The Genetics of ‘Cystinuria’

Abstract

Cystine is a normal constituent of human urine. Under ordinary conditions, healthy individuals excrete mg. of this substance in the free state daily (Reed, 1942). In the urine of certain people, however, much larger quantities of cystine are regularly found, and it is to this condition that the term cystinuria has come to be applied. The disorder was first investigated by Wollaston in 1810 as the result of the discovery of a bladder-stone of unusual composition, and, until the work of Lewis in 1932, it had always been regarded as a rare anomaly. It was thought that most cases suffered a greater or lesser degree of disability, leading eventually to renal failure. This was sometimes attributed to stone formation, sometimes to direct damage to the kidney by the large quantities of cystine in the process of excretion. However, symptomless cases, usually among the close relatives of patients with cystine calculi, had occasionally been recognized. Such individuals were identified by the finding of cystine crystals in their urine.Lewis (1932) threw a completely new light on the situation. By using more reliable chemical tests for cystine, he was able to demonstrate that gross cystinuria could occur in individuals without either the appearance of cystine crystals in the urine or of cystine stone formation, and he showed that, far from being a rare anomaly, the condition was relatively common. He made a systematic examination of the urines of 10,534 students. Besides ordinary microscopic examination for cystine crystals, he also applied the Sullivan and the cyanide-nitroprusside tests for cystine. He found, in all, eighteen individuals who gave strong positive reactions by both these tests, and in only four of these could cystine crystals be demonstrated in the urinary deposit. These eighteen subjects were probably excreting between 200 and 1000 mg. of cystine daily, and repeated examination showed that the phenomenon was constantly present. In none of them was there any history of the occurrence of renal calculi, and in other respects they appeared to be perfectly well developed and healthy. Thus approximately 1 in 600 of the population studied were excreting cystine in quantities greatly in excess of that usually found. I n addition to these eighteen people, another eleven individuals gave weak positive tests for cystine and another eleven were observed who gave occasional weak positives.

The intestinal absorption defect in cystinuria

“…Cystinuria is a recessive hereditary disease (Dent and Harris, 1951;Harris and Warren, 1953;Harris, Mittwoch, Robson, and Warren, 1955a and b;Harris and Robson, 1955), such conditions usually involving a deficiency or absence of a single protein, which may be an enzyme. The biochemical defect in Hartnup disease (Baron, Dent, Harris, Hart, and Jepson, 1956;Milne, Crawford, Girao, and Loughridge, 1960), a comparable recessive hereditary condition, is a reduced ability to transport those amino-acids which are not involved in the transport defect of cystinuria.…”

Disturbances of Cystine Metabolism in Liver Disease

“…It may be increased either as a result of a low renal threshold for cystine or a raised plasma cystine concentration. Cystinuria due to a low renal threshold occurs in 'classical cystinuria,' the Fanconi syndrome and hepatolenticular degeneration (2). In such conditions the excretion of cystine is usually large, 0.5 to 1.0 g. daily, and is associated with other characteristic changes in the pattern of amino acids excreted.…”

Studies on Copper Metabolism. XIII. Hepatolenticular Degeneration1

“…The aminoaciduria which accompanies this disease (18) involves most of the amino acids found in normal urine, but, in addition, proline and citrulline are excreted (19,20). The urinary amino acid pattern varies widely, depending upon the stage of the disease and the protein composition of the diet.…”