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A single human case of autosomal recessive familial hypertryptophanemia was reported in a patient with compound heterozygous variants in TDO2. Genetic analysis identified one missense variant, c.324G>C (p.Met108Ile), and one frameshift, c.491dup (p.Ile165AspfsTer12), in trans in the proband, resulting in profound elevation of plasma tryptophan and serotonin levels without significant clinical sequelae (1 proband) (PMID:28285122).
Functional studies demonstrated that c.491dup abolishes soluble protein production and that p.Met108Ile yields a catalytically impaired enzyme prone to proteolytic degradation, consistent with loss of TDO2 function and accumulation of tryptophan and serotonin (PMID:28285122). The biochemical phenotype aligns with a recessive loss-of-function mechanism. Genetic testing for TDO2 variants should be considered in patients with unexplained hypertryptophanemia to confirm diagnosis and inform metabolic management.
Gene–Disease AssociationLimitedSingle reported proband with compound heterozygous TDO2 variants confirmed by functional studies Genetic EvidenceLimitedOne proband compound heterozygous for two rare variants (1 missense, 1 frameshift) (PMID:28285122) Functional EvidenceModerateMolecular studies showed absent soluble protein for c.491dup and reduced catalytic activity and stability of p.Met108Ile (PMID:28285122) |