In contrast to other disorders characterised by urolithiasis, cystinuria is solely caused by genomic mutations. Nevertheless, the interpretation of the molecular results and genetic counselling in cystinuria families is often complicated by the difficulty to differentiate between patients and heterozygote carriers of mutations with ambiguous clinical significance. In these situations, a prediction of the clinical course or a targeted therapeutic regime is often asked by the patients and their families. However, an unambiguous prognosis is merely possible due to the broad clinical variability even in carriers of the same mutation and the influence of so far unknown modifying endo- and exogenous factors. Nevertheless, a more-directed counselling has become possible based on the molecular classification suggested by DelloStrologo et al. [11
(homozygosity for one or compound heterozygosity for two SLC3A1
mutations) is mainly consistent with an autosomal recessive inheritance of cystinuria. The parents are obligate carriers but with a normal renal cystine excretion, a recurrence risk of 25% can be delineated for children to be affected by cystinuria. However, there is evidence at least the mutation dupE5E9 is associated with non-type I cystinuria, i.e. carriers show an increased cystine excretion [10
]. Heterozygote carriers of this variant should be tested for urinary cystine excretion.
- A? (heterozygosity for a SLC3A1 mutation, a second mutation could not be identified): probably a second mutation in one of the two genes is present but not detectable by the applied methods. However, in the case of clinical diagnosis of cystinuria, the identification of only one mutation in SLC3A1 should be sufficient for confirmation. To further estimate the recurrence risk in these families the urinary excretion patterns and the cystinuria genotype of the parents should be determined. In case of a normal cystine excretion in that parent not contributing the SLC3A1 mutation compound heterozygosity for the identified and an unknown SLC3A1 mutation can be delineated for the patient. If the parent not carrying the detected SLC3A1 mutation shows an increased cystine excretion, a SLC7A9 mutation can be assumed. In that case the clinical prediction for the offspring expected to be heterozygous for the (unknown) SLC7A9 mutations is difficult because of the broad range of biochemical penetrance of mutations in this gene.
- BB (homozygosity for one or compound heterozygosity for two SLC7A9 mutations) is consistent with cystinuria. The recurrence risk for sibs is at least 25%, but due to the possible dominant nature of SLC7A9 mutation and the broad ranges of urinary amino acid excretion even in the same family the risk to develop cystine stones is higher. Here the biochemical analysis of the urine of heterozygote mutation carriers and the knowledge of the pathogenic nature of the mutation might help to further delineate the risk to develop stones.
- B? (heterozygosity for a SLC7A9 mutation, a second mutation could not be identified): this finding is the most difficult one to interpret: as discussed for the BB genotype, the same mutation might behave recessive in one generation and dominant in another in the same family. Thus the identification of just one SLC7A9 mutation might be compatible with an extremely increased cystine excretion, the prognosis in newborns or children is merely possible.
- AB (mixed heterozygosity of a SLC3A1 and a SLC7A9 mutation): this finding explains the clinical phenotype, but as discussed for the A?, BB and the B? genotypes, the probable dominant effect of a SLC7A9 mutation has to be bare in mind in genetic counselling.
- AAA/AAB/ABB (three SLC3A1/SLC7A9 mutations in one patient): this rare finding explains the phenotype, but the parents should be checked for the mutations to identify the chromosome harbouring two mutations and thereby to avoid false-negative carrier testing results in the further family.
In clinical practice, the molecular genetic testing results only scarcely influence the prognosis and therapy of cystinuria as causative therapies do currently not exist. Indeed, more than 95% of all carriers of two SLC3A1
mutations (genotypes AA, BB, AB) will develop kidney stones in their live but the age of kidney stone formation is difficult to predict and shows a broad intrafamilial variability. Furthermore, the urinary excretion pattern in heterozygote SLC7A9
mutation carriers is extremely variable and does therefore hardly allow a prediction of the clinical course whereas the majority of SLC3A1
heterozygotes do not exhibit a biochemical phenotype (for review: [12
]). As far as the comprehensive knowledge on the pathophysiology of cystinuria can not be applied in a causative therapy, the biochemical determination of the urinary cystine excretion pattern remains the basic tool for prognosis and therapeutic management of cystinuria.