ABSTRACT
Cystinuria is an inherited disorder of amino acid metabolism (OMIM 220100) in which there is reduced renal and intestinal transport of cystine and the dibasic amino acids lysine, arginine, and ornithine. Cystine is an amino acid formed by the linkage of two cysteine molecules via a disulfide bond. Cystine has a much lower solubility than cysteine, which leads to the clinically relevant feature of cystinuria, cystine urolithiasis. Cystine stones were first described by Wollaston in 1810 when he reported two bladder stones composed of a previously unrecognized substance.(1) He believed the substance was an oxide and named it cystic oxide in honor of its origin in the bladder. Berzelius later demonstrated the substance was not an oxide and renamed the new compound cystine.(2)
Cystinuria is one of the most common inherited diseases, with an estimated prevalence of 1:7,000.(3) The prevalence of cystine stones varies depending on the population being studied, ranging from 1:2,500 in Libyan Jews to 1:100,000 in Sweden.(4) In the United States the prevalence is estimated as 1:15,000.(5) Prevalence studies may underestimate the level of disease as not all people homozygous for the gene defect will develop kidney stones. Neonatal screening programs provide higher prevalence estimates. In Quebec, 1:1,800 newborns tested positive for cystinuria, a much higher rate than found in the Quebec adult population.(6) Whether this discrepancy is due to identifying large numbers of heterozygotes who will never develop the cystinuric phenotype or if it is due to the fall in urine cystine excretion as children age is not clear.(7) Cystinuria accounts for less than 1% of kidney stone disease in adults (8), though the relatively early onset of the disease makes it more common in the pediatric population, 6-8% of children with stones have cystinuria.(9, 10)
PHENOTYPE
The original phenotypic classification system for cystinuria was developed before knowledge of the genetics of the disease. Three phenotypes were described based on the level of urine excretion of cystine in obligate heterozygotes (i.e. parents) of the proband.(11) Type I patients had parents with normal cystine excretion. Thus type I is an autosomal recessive disorder in which the parents phenotype is normal and they each carry one normal and one mutant gene. Probands with type II and type III phenotypes have parents with elevated cystine excretion. Type II heterozygotes have markedly abnormal cystine excretion (>990 µmol/g creatinine), approaching that of some homozygotes and on occasion they can form cystine stones. Type III heterozygotes have only modest elevations of urine cystine excretion, 100-660 µmol/g creatinine, not high enough for stone formation. However, it was recognized that the classification of subjects into type II and type III phenotypes was somewhat arbitrary and that the distinction was not always clear, especially for subjects whose excretion rates fell between those defined for type II and type III.
