Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria.
BACKGROUND
Marked hyperoxaluria due to liver-specific deficiency of alanine:glyoxylate aminotransferase activity (AGT) characterizes type I primary hyperoxaluria (PHI). Approximately half of PHI patients experience improvement in the degree of hyperoxaluria following pyridoxine (VB6) treatment. Recently, we showed an association between VB6 response and the commonest PHI mutation G170R, with patients possessing one or two copies showing 50% reduction or complete to near complete normalization of oxaluria, respectively. Two patients showed responses varying from this pattern. To further clarify the molecular basis of VB6 response in PHI, we performed additional genotyping.


METHODS
23 PHI patients diagnosed via hepatic enzyme analysis, hyperoxaluria and hyperglycolic aciduria or homozygosity for a known mutation, availability of pre- and post-VB6 24-hour urine oxalate and GFR >40 ml/min/1.73 m2 were included. Data was retrieved retrospectively, oxalate measured by oxalate oxidase, and genotyping performed by PCR-based methods.


RESULTS
VB6 response was associated with the G170R and F152I mutations. Eight new sequence changes were detected.


CONCLUSIONS
In PHI, two mutations resulting in AGT mistargeting are associated with VB6 response. Whether this favorable effect is specific to the peroxisomal-to-mitochondrial mistargeting caused by these changes or due to another mechanism remains to be determined.
Monico
Carla G
CG
Mayo Clinic Hyperoxaluria Center, Division of Pediatric Nephrology, Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minn. 55905, USA. monico.carla@mayo.edu
Olson
Julie B
JB
Milliner
Dawn S
DS
D015331:Cohort Studies; D004798:Enzymes / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006960:Hyperoxaluria, Primary / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype; D011736:Pyridoxine / Q000627:therapeutic use*; D012189:Retrospective Studies; D014815:Vitamins / Q000627:therapeutic use*
D004798:Enzymes; D014815:Vitamins; D011736:Pyridoxine