Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester

Abstract

Tryptophan ethyl ester, a lipid-soluble tryptophan derivative, was used to bypass defective gastrointestinal neutral amino acid transport in a child with Hartnup disease. The child's baseline tryptophan concentrations in serum (20 ± 6 μM) and cerebrospinal fluid (1.0 ± 0.2 μM) were persistently < 50% of normal values. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, was also < 50% of normal (21 ± 2 ng/ml). Serum tryptophan concentrations increased only modestly and briefly after an oral challenge with 200 mg/kg or oral L-tryptophan, reflecting the absorptive defect. An oral challenge with 200 mg/kg of tryptophan ethyl ester resulted in a prompt increase in serum tryptophan to a peak of 555 μM. Sustained treatment with 20 mg/kg q6h resulted in normalization of serum (66 ± 15 μM) and cerebrospinal fluid tryptophan concentrations (mean = 2.3 μM). Cerebrospinal fluid 5-HIAA increased to more normal concentrations (mean = 33 ng/ml). No toxicity was observed over an 8-mo period of treatment, chronic diarrhea resolved, and body weight, which had remained unchanged for 7 mo before ester therapy, increased by ~ 26%. We concluded that tryptophan ethyl ester is effective at circumventing defective gastrointestinal neutral amino acid transport and may be useful in the treatment of Hartnup disease.