Genetic diagnosis in primary hyperoxaluria in Type 1

Primary hyperoxaluria type 1 (PH1) is a rare, autosomal recessive disease, caused by defect of AGXT gene which coding hepatic peroxisomal alanine glyoxylate aminotransferase (AGT) , which is responsible for the conversion of glyoxylate to glycin. In the deficiency of AGT, glyoxylate is converted to oxalate which cannot be metabolized and forms insoluble calcium salts that accumulate in the kidney and other organs. PH1 accounts for about 80 percent of PH cases. PH type 1 is a highly heterogeneous disease and is seen with variable symptoms and findings in even patients who are family members with the same genotype. The diagnosis of PH1 should be suspected with infants and children with nephrocalcinosis or nephrolithiasis, especially in a patient with oxalate crystals in the urine sediment and normal urinary calcium and uric acid excretion, calcium oxalate monohydrate stones, nephrocalcinosis or nephrolithiasis especially if associated with a decrease in glomerular filtration rate. Early diagnosis and treatment is important, particularly in some mutations, prevention of progress and slowdown of the disease. It is known that pyridoxin has a positive effect especially in p.Gly170Arg and p.Phe152Ile mutations. Diagnosing the disease is also important in cases which come with ESRD due to the necessity of transplant of liver and kidney together. In the diagnosis of the disease, the rate of urine oxalate/creatinin, oxalate in 24-hour urine, plasma oxalate concentration, genetic analyses and liver biopsy and measuring AGT catalytic activity are used. (19). In our study, for the patients who are suspected to have PH1 with symptoms and findings, mutation analysis has been done. In the forms that are prepared for the patients, especially story, personel and parental history which might be important for PH1, pathologic findings in physical examination, laboratory and imaging tests have been noted down. In 80 patients' AGXT gene, mutation has been researched thanks to analysis and in 13 patients from 11 families (16%) mutation which causes disease has been found. In three out of 11 families, respectively c.458T>A (p.L153X), c.733_734delAA (p.Lys245Valfs*11), c.52 C>T (p.L18F) new mutation has been found, in other eight families c.508G>A(p.G170R), [c.969_970delTG][p.Val324Glyfs*7], c.823_824dupGA (p.S275Rfs*38), c.52 C>T (p.L18F), c.166-1G>A, [c.121 G>C] [p. G41R] known mutations have been found. It has been discovered that there are 3-year delay between initial symptoms and the time when diagnosis of PH1 is suspected and 5,5 year delay between initial symptoms and exact diagnosis. Consanguinity was present in 77 % of the patients that mutation has been found and in 54% of these patients, renal failure story in family has been found. In 77% of these patients, at least one member in family, kidney stone has been noticed. During exact diagnosis, in 11 patients, (85%) stage 5D cronic kidney disease (CKD), in one patient stage 1 CKD, in one patient nephrocalcinosis without CKD has been discovered. Five patients (38%) bilateral nephrolithiasis in ultrasonography, bilateral nephrocalcinosis with or without bilateral nephrolithiasis in six patients (46%) and bilateral nephrolithiasis, in two patients (16%) bilateral nephrolithiasis and hyperechogenicity have been seen. In the all patients renal, in patients cardiac, in two patients vascular, in one patient joint and one patient neurologic injury has been found. After exact diognosis with mutation analysis to one of the patients, kidney and liver transplant from living donor have been done simultaneously. Early diagnosis and treatment in PH1 is realy crucial that because of high morbidity and mortality in terms of short and long term results and in cases which have CKD, it is crucial for true transplant strategy. In exact diagnosis, mutation analyses have been frequently used in recent years. Keywords: Primary hyperoxaluria type 1, alanine glyoxylate aminotransferase gene, mutation