Cystinuria subtype and the risk of nephrolithiasis.

BACKGROUND: Cystinuria patients may be classified into several subgroups based on the urinary phenotype of heterozygotes. However, the relative 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 assessed prospectively in 23 cystinuria patients identified primarily through the Quebec Newborn Screening Program. Probands were classified as to cystinuria subtype on the basis of parental urinary cystine excretion.
RESULTS: For classical Type I/I cystinuria, both parents excrete cystine in the normal range and probands carry two mutations of the SLC3A1 gene in nearly every case. Between ages 1 to 7 years, mean cystine excretion was high (4566 +/- 480 microns cystine/g creatinine) and exceeded the theoretic threshold for solubility on 70% of visits. Four of eight Type I/I patients began forming stones in the first decade. Type I/III patients (N = 12) excreted less cystine (1544 +/- 163 mumol cystine/g creatinine), exceeded the threshold of urinary cystine solubility less frequently (22% of visits) and had no nephrolithiasis in the first decade; one formed a stone at age 16 years. Only one SLC3A1 mutation was identified in this group. Two Type II/N cystinuria children were identified. In these families, the same level of relatively high excretion (> 600 mumol cystine/g creatinine) was noted in two or three generations, but no SLC3A1 mutations were identified.
CONCLUSIONS: Classical recessive Type I/I cystinuria is genetically and phenotypically distinct from the other subtypes (Type I/III and Type II/N) identified in our population.