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Ontogeny modifies manifestations of cystinuria genes: implications for counseling
Insights
Infantile cystinuria, a condition affecting newborn amino acid excretion, is seven times more common than classic cystinuria. Renal development amplifies its phenotype, impacting genotype classification and requiring follow-up.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Newborn screening identified a significant prevalence of infantile cystinuria, characterized by elevated excretion of cystine and dibasic amino acids.
- The apparent incidence of this phenotype in newborns is substantially higher than that of classic cystinuria in adults.
Purpose of the Study:
- To investigate the longitudinal progression and genotypic classification of infantile cystinuria.
- To understand the influence of renal ontogeny on the phenotypic expression of cystinuria alleles in infants.
Main Methods:
- Screening of 339,868 newborns for elevated cystine and dibasic amino acid excretion.
- Longitudinal study of 26 probands from 2-4 months of age, including parental phenotype analysis and urine amino acid excretion measurements at 6 months.
- Classification of infants into heterozygous (types I, II, III) and homozygous genotypes based on excretion patterns.
Main Results:
- 191 infants showed persistent infantile cystinuria, with an incidence of 562 per million, seven times higher than adult classic cystinuria.
- Urine amino acid excretion decreased with age, reaching parental levels in heterozygotes but not in homozygotes.
- Distinguishing heterozygotes from homozygotes in early infancy was challenging, though homozygotes exhibited higher excretion levels.
Conclusions:
- Renal ontogeny plays a crucial role in amplifying the phenotypic expression of cystinuria alleles, affecting genotype classification.
- Findings highlight the importance of follow-up screening and genetic counseling for infantile cystinuria.
- Early infancy diagnosis is complex, necessitating careful monitoring to differentiate genotypes accurately.
Abstract:
Among 339,868 newborn infants screened at 3 weeks of age (91% compliance rate), 730 had elevated rates of excretion of cystine and the dibasic amino acids lysine, ornithine, and arginine; 191 infants had persistent "infantile cystinuria" on follow-up screening (100% compliance). Apparent incidence of the phenotype was 562 per million infants; this rate is seven times higher than for classic cystinuria in the adult segment of the Quebec population. We studied longitudinally 26 probands 2 to 4 months of age. Initially, each excreted cystine and dibasic amino acids at much higher levels than did normal infants or either parent. From parental phenotypes (heterozygous or homozygous normal) and urine amino acid excretion values at 6 months of age in probands, the infants were classified as either heterozygous for the various classic cystinuria genotypes--type I ("silent"), eight infants; type II (high excretor), three; type III (moderate excretor), nine--or homozygous (and genetic compound), six. Urine amino acid excretion diminished steadily with age, to reach the variant parental value in heterozygous infants but not in homozygotes. Cystinuria heterozygotes, with the possible exception of some type I individuals, could not be distinguished reliably from homozygotes in early infancy, although homozygotes had significantly higher excretion values as a group. We deduce that renal ontogeny amplifies phenotypic expression of cystinuria alleles, thus influencing correct classification of genotype (heterozygote vs homozygote, and type of allele). These findings have implications for counseling and the need for follow-up of infantile cystinuria.