Fatal Neonatal Hyperammonemia Caused by a Novel Large Deletion in the OTC Gene: A Case Report with Genotype-Phenotype Correlation

Background The clinical presentation of ornithine transcarbamylase deficiency (OTCD) ranges from neonatal-onset hyperammonemia to milder, delayed symptoms, including impaired psychomotor development. Methods We present the case of a male newborn from a dichorionic diamniotic twin pregnancy with no family history of metabolic disorders who developed desaturation, cyanosis and hypertonia in the early postnatal period, and was found to have severe hyperammonemia. Brain MRI revealed abnormalities in the white matter and basal ganglia, while elevated plasma glutamine and urine orotic acid confirmed the OTCD diagnosis. Due to the acute metabolic failure, continuous kidney replacement therapy was initiated to support metabolic clearance, alongside high-rate glucose, nitrogen scavengers, and urea cycle substrates. Despite intensive treatment the patient’s metabolic status continued to deteriorate, and he died a few days later. Results Genetic testing by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA) identified a novel, hemizygous 9,896-bp genomic deletion involving exon 3 of the OTC gene, which was inherited from the mother and was absent in the unaffected twin. This finding, confirmed by long-PCR to identify the deletion breakpoints, is likely to result in complete enzyme deficiency. Conclusions This case demonstrates the significant phenotypic variability of OTCD, which is largely influenced by the underlying genetic variant. We also conducted a literature review on the genotype-phenotype correlation of this rare disease to further highlight the importance of genetic testing and counseling for patient and carrier management and reproductive planning.