Longitudinal outcomes of non-transplanted ornithine transcarbamylase deficiency in males and females: a multicentre UK natural history cohort

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.