Decoding clinical heterogeneity in ornithine transcarbamylase deficiency: novel mutations and therapeutic outcomes from a longitudinal cohort study

fan yang; xiumin wang

doi:10.1530/endoabs.110.P798

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Endocrine Abstracts (2025) 110 P798 | DOI: 10.1530/endoabs.110.P798

ECEESPE2025 Poster Presentations Multisystem Endocrine Disorders (43 abstracts)

Decoding clinical heterogeneity in ornithine transcarbamylase deficiency: novel mutations and therapeutic outcomes from a longitudinal cohort study

fan yang ¹ & xiumin wang ²

Author affiliations

¹Department of Clinical Research Ward, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, shanghai, China; ²Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, shanghai, China

JOINT3328

Objective: To characterize the clinical spectrum, genetic landscape, and long-term therapeutic efficacy in pediatric-onset ornithine transcarbamylase deficiency (OTCD).

Methods: A retrospective longitudinal cohort study of 7 OTCD patients (3 males, 4 females) with confirmed biochemical/genetic diagnoses and ≥24-month follow-up (median 38 months, range 16-41). Comprehensive analyses integrated metabolic profiling, next-generation sequencing, and multidisciplinary outcomes assessment (neurological, hepatic, developmental).

Results Clinical presentation: Age at diagnosis ranged from 10 days to 7.3 years. Hyperammonemic crises (71.4%, 5/7) manifested as recurrent vomiting (100%), encephalopathy (60%), and seizures (40%), with 42.9% (3/7) exhibiting pre-existing neurodevelopmental delays. Genetic landscape:Seven distinct *OTC* mutations identified, including two novel pathogenic variants (c.241T>C, c.490T>G; ACMG Class IV) unreported in global databases. Therapeutic trajectories:Medical therapy cohort (n = 2): Intermittent hyperammonemia (45-78 μmol/l) persisted in patients receiving sodium phenylbutyrate or arginine/citrulline, correlating with suboptimal adherence (30% missed doses). Despite episodic vomiting (1-2 annual episodes), anthropometric parameters remained age-appropriate. Transplant cohort (n = 5): All achieved complete metabolic normalization (ammonia ≤40 μmol/l, stable hepatic function) post-transplant, with neurodevelopmental improvement (ΔDQ +1.2-2.3 SD) and age-appropriate cognition (DQ 85-102) at final assessment.

Conclusions: This study establishes three critical insights for OTCD management:

1. Diagnostic urgency:Plasma amino acid profiling with urinary orotic acid quantification enables rapid triage of suspected cases.

2. Therapeutic hierarchy:Liver transplantation delivers superior outcomes for severe phenotypes, achieving sustained metabolic control and neurocognitive recovery.

3. Precision care imperative:Novel mutation identification reinforces genotype-phenotype correlations, while suboptimal pharmacotherapy adherence highlights the need for structured transition programs.