Clinical heterogeneity, genotype, and neurological outcomes in six Palestinian patients with ornithine transcarbamylase deficiency

Ornithine transcarbamylase deficiency (OTCD) is the most common urea cycle disorder. This X-linked condition, mapped to Xp21.1, results from a deficiency of the mitochondrial enzyme ornithine transcarbamylase, which catalyzes a critical step in ureagenesis. Disease severity ranges from a complete enzymatic block, presenting as neonatal hyperammonemic coma with high mortality, to partial deficiencies that can cause life-threatening hyperammonemia at any age. This report describes six patients diagnosed with OTCD, with ages ranging from 8 days to 17 years at the time of diagnosis. The onset of symptoms occurred at different ages, from just 2 days to 17 years. Two male patients experienced severe neonatal courses and, unfortunately, died from hyperammonemic coma shortly after birth. In contrast, four other patients (three males and one female) presented with symptoms later in life. Molecular analysis identified pathogenic variants in the OTC gene, which included four missense variants and one in-frame deletion. Notably, a recurrent variant was found in two individuals from unrelated families. The cohort comprised six patients with two distinct clinical presentations. Two hemizygous males presented neonatally and progressed to severe hyperammonemic coma within the first days of life. The other four patients (3 males, 1 female) exhibited a late-onset form, with symptom onset ranging from infancy to 17 years. Their phenotypes were highly variable, encompassing acute hyperammonemic episodes and a chronic neurological course characterized by speech and motor delay, muscle cramps, and persistent toe-walking. Genetic analysis revealed five distinct pathogenic or likely pathogenic variants (four missense substitutions and one in-frame deletion). These were identified by whole-exome sequencing in five patients and by targeted Sanger sequencing in one patient. This study highlights the molecular and phenotypic heterogeneity of OTCD and explores the correlation between genotype and phenotype. The manifestation of the disease in a heterozygous female suggests that skewed X-inactivation may serve as a potential pathogenic mechanism. The variation in age at symptom onset, alongside the genetic diversity observed, underscores the continuum between neonatal and late-onset OTCD.