Longitudinal outcomes of non-transplanted ornithine transcarbamylase deficiency in males and females: a multicentre UK natural history cohort
6 affiliations
- 1Genetics and Genomic Medicine Department, Great Ormond Street Institute of Child Health, University College London, London, WC1N 1EH UK
- 2Department of Paediatric Inherited Metabolic Disease, Evelina Children’s Hospital, Guy’s, and St Thomas’ NHS Foundation Trust, London, SE1 7EH UK
- 3Department of Paediatric Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH UK
- 4Department of Adult Inherited Metabolic Disease, Guy’s and St Thomas’ NHS Foundation Trust, London, SE1 7EH UK
- 5Dietetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, WC1N 3JH UK
- 6Willink Unit, Manchester Academic Health Sciences Centre, Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Oxford Road, Manchester, M13 9WL UK
Abstract
Background: Ornithine transcarbamylase deficiency (OTCD) demonstrates marked phenotypic heterogeneity, ranging from severe neonatal hyperammonaemia to asymptomatic disease. While acute hyperammonaemic crises are well recognised, the long-term burden in medically managed, non-transplanted individuals across the phenotypic spectrum remains incompletely defined. This study aimed to characterise longitudinal clinical outcomes and disease burden in a multicentre cohort and to explore genotype–phenotype relationships.
Results: Forty-five individuals were included (27 decompensated: 26 late-onset and 1 neonatal-onset; 18 non-decompensated), with median age at last follow-up of 13.3 years (IQR, 7.8–17.7). Molecular confirmation was available in 40/45 (88.9%). Among the decompensated cohort, 111 hyperammonaemic decompensation episodes, 224 hospital admissions, and 70 episodes requiring intravenous nitrogen-scavenger rescue were recorded; 16/26 (61.5%) late-onset individuals experienced recurrent decompensations. Individuals without documented decompensation also demonstrated clinically relevant morbidity, including behavioural problems (38.9%), recurrent vomiting (44.4%), chronic fatigue (33.3%), and learning difficulties (16.7%).
Conclusion: In this multicentre cohort of non-transplanted individuals, OTCD was associated with substantial morbidity across the phenotypic spectrum. Late-onset disease was characterised by recurrent metabolic instability, frequent hospitalisation, and neurodevelopmental burden, while individuals without overt hyperammonaemic episodes also experienced clinically relevant symptoms. These findings highlight that clinically relevant disease burden extends across the OTCD phenotypic spectrum. Improved risk stratification and disease-modifying therapies remain important unmet needs.
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BibTeX
@article{sekeryilmaz2026longitudinal,
title = {{Longitudinal outcomes of non-transplanted ornithine transcarbamylase deficiency in males and females: a multicentre UK natural history cohort}},
author = {Berna Seker-Yilmaz and Julien Baruteau and Raphael Buttigieg and Anupam Chakrapani and Michael Champion and Catherine Davies and James Davison and Marjorie Dixon and Sherry Fang and Emma Footitt and Joanna Gribben and Stephanie Grunewald and Gemma Hack and Thomas Hartley and Hugh Lemonde and Philippa Mills and Andrew A. M. Morris and Helen Mundy and Dinusha Pandithan and Radha Ramachandran and Siyamini Sivananthan and Chern Tan and Dexter Tarr and Louise Van Dorp and Roshni Vara and Abigail Woodward and Paul Gissen},
journal = {Orphanet Journal of Rare Diseases},
year = {2026},
month = jul,
doi = {10.1186/s13023-026-04517-w},
url = {https://doi.org/10.1186/s13023-026-04517-w},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Longitudinal outcomes of non-transplanted ornithine transcarbamylase deficiency in males and females: a multicentre UK natural history cohort
AU - Berna Seker-Yilmaz
AU - Julien Baruteau
AU - Raphael Buttigieg
AU - Anupam Chakrapani
AU - Michael Champion
AU - Catherine Davies
AU - James Davison
AU - Marjorie Dixon
AU - Sherry Fang
AU - Emma Footitt
AU - Joanna Gribben
AU - Stephanie Grunewald
AU - Gemma Hack
AU - Thomas Hartley
AU - Hugh Lemonde
AU - Philippa Mills
AU - Andrew A. M. Morris
AU - Helen Mundy
AU - Dinusha Pandithan
AU - Radha Ramachandran
AU - Siyamini Sivananthan
AU - Chern Tan
AU - Dexter Tarr
AU - Louise Van Dorp
AU - Roshni Vara
AU - Abigail Woodward
AU - Paul Gissen
PY - 2026
DA - 2026/07/28
JO - Orphanet Journal of Rare Diseases
DO - 10.1186/s13023-026-04517-w
UR - https://doi.org/10.1186/s13023-026-04517-w
AB - Background: Ornithine transcarbamylase deficiency (OTCD) demonstrates marked phenotypic heterogeneity, ranging from severe neonatal hyperammonaemia to asymptomatic disease. While acute hyperammonaemic crises are well recognised, the long-term burden in medically managed, non-transplanted individuals across the phenotypic spectrum remains incompletely defined. This study aimed to characterise longitudinal clinical outcomes and disease burden in a multicentre cohort and to explore genotype–phenotype relationships. Results: Forty-five individuals were included (27 decompensated: 26 late-onset and 1 neonatal-onset; 18 non-decompensated), with median age at last follow-up of 13.3 years (IQR, 7.8–17.7). Molecular confirmation was available in 40/45 (88.9%). Among the decompensated cohort, 111 hyperammonaemic decompensation episodes, 224 hospital admissions, and 70 episodes requiring intravenous nitrogen-scavenger rescue were recorded; 16/26 (61.5%) late-onset individuals experienced recurrent decompensations. Individuals without documented decompensation also demonstrated clinically relevant morbidity, including behavioural problems (38.9%), recurrent vomiting (44.4%), chronic fatigue (33.3%), and learning difficulties (16.7%). Conclusion: In this multicentre cohort of non-transplanted individuals, OTCD was associated with substantial morbidity across the phenotypic spectrum. Late-onset disease was characterised by recurrent metabolic instability, frequent hospitalisation, and neurodevelopmental burden, while individuals without overt hyperammonaemic episodes also experienced clinically relevant symptoms. These findings highlight that clinically relevant disease burden extends across the OTCD phenotypic spectrum. Improved risk stratification and disease-modifying therapies remain important unmet needs.
SN - 1750-1172
ER -