Clinical implications of mutation analysis in primary hyperoxaluria type 1.
BACKGROUND
Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism with an extensive clinical and genetic heterogeneity. Although over 50 disease-causing mutations have been identified, the relationship between genotype and clinical outcome remains unclear. The aim of this study was to determine this association in order to find clues for improvement of patient care.


METHODS
AGXT mutation analysis and assessment of biochemical characteristics and clinical outcome were performed on patients from a Dutch PH1 cohort.


RESULTS
Thirty-three of a cohort of 57 PH1 patients, identified in The Netherlands over a period of 30 years, were analyzed. Ten different mutations were found. The most common mutations were the Gly170Arg, Phe152Ile, and the 33insC mutations, with an allele frequency of 43%, 19%, and 15%, respectively. Homozygous Gly170Arg and Phe152Ile mutations were associated with pyridoxine responsiveness and a preserved renal function over time when treatment was timely initiated. All patients homozygous for the 33insC mutation had end-stage renal disease (ESRD) before the first year of age. In two unrelated patients, a new Val336Asp mutation was found coupled with the Gly170Arg mutation on the minor allele. We also found 3 patients homozygous for a novel Gly82Arg mutation with adverse outcome in 2 of them.


CONCLUSIONS
Early detection of Gly170Arg and Phe152Ile mutations in PH1 has important clinical implications because of their association with pyridoxine responsiveness and clinical outcome. The association of a homozygous 33insC mutation with severe infantile ESRD, resulting in early deaths in 2 out of 3 cases, warrants a choice for prenatal diagnostics in affected families.
van Woerden
Christiaan S
CS
Emma Children's Hospital AMC, Amsterdam, The Netherlands.
Groothoff
Jaap W
JW
Wijburg
Frits A
FA
Annink
Carla
C
Wanders
Ronald J A
RJ
Waterham
Hans R
HR
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D010641:Phenotype; D017354:Point Mutation; D000637:Transaminases / Q000235:genetics*
D000637:Transaminases; C019635:Alanine-glyoxylate transaminase