Hartnup disease

A number of genetic diseases that result in defects of tryptophan metabolism are associated with the development of pellagra despite an apparently adequate intake of both tryptophan and niacin. Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan, resulting in large losses due to intestinal malabsorption and failure of the renal resorption mechanism. In carcinoid syndrome there is metastasis of a primary liver tumor of enterochromaffin cells which synthesize 5-hydroxy-tryptamine. Overproduction of 5-hydroxytryptamine may account for as much as 60% of the body s tryptophan metabolism, causing pellagra because of the diversion away from NAD synthesis. 

Having briefly defined these four endpoints, I would like to ask, Are they related to known human disease Can they be measured quantitatively and Can they be measured with facility for inclusion in an overall plan for environmental bioassay Table I lists examples of gene locus mutations resulting in human disease phenylketonuria, histidinemia, Hartnup disease, and cvstinuria. Phenvlketonuria is... 

It is indicated in pellagra, for prophylaxis, Hartnup disease, hyperlipoprotein-aemia. 

Jl. Jepson, J. B., Indolylacetyl-glutamine and other indole metabolites in Hartnup disease. Biochem. ]. 64, 14P (1956). 

A number of inborn errors of metabolism of the tryptophan oxidative pathway (see Figure 8.4) have been reported, aU of which result in the development of pellagra that responds to high doses of niacin. These conditions include vitamin Be-responsive xanthurenic aciduria, caused by a defect of kynureni-nase (Section 9.4.3) hydroxykynureninuria, apparentiy caused by a defect of kynureninase tryptophanuria, apparentiy caused by tryptophan dioxygenase deficiency a hereditary pellagra-like condition, apparentiy caused by an increase in activity of picoUnate carboxylase and Hartnup disease. 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

Metabolic studies by Milne et al. (M8) showed that in Hartnup disease the renal aminoaciduria is more constant than the excessive excretion of indican and indolic acids (indoleacetic acid, indolelactic acid, and indoleacetylglutamine). After ingestion of L-tryptophan in this disease there is usually delayed and incomplete absorption from the gut of the amino acid which is partly converted, by intestinal bacteria, to indole... 

The Hartnup disease described in 1956 (B2) under the title hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria, and other bizarre biochemical features evidently belongs to the diseases related to inborn errors of metabolism due to inherited differences. As was pointed out by Harris (H3), very often the detection of urinary amino acid metabolites has represented the starting point of the investigation of different genetic biochemical disorders. A recent study (A8) showed that the excess production of indole by colon bacteria in 15 cases of Hartnup disease was due entirely to an increased amount of tryptophan contained in the large bowel, and not to an abnormality of the bacteria themselves. 

Several physiological conditions (e.g. Hartnup disease and malignant carcinoid syndrome) can lead to niacin deficiency. 

In Hartnup disease tryptophan absorption is impaired and in malignant carcinoid syndrome tryptophan metabolism is altered resulting in excess serotonin synthesis. 

Inherited defects in amino acid transport affect epithelial cells of the gastrointestinal tract and renal tubules. Some affect transport of neutral amino acids Hartnup disease), others that of basic amino acids and ornithine and cystine (cystinuria), or of glycine and proline (Chapter 12). Cystinosis is an intracellular transport defect characterized by high intralysosomal content of free cystine in the reticuloendothelial system, bone marrow, kidney, and eye. After degradation of endocytosed protein to amino acids within lysosomes, the amino acids normally are transported to the cytosol. The defect in cystinosis may reside in the ATP-dependent efflux system for cystine transport, and particularly in the carrier protein. 

Hartnup disease is a disorder of renal tubular and intestinal absorption of tryptophan and other neutral amino acids. 

Niacin (adult RDA = 13 mg = 13 niacin equiv.) 50-250 mg Hartnup disease Intestinal and renal transport of tryptophan (high protein diet needed in addition to niacin to relieve symptoms)... 

Which clinical laboratory observation below is suggestive of Hartnup disease (neutral amino acid transport deficiency) ... 

Glycogen storage diseases Gyrate atrophy of the retina Hartnup disease Heart attack... 

Hartnup disease is an inherited autosomal recessive disease that manifests itself in malabsorption of neutral amino acids, including tryptophan, in the gastrointestinal tract and also in deficient reabsorption of these amino acids in the renal tubules. The deficient uptake of tryptophan can result in a pellagra-like condition, which may include mental manifestations such as... 

Jonas, A. J. and Butler, I. J., Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester, /. Clin. Invest., 84, 200, 1989. 

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