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      Primary Hyperoxaluria Type 1 in Japan

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          Abstract

          Background/Aims: Current status of primary hyperoxaluria (PH) has not been surveyed in Japan. Methods: Japanese patients with PH were reviewed in the published literature. Results: Fifty-nine patients were diagnosed as PH from 1962 to 2003. The median ages both at diagnosis and at the onset of initial symptoms were 17 (range: 0.02–63) and 13 (range: 0–58) years, respectively. Twenty-nine (49%) patients were older than 20 years at diagnosis, among whom 26 (90%) already presented end-stage renal failure (ESRF) or soon evolved into ESRF. Among 30 (51%) diagnosed as PH under 20 years old, only 13 (43%) were already in a terminal stage of renal insufficiency. Ten patients were diagnosed as PH1 by liver biopsy. We identified two types of enzymatic phenotypes in 3 of those patients examined. In 1 case, immunoreactive SPT/AGT protein level was very low due to accelerated proteolysis, while in other 2 cases, the immunoreactivity was detected on mitochondria due to mistargeting. Of 9 cases having been subjected to kidney transplantation at a median age of 20 years (range 7.3–40.0), it was only 2 cases that were reported to be successful, while the median survival time of the kidney grafts being 1.4 years (range 0–7). Of 4 patients having undergone combined liver/kidney transplantations (at the ages of 1.3, 1.4, 9 and 41 years, respectively), the surgery was successful in 3 cases; in the remaining one case, however, rejection required removal of the transplanted kidney was observed. The overall survival ratio of all the 59 PH cases accounted for 77, 71 and 55% at 5, 10 and 20 years, respectively. Conclusion: Assuming that the majority of the 59 patients with PH reported was classified as PH1, it is postulated that morbidity of violent infantile PH1 in Japan might be less than those in the USA and Europe, and symptoms of elderly Japanese PH1 patients seem to be milder than those of Western patients. Establishment of an early detection system of PH1 and more popular application of combined liver/kidney transplantation deserve further study.

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          Most cited references 13

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          Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type I.

          Activities of alanine:glyoxylate aminotransferase in the livers of two patients with primary hyperoxaluria type I were substantially lower than those found in five control human livers. Detailed subcellular fractionation of one of the hyperoxaluric livers, compared with a control liver, showed that there was a complete absence of peroxisomal alanine:glyoxylate aminotransferase. This enzyme deficiency explains most of the biochemical characteristics of the disease and means that primary hyperoxaluria type I should be added to the rather select list of peroxisomal disorders.
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            Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias.

            A definitive diagnosis of primary hyperoxaluria type 1 (PH1) and primary hyperoxaluria type 2 (PH2) requires the measurement of alanine:glyoxylate aminotransferase (AGT) and glyoxylate reductase (GR) activities, respectively, in a liver biopsy. We have evaluated a molecular genetic approach for the diagnosis of these autosomal-recessive diseases. Polymerase chain reaction (PCR) was used to detect three common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) and one, c.103delG, in the GRHPR gene in DNA samples from 365 unrelated individuals referred for diagnosis of PH1 and/or PH2 by liver enzyme analysis. One or more of these mutations was found in 183 (68.8%) biopsy proven cases of PH1 and PH2 with a test negative predictive value of 62% and 2%, respectively. 102 (34.1%) patients were homozygous or compound heterozygous, making a molecular diagnosis possible. Age of onset and presenting features were similar in patients homozygous for any of the four mutations. Of the AGXT homozygotes, only the c.508G>A mutant was associated with significant AGT catalytic activity and in two of these activity was in the low normal range, possibly reflecting variation in mitochondrial content of the biopsy as this particular mutation is associated with mitochondrial mistargeting. Limited mutation analysis can provide a useful first line test for PH1 and PH2 in patients in whom primary hyperoxaluria is suspected and in whom secondary causes have been excluded. Those patients in whom a single mutation, or no mutation, is found can then be selectively targeted for liver biopsy.
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              Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.

              The autosomal recessive disorder primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver-specific pyridoxal-phosphate-dependent enzyme alanine:glyoxylate aminotransferase (AGT). Numerous mutations and polymorphisms in the gene encoding AGT have been identified, but in only a few cases has the causal relationship between genotype and phenotype actually been demonstrated. In this study, we have determined the effects of the most common naturally occurring amino acid substitutions (both normal polymorphisms and disease-causing mutations) on the properties, especially specific catalytic activity, of purified recombinant AGT. The results presented in this paper show the following: 1) normal human His-tagged AGT can be expressed at high levels in Escherichia coli and purified in a correctly folded, dimerized and catalytically active state; 2) presence of the common P11L polymorphism decreases the specific activity of purified recombinant AGT by a factor of three; 3) AGTs containing four of the most common PH1-specific mutations (G41R, F152I, G170R, and I244T) are all soluble and catalytically active in the absence of the P11L polymorphism, but in its presence all lead to protein destabilization and aggregation into inclusion bodies; 4) naturally occurring and artificial amino acid substitutions that lead to peroxisome-to-mitochondrion AGT mistargeting in mammalian cells also lead to destabilization and aggregation in E. coli; and 5) the PH1-specific G82E mutation abolishes AGT catalytic activity by interfering with cofactor binding, as does the artificial K209R mutation at the putative site of cofactor Shiff base formation. These results are discussed in the light of the high allelic frequency ( approximately 20%) of the P11L polymorphism and its importance in determining the phenotypic manifestations of mutations in PH1.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2005
                June 2005
                01 July 2005
                : 25
                : 3
                : 297-302
                Affiliations
                Department of Urology, Hamamatsu University School of Medicine, Shizuoka, Japan
                Article
                86361 Am J Nephrol 2005;25:297–302
                10.1159/000086361
                15961950
                © 2005 S. Karger AG, Basel

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                Page count
                Figures: 2, Tables: 3, References: 28, Pages: 6
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/86361
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