CYSTINURIA SUBTYPE AND THE RISK OF NEPHROLITHIASIS

Background. Cystinuria patients may be classified into several subgrou ps based on the urinary phenotype of heterozygotes. However, the relat ive risk for nephrolithiasis and the prevalence of SLC3A1 mutations in these subgroups are unknown. Methods. Urinary cystine excretion, age at onset of nephrolithiasis and nature of SLC3A1 mutations were assess ed prospectively in 23 cystinuria patients identified primarily throug h the Quebec Newborn Screening Program. Probands were classified as to cystinuria subtype on the basis of parental urinary cystine excretion . Results. For classical Type III cystinuria, both parents excrete cys tine in the normal range and probands carry two mutations of the SLC3A 1 gene in nearly every case. Between ages 1 to 7 years, mean cystine e xcretion was high (4566 +/- 480 mu mol cystine/g creatinine) and excee ded the theoretic threshold for solubility on 70% of visits. Four of e ight Type III patients began forming stones in the first decade. Type I/III patients (N = 12) excreted less cystine (1544 +/- 163 mu mol cys tine/g creatinine), exceeded the threshold of urinary cystine solubili ty less frequently (22% of visits) and had no nephrolithiasis in the f irst decade; one formed a stone at age 16 years. Only one SLC3A1 mutat ion was identified in this group. Two Type II/N cystinuria children we re identified. In these families, the same level of relatively high ex cretion (>600 mu mol cystine/g creatinine) was noted in two or three g enerations, but no SLC3A1 mutations were identified. Conclusions. Clas sical recessive Type III cystinuria is genetically and phenotypically distinct from the other subtypes (Type I/III and Type II/N) identified in our population.