.
- Nettesheim S, Kolker S, Karall D, et al. Incidence, disease onset and short‐term outcome in urea cycle disorders ‐cross‐border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis. 2017;12(1):111.
- Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. 2013;110(1‐2):179‐180.
- Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M. Urea cycle disorders consortium of the rare diseases clinical research N. clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013. Feb;162(2):324‐9 e1.
- Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003. Jun;162(6):410‐416.
- Burgard P, Kolker S, Haege G, Lindner M, Hoffmann GF. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders—review and meta‐analysis of observational studies published over more than 35 years. J Inherit Metab Dis. 2016;39(2):219‐229.
- Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW, Hamosh A. Survival after treatment with phenylacetate and benzoate for urea‐cycle disorders. N Engl J Med. 2007;356(22):2282‐2292.
- Waisbren SE, Stefanatos AK, Kok TMY, Ozturk‐Hismi B. Neuropsychological attributes of urea cycle disorders: a systematic review of the literature. J Inherit Metab Dis. 2019;42(6):1176‐1191.
- Haberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42(6):1192‐1230.
- Kolker S, Garcia‐Cazorla A, Valayannopoulos V, et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. 2015;38(6):1041‐1057.
- Kolker S, Valayannopoulos V, Burlina AB, et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J Inherit Metab Dis. 2015;38(6):1059‐1074.
- Buerger C, Garbade SF, Dietrich Alber F, et al. Impairment of cognitive function in ornithine transcarbamylase deficiency is global rather than domain‐specific and is associated with disease onset, sex, maximum ammonium, and number of hyperammonemic events. J Inherit Metab Dis. 2019;42(2):243‐253.
- Posset R, Garcia‐Cazorla A, Valayannopoulos V, et al. Age at disease onset and peak ammonium level rather than interventional variables predict the neurological outcome in urea cycle disorders. J Inherit Metab Dis. 2016;39(5):661‐672.
- Posset R, Gropman AL, Nagamani SCS, et al. Impact of diagnosis and therapy on cognitive function in urea cycle disorders. Ann Neurol. 2019;86(1):116‐128.
- Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21‐year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008;97(10):1420‐1425.
- Caldovic L, Abdikarim I, Narain S, Tuchman M, Morizono H. Genotype‐phenotype correlations in ornithine Transcarbamylase deficiency: a mutation update. J Genet Genomics. 2015;42(5):181‐194.
- Zielonka M, Kolker S, Gleich F, et al. Early prediction of phenotypic severity in citrullinemia type 1. Ann Clin Transl Neurol. 2019;6(9):1858‐1871.
- Zielonka M, Garbade SF, Gleich F, et al. From genotype to phenotype: early prediction of disease severity in argininosuccinic aciduria. Hum Mutat. 2020;41:946‐960.
- Posset R, Garbade SF, Boy N, et al. 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.
- Hothorn T, Hornik K, Zeileis A. Unbiased recursive partitioning: a conditional inference framework. J Comput Graph Stat. 2006;15(3):651‐674.
- Katz R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx. 2004;1(2):189‐195.
- FDA UFaDACfDEaR . Guidance for Industry and Staff; Qualification Process for Drug Development Tools. 2014. Available from:
- Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8(4):431‐440.
- Allegri G, Deplazes S, Rimann N, et al. Comprehensive characterization of ureagenesis in the spf(ash) mouse, a model of human ornithine transcarbamylase deficiency, reveals age‐dependency of ammonia detoxification. J Inherit Metab Dis. 2019;42(6):1064‐1076.
- Batshaw ML, Yudkoff M, McLaughlin BA, et al. The sparse fur mouse as a model for gene therapy in ornithine carbamoyltransferase deficiency. Gene Ther. 1995;2(10):743‐749.
- Tarasenko TN, Rosas OR, Singh LN, Kristaponis K, Vernon H, McGuire PJ. A new mouse model of mild ornithine transcarbamylase deficiency (spf‐j) displays cerebral amino acid perturbations at baseline and upon systemic immune activation. PLoS One. 2015;10(2):e0116594.
- Wang L, Bell P, Morizono H, et al. AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC‐knock out heterozygous mice. Mol Genet Metab. 2017;120(4):299‐305.
- Brunetti‐Pierri N, Clarke C, Mane V, et al. Phenotypic correction of ornithine transcarbamylase deficiency using low dose helper‐dependent adenoviral vectors. J Gene Med. 2008;10(8):890‐896.
- De Sabbata G, Boisgerault F, Guarnaccia C, et al. Long‐term correction of ornithine transcarbamylase deficiency in Spf‐ash mice with a translationally optimized AAV vector. Mol Ther Methods Clin Dev. 2021;12(20):169‐180.
- Ginn SL, Amaya AK, Liao SHY, et al. Efficient in vivo editing of OTC‐deficient patient‐derived primary human hepatocytes. JHEP Rep. 2020;2(1):100065.
- Kiwaki K, Kanegae Y, Saito I, et al. Correction of ornithine transcarbamylase deficiency in adult spf(ash) mice and in OTC‐deficient human hepatocytes with recombinant adenoviruses bearing the CAG promoter. Hum Gene Ther. 1996;7(7):821‐830.
- Wang L, Morizono H, Lin J, et al. Preclinical evaluation of a clinical candidate AAV8 vector for ornithine transcarbamylase (OTC) deficiency reveals functional enzyme from each persisting vector genome. Mol Genet Metab. 2012;105(2):203‐211.
- Wang L, Yang Y, Breton C, et al. A mutation‐independent CRISPR‐Cas9‐mediated gene targeting approach to treat a murine model of ornithine transcarbamylase deficiency. Sci Adv. 2020;6(7):eaax5701.
- Chiriboga CA, Darras BT, Iannaccone ST, et al. Results from a phase 1 study ofnusinersen (ISIS‐SMNRx) in children with spinal muscular atrophy. Neurology. 2016;86:890‐897.
- Germain DP, Nicholls K, Giugliani R, et al. Efficacy of the pharmacologic chaperone migalastat in a subset of male patients with the classic phenotype of Fabry disease and migalastat‐amenable variants: data from the phase 3 randomized, multicenter, double‐blind clinical trial and extension study. Genet Med. 2019;21(9):1987‐1997.
- Silvera‐Ruiz SM, Arranz JA, Haberle J, et al. Urea cycle disorders in argentine patients: clinical presentation, biochemical and genetic findings. Orphanet J Rare Dis. 2019;14(1):203.
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