Chapter 193

## Abstract

Abstract

1. Hartnup disorder is an autosomal recessive impairment of neutral amino acid transport limited to the kidneys and small intestine. It is believed to be caused by a genetic defect in a specific system responsible for neutral amino acid transport across the brush-border membrane of renal and intestinal epithelium. A cell surface receptor for neutral amino acid transport known as ATB0 has been identified in human kidney and intestine. A cDNA for this transporter has been cloned and the gene mapped to chromosome 19q13.3, but neither the transporter nor the gene has yet been examined in the Hartnup disorder. The diagnostic feature is a striking neutral hyperaminoaciduria. Most affected individuals also have increased excretion of indolic compounds, notably indican (indoxyl sulfate). These indoles originate in the gut from bacterial degradation of unabsorbed tryptophan. Reduced intestinal absorption of tryptophan and increased tryptophan loss in the urine lead to reduced availability of tryptophan for the synthesis of niacin.

2. Pellagra-like clinical features have been described in patients with Hartnup disorder. These include a photosensitive skin rash, intermittent ataxia, and psychotic behavior. Some affected individuals have also been mentally retarded or mentally subnormal to a mild degree. Treatment with nicotinamide has been associated with clearing of the rash and, on occasion, disappearance of the ataxia. This has led to the theory that the clinical abnormalities are due to niacin deficiency. Most subjects identified by routine newborn screening, however, as well as most affected sibs of probands, have remained clinically normal without treatment. The most plausible explanation for the disparity in clinical expression is that, while the disorder is monogenic, the “disease” is multifactorial and requires the presence of complicating environmental influences, such as poor diet or diarrhea, and perhaps also a polygenic influence, such as a tendency for low plasma amino acid levels.

3. The renal and intestinal defects are not always expressed concordantly. Some individuals with the Hartnup hyperaminoaciduria do not have increased urinary excretion of indolic acids, suggesting that they have the renal defect without the intestinal defect. Conversely, one individual with evidence of an intestinal neutral amino acid transport defect but without the Hartnup hyperaminoaciduria has been reported.

4. Maternal Hartnup disorder is probably benign to the fetus and to the pregnancy. At least 14 offspring from women with Hartnup disorder are known, and almost all are normal. One man with Hartnup disorder has fathered two normal children.

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