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 microM) and cerebrospinal fluid (1.0 +/- 0.2 microM) were persistently less than 50% of normal values. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, was also less than 50% of normal (21 +/- 2 ng/ml). Serum tryptophan concentrations increased only modestly and briefly after an oral challenge with 200 mg/kg of 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 microM. Sustained treatment with 20 mg/kg q6h resulted in normalization of serum (66 +/- 15 microM) and cerebrospinal fluid tryptophan concentrations (mean = 2.3 microM). 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 approximately 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.
Subject(s)
Amino Acids/metabolism , Hartnup Disease/metabolism , Tryptophan/analogs & derivatives , Amino Acids/blood , Animals , Biological Transport , Child, Preschool , Female , Hartnup Disease/drug therapy , Humans , Hydrolysis , Hydroxyindoleacetic Acid/cerebrospinal fluid , Male , Niacinamide/therapeutic use , Rats , Rats, Inbred Strains , Serotonin/cerebrospinal fluid , Tryptophan/blood , Tryptophan/cerebrospinal fluid , Tryptophan/therapeutic useSubject(s)
Hartnup Disease/epidemiology , Australia , Child, Preschool , Female , Follow-Up Studies , Hartnup Disease/drug therapy , Humans , Infant , Male , Nicotinic Acids/therapeutic useSubject(s)
Hartnup Disease , Adolescent , Cerebellar Ataxia/etiology , Diagnosis, Differential , Dietary Proteins , Electroencephalography , Hartnup Disease/complications , Hartnup Disease/diagnosis , Hartnup Disease/drug therapy , Humans , Malabsorption Syndromes/etiology , Muscle Tonus , Neomycin/therapeutic use , Neurologic Manifestations , Niacinamide/therapeutic use , Photosensitivity Disorders/etiology , Psychotic Disorders/etiology , Pyridoxine/therapeutic useABSTRACT
A severely affected case of Hartnup disease is reported, where the patient responded rapidly to nicotinamide. This supports the view that all the clinical features, except reduced stature from general nutritional defect, are secondary to tryptophan and nicotinamide deficiency rather than to an unknown toxic factor. Severe malabsorption of both tryptophan and phenylalanine was demonstrated. The dipeptide carnosine was absorbed normally whereas when the two constituent amino acids, beta-alanine and L-histidine, were ingested, absorption of the former was normal but that of the latter was grossly defective. The suggestion is advanced that in cases of Hartnup disease protein nutrition is maintained by intestinal uptake of amino acids as oligopeptides rather than as free amino acids. By contrast, both modes of absorption are probably important in normal subjects. Radiology of the small intestine is abnormal in Hartnup disease when a large amount of protein is admixed with the barium meal.
