Natural History of Symptomatic Partial Ornithine Transcarbamylase Deficiency

We reviewed the natural history and differential diagnosis of ornithine transcarbamylase deficiency (an X-linked inborn error of urea synthesis) in 13 symptomatic female heterozygotes. The patients presented as early as the first week of life or as late as the sixth year. The most common symptoms before diagnosis were nonspecific: episodic extreme irritability (100 percent), episodic vomiting and lethargy (100 percent), protein avoidance (92 percent), ataxia (77 percent), Stage II coma (46 percent), delayed physical growth (38 percent), developmental delay (38 percent), and seizures (23 percent). Including the proband, 42 percent of the female members of the 13 families studied had symptoms. The median interval between the onset of major symptoms (vomiting and lethargy, seizures, and coma) and diagnosis was 16 months (range, 1 to 142). Five patients had IQ scores below 70 at the time of diagnosis. We suggest that careful evaluation of the family history, the dietary history, the episodic nature of the nonspecific symptoms, the response of these symptoms to the withdrawal of protein, and their frequent onset at the time of weaning from breast milk will permit early diagnosis and might thereby reduce the risk of death or neurologic impairment in female patients with partial ornithine transcarbamylase deficiency. (N Engl J Med 1986; 314:541–7.), ORNITHINE transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that is inherited as an X-linked trait¹ (Fig. 1). Although there have been advances in the treatment of urea-cycle enzymopathies since Russell's description of OTCD in 1962,² the prognosis remains poor for affected males. Unless treated, almost all hemizygotes die of hyperammonemic coma in the neonatal period,³ and treated survivors are likely to be neurologically handicapped.⁴ Females who carry the mutant gene present with a phenotype that may vary from apparent normality to the profound neurologic impairment observed in male hemizygotes.^6,7 This phenotypic variability reflects both genetic heterogeneity^8,9 and…