Intra-familial clinical heterogeneity: Absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel

Background/Aims: Primary hyperoxaluria type 1 (PH1) is caused by the deficiency of the liver enzyme alanine: glyoxylate aminotransferase which results in increased synthesis and excretion of oxalate. The clinical manifestations of PH1 are heterogeneous with respect to the age of onset and rate of progression. The aim of this study was to investigate possible relationships between a given genotype, the biochemical profile and the clinical phenotype. Methods: We conducted a study of 56 patients from 22 families with PH1 from Israel. The clinical and biochemical data were compiled and the genotype was determined for each family. Results: The prevalent phenotype was of early onset with progression to end-stage renal disease during the first decade of life. Fifteen PH1-causing mutations were detected in 21 families: 10 were first described in this patient population. Marked intra-familial clinical heterogeneity was noted, meaning that there was no correlation between a given genotype and the phenotype. Conclusions: The clinical course of patients with PH1 is not dictated primarily by its genotype. Other genetic and/or environmental factors play a role in determining the ultimate phenotype.