Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom

Abstract

Background and objectives Cystinuria is a rare inherited renal stone disease. Mutations in the amino acid exchanger System b 0,+ , the two subunits of which are encoded by SLC3A1 and SLC7A9, predominantly underlie this disease. The work analyzed the epidemiology of cystinuria and the influence of mutations in these two genes on disease severity in a United Kingdom cohort.Design, setting, participants, & measurements Prevalent patients were studied from 2012 to 2014 in the northeast and southwest of the United Kingdom. Clinical phenotypes were defined, and genetic analysis of SLC3A1 and SLC7A9 combining Sanger sequencing and multiplex ligation probe-dependent amplification was performed.Results In total, 76 patients (42 men and 34 women) were studied. All subjects had proven cystine stones. Median age of presentation (first stone episode) was 24 years old, but 21% of patients presented after 40 years old. Patients had varied clinical courses, with 37% of patients having $10 stone episodes; 70% had evidence of CKD, and 9% had reached ESRD as a result of cystinuria and its complications. Patients with cystinuria received a variety of different therapies, with no obvious treatment consensus. Notably, 20% of patients had staghorn calculi, with associated impaired renal function in 80% of these patients. Genetic analysis revealed that biallelic mutations were present in either SLC3A1 (n=27) or SLC7A9 (n=20); 22 patients had only one mutated allele detected (SLC3A1 in five patients and SLC7A9 in 17 patients). In total, 37 different mutant variant alleles were identified, including 12 novel mutations; 22% of mutations were caused by large gene rearrangements. No genotypephenotype association was detected in this cohort.Conclusions Patients with cystinuria in the United Kingdom often present atypically with staghorn calculi at $40 years old and commonly develop significant renal impairment. There is no association of clinical course with genotype. Treatments directed toward reducing stone burden need to be rationalized and developed to optimize patient care.

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria

“…In a recent UK study (16), the level of renal impairment observed was similar across all genotypes. Recently, a recent large retrospective study conducted by the French Cystinuria Group (27) showed that 5 (1.1%) of 442 patients with cystinuria progressed to end stage renal disease at a median age of 35.0 (11.8–70.7) years.…”

“…Several previous studies examining genotype-phenotype correlations in cystinuria did not show any correlation between patients with type A genotype and patients with non-A genotypes (81516). In a UK study (15), patients with at least one missense mutation in SLC3A1 had significantly lower levels of lysine, arginine, and ornithine, but not cystine, than patients with all other types of SLC3A1 mutations.…”

“…In a UK study (15), patients with at least one missense mutation in SLC3A1 had significantly lower levels of lysine, arginine, and ornithine, but not cystine, than patients with all other types of SLC3A1 mutations. Another UK study (16) revealed no difference between patients with type AA and patients with type BB in a variety of clinical parameters. In addition, patients with a single mutated allele also had variable disease severity and could not be differentiated from patients with 2 mutated alleles (16).…”

“…Another UK study (16) revealed no difference between patients with type AA and patients with type BB in a variety of clinical parameters. In addition, patients with a single mutated allele also had variable disease severity and could not be differentiated from patients with 2 mutated alleles (16). In our study, the only difference between patients with the AA genotype and those with non-AA genotypes was the later age of onset in the former group.…”

Cystinuria: A Review of Inheritance Patterns, Diagnosis, Medical Treatment and Prevention of Stones

“…The SLC7A9 gene, located on chromosome 19, encodes b 0,AT and homozygous mutations in this gene produce type B cystinuria. Due to digenic inheritance of two or more mutant alleles there exist much rarer forms, including type AB, type ABB and type AAB cystinuria [8]. Such mutations account for only 2% of cases [7] ( Table 1).…”