Regular ArticleHypertryptophanemia due to tryptophan 2,3-dioxygenase deficiency

•The first clinical case report of human tryptophan 2,3-dioxygenase deficiency•Biochemical phenotype is hypertryptophanemia and hyperserotoninemia, but no clearly discernable clinical phenotype•Compound heterozygosity for two rare TDO2 variants: c.324G > C, p.Met108Ile and c.491dup, p.Ile165Aspfs*12•p.Met108Ile has an increased Km and is prone to proteolytic degradation via decreased KD at an exo regulatory site•c.491dup does not produce soluble protein

In this report we describe the first human case of hypertryptophanemia confirmed to be due to tryptophan 2,3-dioxygenase deficiency. The underlying etiology was established by sequencing the TDO2 gene, in which there was compound heterozygosity for two rare variants: c.324G > C, p.Met108Ile and c.491dup, p.Ile165Aspfs*12. The pathogenicity of these variants was confirmed by molecular-level studies, which showed that c.491dup does not produce soluble protein and c.324G > C results in a catalytically less efficient Met108Ile enzyme that is prone to proteolytic degradation. The biochemical phenotype of hypertryptophanemia and hyperserotoninemia does not appear to have significant clinical consequences.