Genotypic and Clinical Characteristics of Long-term Surviving Adult Patients with Urea Cycle Disorders: A Nationwide Study in Japan

Background: Urea cycle disorders (UCDs) are rare inherited metabolic conditions characterized by impaired nitrogen disposal due to defects in enzymes or transporters. Although genotype–phenotype correlations have ever been tried in UCD patients, there is no report about the genetic background and long-term outcomes of adult survivors with UCDs. This study is aimed to investigate the genotypic and clinical characteristics of adult long-term survivors with UCDs in Japan and evaluate genotype–phenotype correlations. Methods: We conducted a nationwide survey and collected clinical and genetic data from 116 adult patients with UCDs. Pathogenic variants were identified in 48 patients, and clinical data including age at onset, peak plasma ammonia levels, intellectual outcomes, and long-term prognosis were analyzed. Particular attention was paid to genotype–phenotype correlations in male patients with ornithine transcarbamylase deficiency (OTCD). Results: Among 48 patients with identified variants (34 OTCD, 2 CPS1D, 6 ASS1D, 3 ASLD, 1 ARG1D, and 2 HHH syndrome), most OTCD variants in males were associated with late-onset phenotypes. Intellectual disability was present in 48% of patients and was significantly associated with peak ammonia levels exceeding 360 µmol/L ( P  = 0.046), particularly in male OTCD patients ( P  = 0.018). Clinical presentations varied even among patients with identical variants, indicating that genotype alone is insufficient to predict outcomes, although it may help estimate onset type and initial disease severity. Conclusion: This is the first nationwide study to characterize the genetic and clinical profiles of adult long-term survivors with UCDs in Japan. The findings highlight the marked clinical heterogeneity of UCDs and emphasize the importance of integrating genetic diagnosis with early recognition and prompt intervention to improve long-term outcomes.