Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel.
OBJECTIVE
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.
Frishberg
Yaacov
Y
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel. yaacov@md.huji.ac.il
Rinat
Choni
C
Shalata
Adel
A
Khatib
Ihab
I
Feinstein
Sofia
S
Becker-Cohen
Rachel
R
Weismann
Irit
I
Wanders
Ronald J A
RJ
Rumsby
Gill
G
Roels
Frank
F
Mandel
Hanna
H
D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000150:complications / Q000201:enzymology / Q000235:genetics*; D007223:Infant; D007557:Israel; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000401:mortality; D008099:Liver / Q000201:enzymology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D000637:Transaminases / Q000378:metabolism
D000637:Transaminases; C019635:Alanine-glyoxylate transaminase