OTC – Urea Cycle Disorder

Ornithine transcarbamylase (OTC) deficiency is an X-linked urea cycle disorder characterized by hyperammonemia, which can precipitate encephalopathy, vomiting, somnolence, and coma due to ammonia accumulation in blood and brain tissue (PMID:22563224). Onset ranges from severe neonatal presentations in hemizygous males to late-onset forms in both sexes, often triggered by metabolic stressors such as protein load or chemotherapy (PMID:32601573).

Genetic evidence supports X-linked recessive inheritance, with >100 unrelated affected individuals reported across case series and registries worldwide, including 62 OTCD patients in a Japanese cohort (PMID:33851512) and familial segregation in multiple pedigrees. A novel hemizygous OTC variant, c.535C>T (p.Leu179Phe), was identified in a late-onset 17-month-old boy presenting with recurrent somnolence and hyperammonemia (PMID:22727265).

The OTC variant spectrum comprises >200 mutations: missense (e.g., p.Leu179Phe, p.Arg277Gln), nonsense, frameshift (e.g., c.970_979del (p.Phe324GlnfsTer16)), splice-site, exonic duplications, deep-intronic changes (c.540+265G>A) and regulatory region variants (c.-106C>A). Many mutations recur at CpG dinucleotides (e.g., p.Arg40Cys) and founder alleles have been described in population studies (PMID:7860066; PMID:40206416).

Functional assays demonstrate pathogenicity via reduced enzyme activity and protein stability. High-throughput mutagenesis of 1,570 OTC variants distinguished neonatal from late-onset alleles, with 84% coverage of SNVs and correlation of functional scores with clinical severity (PMID:37146589). Splice-defective alleles (c.386G>A) were rescued by engineered U1snRNA in the spf/ash mouse model, increasing correct OTC transcripts and protein levels (~3-fold) and ameliorating hyperammonemia (PMID:33228018).

Phenotypic heterogeneity is pronounced in heterozygous females, with 64% displaying neuropsychiatric or metabolic decompensation under stress. Survival rates for late-onset OTCD exceed 97% at age 20, but peak ammonia ≥360 μmol/L predicts poor neurodevelopmental outcome despite dialysis or transplantation (PMID:33840128). Carrier detection and preimplantation genetic testing enable informed reproductive choices and early intervention (PMID:39039447).

No definitive opposing data have refuted the OTC–UCD association; variant effects are concordant across biochemical, cellular, and animal models. Integrative evidence from >30 years of clinical and experimental studies establishes a Definitive gene–disease relationship.

Key Take-home: Early genetic and biochemical diagnosis of OTC deficiency enables prompt ammonia-lowering therapy and tailored management, reducing mortality and improving neurological outcomes.

References

• Journal of Korean medical science • 2012 • Hyperammonemia in a patient with late-onset ornithine carbamoyltransferase deficiency. PMID:22563224
• European Journal of Paediatric Neurology • 2013 • Recurrent somnolence in a 17-month-old infant: late-onset ornithine transcarbamylase (OTC) deficiency due to the novel hemizygous mutation c.535C>T (p.Leu179Phe). PMID:22727265
• Journal of inherited metabolic disease • 1998 • Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan. PMID:9686352
• Molecular Genetics and Metabolism Reports • 2021 • A deep intronic variant is a common cause of OTC deficiency in individuals with previously negative genetic testing. PMID:33489762
• American Journal of Human Genetics • 2023 • The functional impact of 1,570 individual amino acid substitutions in human OTC. PMID:37146589
• International Journal of Molecular Sciences • 2020 • An Exon-Specific Small Nuclear U1 RNA (ExSpeU1) Improves Hepatic OTC Expression in a Splicing-Defective spf/ash Mouse Model of Ornithine Transcarbamylase Deficiency. PMID:33228018

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