Artículos de revistas: "Primary Hyperoxaluria Type I (PHI)"

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Knight, John, Ross P. Holmes, Scott D. Cramer, Tatsuya Takayama y Eduardo Salido. "Hydroxyproline metabolism in mouse models of primary hyperoxaluria". American Journal of Physiology-Renal Physiology 302, n.º 6 (15 de marzo de 2012): F688—F693. http://dx.doi.org/10.1152/ajprenal.00473.2011.

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Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in glyoxylate reductase/hydroxypyruvate reductase (GRHPR KO) developed severe nephrocalcinosis in contrast to animals deficient in alanine-glyoxylate aminotransferase (AGXT KO) where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney.

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Danpure, Christopher J. y Gill Rumsby. "Molecular aetiology of primary hyperoxaluria and its implications for clinical management". Expert Reviews in Molecular Medicine 6, n.º 1 (9 de enero de 2004): 1–16. http://dx.doi.org/10.1017/s1462399404007203.

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The primary hyperoxalurias type 1 (PH1) and type 2 (PH2) are autosomal recessive calcium oxalate kidney stone diseases caused by deficiencies of the metabolic enzymes alanine:glyoxylate aminotransferase (AGT) and glyoxylate/hydroxypyruvate reductase (GR/HPR), respectively. Over 50 mutations have been identified in the AGXT gene (encoding AGT) in PH1, associated with a wide variety of effects on AGT, including loss of catalytic activity, aggregation, accelerated degradation, and peroxisome-to-mitochondrion mistargeting. Some of these mutations segregate and interact synergistically with a common polymorphism. Over a dozen mutations have been found in the GRHPR gene (encoding GR/HPR) in PH2, all associated with complete loss of glyoxylate reductase enzyme activity and immunoreactive protein. The crystal structure of human AGT, but not human GR/HPR, has been solved, allowing the effects of many of the mutations in PH1 to be rationalised in structural terms. Detailed analysis of the molecular aetiology of PH1 and PH2 has led to significant improvements in all aspects of their clinical management. Enzyme replacement therapy by liver transplantation can provide a metabolic cure for PH1, but it has yet to be tried for PH2. New treatments that aim to counter the effects of specific mutations on the properties of the enzymes could be feasible in the not-too-distant future.

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Brooks, Ellen R., Bernd Hoppe, Dawn S. Milliner, Eduardo Salido, John Rim, Leah M. Krevitt, Julie B. Olson, Heather E. Price, Gulsah Vural y Craig B. Langman. "Assessment of Urine Proteomics in Type 1 Primary Hyperoxaluria". American Journal of Nephrology 43, n.º 4 (2016): 293–303. http://dx.doi.org/10.1159/000445448.

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Background: Primary hyperoxaluria type 1 (PH1) and idiopathic hypercalciuria (IHC) are stone-forming diseases that may result in the formation of calcium (Ca) oxalate (Ox) stones, nephrocalcinosis, and progressive chronic kidney disease (CKD). Poorer clinical outcome in PH1 is segregated by the highest urine (Ur)-Ox (UrOx), while IHC outcomes are not predictable by UrCa. We hypothesized that differences would be found in selected Ur-protein (PRO) patterns in PH1 and IHC, compared to healthy intra-familial sibling controls (C) of PH1 patients. We also hypothesized that the PRO patterns associated with higher UrOx levels would reflect injury, inflammation, biomineralization, and abnormal tissue repair processes in PH1. Methods: Twenty four-hour Ur samples were obtained from 3 cohorts: PH1 (n = 47); IHC (n = 35) and C (n = 13) and were analyzed using targeted platform-based multi-analyte profile immunoassays and for UrOx and UrCa by biochemical measurements. Results: Known stone matrix constituents, osteopontin, calbindin, and vitronectin were lowest in PH1 (C > IHC > PH1; p < 0.05). Ur-interleukin-10; chromogranin A; epidermal growth factor (EGF); insulin-like growth factor-1 (IGF-1), and macrophage inflammatory PRO-1α (MIP-1α) were higher in PH1 > C (p = 0.03 to p < 0.05). Fetuin A; IGF-1, MIP-1α, and vascular cell adhesion molecule-1 were highest in PH1 > IHC (p < 0.001 to p = 0.005). Conclusion: PH1 Ur-PROs reflected overt inflammation, chemotaxis, oxidative stress, growth factors (including EGF), and pro-angiogenic and calcification regulation/inhibition compared to the C and IHC cohorts. Many of the up- and downregulated PH1-PROs found in this study are also found in CKD, acute kidney injury, stone formers, and/or stone matrices. Further data analyses may provide evidence for PH1 unique PROs or demonstrate a poorer clinical outcome.

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Hatch, Marguerite, Altin Gjymishka, Eduardo C. Salido, Milton J. Allison y Robert W. Freel. "Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization withOxalobacter". American Journal of Physiology-Gastrointestinal and Liver Physiology 300, n.º 3 (marzo de 2011): G461—G469. http://dx.doi.org/10.1152/ajpgi.00434.2010.

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Oxalobacter colonization of rat intestine was previously shown to promote enteric oxalate secretion and elimination, leading to significant reductions in urinary oxalate excretion (Hatch et al. Kidney Int 69: 691–698, 2006). The main goal of the present study, using a mouse model of primary hyperoxaluria type 1 (PH1), was to test the hypothesis that colonization of the mouse gut by Oxalobacter formigenes could enhance enteric oxalate secretion and effectively reduce the hyperoxaluria associated with this genetic disease. Wild-type (WT) mice and mice deficient in liver alanine-glyoxylate aminotransferase (Agxt) exhibiting hyperoxalemia and hyperoxaluria were used in these studies. We compared the unidirectional and net fluxes of oxalate across isolated, short-circuited large intestine of artificially colonized and noncolonized mice. In addition, plasma and urinary oxalate was determined. Our results demonstrate that the cecum and distal colon contribute significantly to enteric oxalate excretion in Oxalobacter-colonized Agxt and WT mice. In colonized Agxt mice, urinary oxalate excretion was reduced 50% (to within the normal range observed for WT mice). Moreover, plasma oxalate concentrations in Agxt mice were also normalized (reduced 50%). Colonization of WT mice was also associated with marked (up to 95%) reductions in urinary oxalate excretion. We conclude that segment-specific effects of Oxalobacter on intestinal oxalate transport in the PH1 mouse model are associated with a normalization of plasma oxalate and urinary oxalate excretion in otherwise hyperoxalemic and hyperoxaluric animals.

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Shah, Chintan G., Alpana J. Ohri y Amish H. Udani. "Primary Hyperoxaluria Type 1: A great masquerader". Wadia Journal of Women and Child Health 1 (1 de julio de 2022): 13–17. http://dx.doi.org/10.25259/wjwch_2022_05.

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Primary hyperoxaluria (PH) Types I, II, and III is an autosomal recessive inherited disorder of defect in glyoxylate metabolism due to specific hepatic enzyme deficiencies causing renal damage due to deposition of oxalate crystals that induce renal epithelial cell injury, and inflammation resulting in reduced renal oxalate elimination leading to extra renal deposition of calcium oxalate crystals. PH is under diagnosed because of phenotypic heterogeneity masquerading as infantile nephrocalcinosis (NC) with or without renal failure or renal calculus disease in adults. We present three children with genetically proven PH1 seen over last 2 years along with a brief review of the literature. In this series all cases were female. Two girls had infantile onset of symptoms and one presented in childhood. Renal failure in all with varying sonography features including small size kidneys, multiple renal calculi, bulky kidneys with loss of corticomedullary differentiation were seen. Extrarenal affection was seen in one child. Renal replacement therapy was provided in all. Awareness of PH and early diagnosis by measurement of plasma and urinary oxalate and molecular characterization helps in prompt aggressive therapy, preventing extrarenal manifestations and plan long term management.

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Garrelfs, Sander F., Dewi van Harskamp, Hessel Peters-Sengers, Chris H. P. van den Akker, Ronald J. A. Wanders, Frits A. Wijburg, Johannes B. van Goudoever, Jaap W. Groothoff, Henk Schierbeek y Michiel J. S. Oosterveld. "Endogenous Oxalate Production in Primary Hyperoxaluria Type 1 Patients". Journal of the American Society of Nephrology 32, n.º 12 (22 de octubre de 2021): 3175–86. http://dx.doi.org/10.1681/asn.2021060729.

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BackgroundPrimary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism, characterized by increased endogenous oxalate production. The metabolic pathways underlying oxalate synthesis have not been fully elucidated, and upcoming therapies require more reliable outcome parameters than the currently used plasma oxalate levels and urinary oxalate excretion rates. We therefore developed a stable isotope infusion protocol to assess endogenous oxalate synthesis rate and the contribution of glycolate to both oxalate and glycine synthesis in vivo.MethodsEight healthy volunteers and eight patients with PH1 (stratified by pyridoxine responsiveness) underwent a combined primed continuous infusion of intravenous [1-13C]glycolate, [U-13C2]oxalate, and, in a subgroup, [D5]glycine. Isotopic enrichment of 13C-labeled oxalate and glycolate were measured using a new gas chromatography–tandem mass spectrometry (GC-MS/MS) method. Stable isotope dilution and incorporation calculations quantified rates of appearance and synthetic rates, respectively.ResultsTotal daily oxalate rates of appearance (mean [SD]) were 2.71 (0.54), 1.46 (0.23), and 0.79 (0.15) mmol/d in patients who were pyridoxine unresponsive, patients who were pyridoxine responsive, and controls, respectively (P=0.002). Mean (SD) contribution of glycolate to oxalate production was 47.3% (12.8) in patients and 1.3% (0.7) in controls. Using the incorporation of [1-13C]glycolate tracer in glycine revealed significant conversion of glycolate into glycine in pyridoxine responsive, but not in patients with PH1 who were pyridoxine unresponsive.ConclusionsThis stable isotope infusion protocol could evaluate efficacy of new therapies, investigate pyridoxine responsiveness, and serve as a tool to further explore glyoxylate metabolism in humans.

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Danpure, Christopher J. y Patricia R. Jennings. "Further studies on the activity and subcellular distribution of alanine: Glyoxylate aminotransferase in the livers of patients with primary hyperoxaluria type 1". Clinical Science 75, n.º 3 (1 de septiembre de 1988): 315–22. http://dx.doi.org/10.1042/cs0750315.

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1. The activity of alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44) has been measured in the unfractionated livers of 20 patients with primary hyperoxaluria type 1 (PH1), three patients with other forms of primary hyperoxaluria and one PH1 heterozygote. The subcellular distribution of AGT activity was examined in four of the PH1 livers and in the liver of the PH1 heterozygote. 2. The mean AGT activity in the unfractionated PH1 livers was 12.6% of the mean control value. The activities of other aminotransferases and the peroxisomal marker enzymes were normal. When corrected for cross-over from glutamate:glyoxylate aminotransferase (GGT; EC 2.6.1.4), the mean AGT activity in the PH1 livers was reduced to 3.3% of the control values. 3. The livers from a patient with primary hyperoxaluria type 2 (d-glycerate dehydrogenase deficiency) and one with an undefined form of primary hyperoxaluria (possibly oxalate hyperabsorption) had normal AGT levels. The livers of a very mild PH1-type variant and a PH1 heterozygote had intermediate levels of AGT activity. 4. Subcellular fractionation of four PH1 livers by sucrose gradient isopycnic centrifugation demonstrated a complete absence of peroxisomal AGT activity. The subcellular distribution of the residual AGT activity was very similar to that of GGT activity (i.e. mainly cytosolic with a small amount mitochondrial). There were no alterations in the subcellular distributions of any of the peroxisomal marker enzymes. The subcellular distribution of AGT activity in the PH1 heterozygote liver was similar to that of the control (i.e. mainly peroxisomal). 5. The residual AGT activity in two of the PH1 livers, which could be accounted for largely by cross-over from GGT, was only slightly dependent on substrate (glyoxylate and alanine) concentration and virtually independent of cofactor (pyridoxal phosphate) concentration. 6. These data confirm our previous findings (C. J. Danpure & P. R. Jennings, FEBS Letters, 1986, 201, 20–24), but on a much larger number of patients, that AGT deficiency is pathognomic for PH1, and is not found in other forms of hyperoxaluria.

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Lin, Jin-ai, Xin Liao, Wenlin Wu, Lixia Xiao, Longshan Liu y Jiang Qiu. "Clinical analysis of 13 children with primary hyperoxaluria type 1". Urolithiasis 49, n.º 5 (15 de marzo de 2021): 425–31. http://dx.doi.org/10.1007/s00240-021-01249-3.

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AbstractA retrospective statistical analysis of primary hyperoxaluria type 1 (PH1) in children from June 2016 to May 2019 was carried out to discover its clinical and molecular biological characteristics. Patients were divided into two groups (infant and noninfant) according to clinic type. There were 13 pediatric patients (male:female = 6:7) with PH1 in the cohort from 11 families (four of which were biological siblings from two families), whose median age of symptom onset was 12 months and median confirmed diagnosis age was 14 months. Infant type (6 patients) was the most common type. The infant type mortality rate (100%) was higher than the noninfant (14.3%) (p = 0.029). The incidence of renal failure in infant patients was 67%, while the noninfant was 14.3%. 8 of 10 patients with nephrocalcinosis (NC) (76.92%, 10/13) were diagnosed by radiological imaging examinations, including X-ray (3 patients), CT (4 patients) and MRI (1 patient). NC was an independent risk factor for renal insufficiency [OR 3.33, 95% CI (0.7–1.2)], p < 0.05). Nine types of AGXT gene mutations were found; 1 type, c.190A > T, were first reported here. The most common AGXT gene mutation was c.679_680del, which occurred in exon 6 (5 patients). The infant type is the most common type of pediatric PH, with a relatively higher ratio of renal failure at symptom onset and poor prognosis. NC is an independent risk factor leading to renal failure, and radiological imaging examination is recommended for patients with abnormal ultrasound examination to identify NC. AGXT gene detection is important for the diagnosis and treatment of PH1 in children.

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Hasan, Asma, Sharon Maynard, Dominick Santoriello y Henry Schairer. "Primary Hyperoxaluria Type 1 with Thrombophilia in Pregnancy: A Case Report". Case Reports in Nephrology and Dialysis 8, n.º 3 (4 de octubre de 2018): 223–29. http://dx.doi.org/10.1159/000493091.

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Background: Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disease caused by a mutation in the AGXT gene, resulting in deficiency of the alanineglyoxylate:aminotransferase enzyme. It is characterized by accumulation of oxalate in the kidneys and other organs. Case Presentation: A Syrian woman with a history of nephrolithiasis and heterozygosity for factor V Leiden and prothrombin gene mutations presented with postpartum renal failure. She required initiation of renal replacement therapy at 14 weeks postpartum. Kidney biopsy showed severe acute and chronic crystalline deposition consistent with oxalate nephropathy. Genetic testing revealed a Gly170Arg mutation in the AGXT gene, confirming the diagnosis of PH1. Conclusions: The diagnosis of PH should be considered in patients with severe, recurrent calcium oxalate nephrolithiasis. Early treatment with pyridoxine reduces urinary oxalate excretion and can delay progression to end-stage renal disease (ESRD). After ESRD, intensive dialysis is needed to prevent systemic oxalate accumulation and deposition. Combined liver and kidney transplantation is curative. In our patient, we anticipate that liver transplantation will cure both the hyperoxaluria and the hypercoagulable state.

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Al Riyami, Mohamed S., Badria Al Ghaithi, Nadia Al Hashmi y Naifain Al Kalbani. "Primary Hyperoxaluria Type 1 in 18 Children: Genotyping and Outcome". International Journal of Nephrology 2015 (2015): 1–6. http://dx.doi.org/10.1155/2015/634175.

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Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of theAGXTgene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type ofAGXTmutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman.Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013.Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in theAGXTgene.Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening.

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Letko, Anna, Reinie Dijkman, Ben Strugnell, Irene M. Häfliger, Julia M. Paris, Katrina Henderson, Tim Geraghty, Hannah Orr, Sandra Scholes y Cord Drögemüller. "Deleterious AGXT Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep". Genes 11, n.º 10 (29 de septiembre de 2020): 1147. http://dx.doi.org/10.3390/genes11101147.

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Severe oxalate nephropathy has been previously reported in sheep and is mostly associated with excessive oxalate in the diet. However, a rare native Dutch breed (Zwartbles) seems to be predisposed to an inherited juvenile form of primary hyperoxaluria and no causative genetic variant has been described so far. This study aims to characterize the phenotype and genetic etiology of the inherited metabolic disease observed in several purebred Zwartbles sheep. Affected animals present with a wide range of clinical signs including condition loss, inappetence, malaise, and, occasionally, respiratory signs, as well as an apparent sudden unexpected death. Histopathology revealed widespread oxalate crystal deposition in kidneys of the cases. Whole-genome sequencing of two affected sheep identified a missense variant in the ovine AGXT gene (c.584G>A; p.Cys195Tyr). Variants in AGXT are known to cause type I primary hyperoxaluria in dogs and humans. Herein, we present evidence that the observed clinicopathological phenotype can be described as a form of ovine type I primary hyperoxaluria. This disorder is explained by a breed-specific recessively inherited pathogenic AGXT variant. Genetic testing enables selection against this fatal disorder in Zwartbles sheep as well as more precise diagnosis in animals with similar clinical phenotype. Our results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 001672-9940).

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Qingqi, Ren, Ju Weiqiang, Wang Dongping, Guo Zhiyong, Chen Maogen y He Xiaoshun. "Multidisciplinary Cooperation in a Simultaneous Combined Liver and Kidney Transplantation Patient of Primary Hyperoxaluria". Journal of Nepal Medical Association 56, n.º 205 (31 de marzo de 2017): 175–78. http://dx.doi.org/10.31729/jnma.2671.

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Primary hyperoxaluria type 1 is an autosomal recessive hereditary glyoxylate metabolism disorder characterized by excessive production of oxalate, caused by the deficiency of liver specific peroxisomal enzyme: alanineglyoxylate aminotransferase. For patients with end-stage renal disease, combined liver and kidney transplantation was needed. This report describes one patient, with a diagnosis of end-stage renal disease and primary hyperoxaluria 1 confirmed by PCR and direct sequencing with genomic DNA, received the simultaneous combined liver and kidney transplantation after seven months’ waiting. However, there were several complications observed post surgery, such as protracted bleeding, common bile duct anastomotic stenosis, biliary calculi and recurrence of urolithiasis. All these were well solved by relevant department, and finally a satisfactory outcome was achieved. Multidisciplinary cooperation plays an important role on the PH1 patient management, especially when multiple complications are encountered. Keywords: primary hyperoxaluria type 1; end-stage renal disease; liver transplantation; kidney transplantation.

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Morgan, S. H., C. J. Danpure, M. R. Bending y A. J. Eisinger. "Exclusion of Primary Hyperoxaluria Type I (PHI) in End-Stage Renal Failure by Enzymatic Analysis of a Percutaneous Hepatic Biopsy". Nephron 55, n.º 3 (1990): 336–37. http://dx.doi.org/10.1159/000185987.

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Hameed, Mohammed, Kashif Eqbal, Beena Nair, Alexander Woywodt y Aimun Ahmed. "Late Diagnosis of Primary Hyperoxaluria by Crystals in the Bone Marrow!" Nephrology @ Point of Care 1, n.º 1 (enero de 2015): napoc.2015.1467. http://dx.doi.org/10.5301/napoc.2015.14679.

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Primary hyperoxaluria type 1 (PH1) is a rare, inherited, autosomal recessive, metabolic disorder caused by a deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT). We describe here a case of a 57-year-old man with End Stage Renal Disease, where the late age of presentation of PH T1 due to marked heterogeneity of disease expression caused a delay in diagnosis, and we discuss the causes of the poor outcome typical of this condition

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AMOROSO, ANTONIO, DOROTI PIRULLI, FIORELLA FLORIAN, DANIELA PUZZER, MICHELE BONIOTTO, SERGIO CROVELLA, SILVIA ZEZLINA et al. "AGXTGene Mutations and Their Influence on Clinical Heterogeneity of Type 1 Primary Hyperoxaluria". Journal of the American Society of Nephrology 12, n.º 10 (octubre de 2001): 2072–79. http://dx.doi.org/10.1681/asn.v12102072.

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Abstract. Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder that is caused by a deficiency of alanine: glyoxylate aminotransferase (AGT), which is encoded by a single copy gene (AGXT). Molecular diagnosis was used in conjunction with clinical, biochemical, and enzymological data to evaluate genotype-phenotype correlation. Twenty-three unrelated, Italian PH1 patients were studied, 20 of which were grouped according to severe form of PH1 (group A), adult form (group B), and mild to moderate decrease in renal function (group C). All 23 patients were analyzed by using the single-strand conformation polymorphism technique followed by the sequencing of the 11AGXTexons. Relevant chemistries, including plasma, urine and dialyzate oxalate and glycolate assays, liver AGT activity, and pyridoxine responsiveness, were performed. Both mutant alleles were found in 21 out of 23 patients, and 13 different mutations were recognized in exons 1, 2, 4, and 10. Normalized AGT activity was lower in the severe form than in the adult form (P< 0.05). Double heterozygous patients presented a lower age at the onset of the disease (P= 0.025), and they were more frequent in group A (75%) than in the group B (14%;P= 0.0406). The T444C mutation was more frequent in the severe form (P< 0.05), and the opposite was observed for G630A (P< 0.05). G630A mutation homozygotes had a higher AGT residual activity (P= 0.00001). This study confirms the allelic heterogeneity of theAGXT, which could to some extent be responsible for the phenotypic heterogeneity in PH1.

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Wong, Ping-Nam, Eric L. K. Law, Gensy M. W. Tong, Siu-Ka Mak, Kin-Yee Lo y Andrew K. M. Wong. "Diagnosis of Primary Hyperoxaluria Type 1 by Determination of Peritoneal Dialysate Glycolic Acid Using Standard Organic-Acids Analysis Method". Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 23, n.º 2_suppl (diciembre de 2003): 210–13. http://dx.doi.org/10.1177/089686080302302s44.

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Objective Hyperglycolic hyperoxaluria is an important biochemical diagnostic hallmark for primary hyperoxaluria type 1 (PH1). Biochemical work-up on urinary specimens becomes impossible after the development end-stage renal failure and anuria. We studied the diagnostic value of determining glycolic acid content in peritoneal dialysate effluent in PH1. Patients and Methods We performed a comparative study on an anuric continuous ambulatory peritoneal dialysis (CAPD) patient whose PH1 was confirmed by genetic study and on 5 anuric CAPD controls. Specimens were taken from each bag of peritoneal dialysate effluent over a 24-hour period, and the corresponding drainage volume was noted. The specimens were then processed using standard procedures for organic-acid analysis. They underwent ethyl acetate extraction, followed by semiquantitative analysis of organic acids by gas chromatography mass spectrometry (GCMS). The daily output of glycolic acid in peritoneal dialysate for each individual was then estimated. Results All 6 patients were receiving four 2-L CAPD exchanges daily. The estimated daily glycolic acid output for the PH1 patient was 48.3 μmol daily. The mean glycolic acid output for the 5 controls was estimated to be much lower at 19.6 μmol daily (range: 15.1 – 27.5 μmol daily). Conclusion Standard organic-acid analysis for glycolic acid in peritoneal dialysate could be a useful initial screening tool before invasive or sophisticated testing is done in CAPD patients with suspected PH1.

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Vanmassenhove, Jill, Raymond Vanholder, Ramses Forsyth y Annemieke Dhondt. "Encapsulating Peritoneal Sclerosis in a Patient with Primary Hyperoxaluria Type 1: A Case Report". Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 30, n.º 1 (enero de 2010): 108–11. http://dx.doi.org/10.3747/pdi.2008.00269.

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Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder caused by a defect in glyoxylate metabolism attributable to low or absent activity of the liver-specific peroxisomal enzyme alanine/glyoxylate aminotransferase. This defect leads to enhanced conversion of glyoxylate to poorly soluble oxalate, which is then excreted into the urine. This process may lead to deposition of calcium oxalate crystals in many tissues as well as in the kidneys, resulting in nephrolithiasis, nephrocalcinosis, and/or renal failure.We present a 39-year-old patient with end-stage renal failure due to PH1, who was admitted with symptoms of feeling bloated, vomiting, diarrhea, and abdominal pain related to encapsulating peritoneal sclerosis (EPS). He had been treated with peritoneal dialysis for a total period of 5 years.EPS is a rare condition characterized by fibrosis and adhesions of the peritoneum to loops of the small intestine and has been described secondary to treatment with peritoneal dialysis. It also occurs in a variety of other clinical conditions such as autoimmune diseases and peritoneal and intra-abdominal malignancies.The calcium oxalate crystals found in the peritoneal fascia of this particular patient may suggest a causative relationship between crystal deposits and evolution to fibrosis and sclerosis of the peritoneum. The degree of impact of the peritoneal dialysis treatment itself on the development of EPS, however, is uncertain.

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Wang, Xinsheng, Xiangzhong Zhao, Xiaoling Wang, Jian Yao, Feifei Zhang, Yanhua Lang, Sylvie Tuffery-Giraud, Irene Bottillo y Leping Shao. "Two Novel HOGA1 Splicing Mutations Identified in a Chinese Patient with Primary Hyperoxaluria Type 3". American Journal of Nephrology 42, n.º 1 (2015): 78–84. http://dx.doi.org/10.1159/000439232.

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Background: Twenty-six HOGA1 mutations have been reported in primary hyperoxaluria (PH) type 3 (PH3) patients with c.700 + 5G>T accounting for about 50% of the total alleles. However, PH3 has never been described in Asians. Methods: A Chinese child with early-onset nephrolithiasis was suspected of having PH. We searched for AGXT, GRHPR and HOGA1 gene mutations in this patient and his parents. All coding regions, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. Results: Two heterozygous mutations not previously described in the literature about HOGA1 were identified (compound heterozygous). One mutation was a successive 2 bp substitution at the last nucleotide of exon 6 and at the first nucleotide of intron 6, respectively (c.834_834 + 1GG>TT), while the other one was a guanine to adenine substitution of the last nucleotide of exon 6 (c.834G>A). Direct sequencing analysis failed to find these mutations in 100 unrelated healthy subjects and the functional role on splicing of both variants found in this study was confirmed by a minigene assay based on the pSPL3 exon trapping vector. In addition, we found a SNP in this family (c.715G>A, p.V239I). There were no mutations detected in AGXT and GRHPR. Conclusion: Two novel HOGA1 mutations were identified in association with PH3. This is the first description and investigation on mutant gene analysis of PH3 in an Asian.

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Worcester, Elaine M., Andrew P. Evan, Fredric L. Coe, James E. Lingeman, Amy Krambeck, Andre Sommers, Carrie L. Phillips y Dawn Milliner. "A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I". American Journal of Physiology-Renal Physiology 305, n.º 11 (1 de diciembre de 2013): F1574—F1584. http://dx.doi.org/10.1152/ajprenal.00382.2013.

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The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term ( 2 ) or longer term ( 2 ) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.

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Cooper, P. J., C. J. Danpure, P. J. Wise y K. M. Guttridge. "Immunocytochemical localization of human hepatic alanine: glyoxylate aminotransferase in control subjects and patients with primary hyperoxaluria type 1." Journal of Histochemistry & Cytochemistry 36, n.º 10 (octubre de 1988): 1285–94. http://dx.doi.org/10.1177/36.10.3418107.

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Primary hyperoxaluria type 1 (PH1) is an inherited disorder of glyoxylate metabolism caused by a deficiency of the hepatic peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT; EC 2.6.1.44) [FEBS Lett (1986) 201:20]. The aim of the present study was to investigate the intracellular distribution of immunoreactive AGT protein, using protein A-gold immunocytochemistry, in normal human liver and in livers of PH1 patients with (CRM+) or without (CRM-) immunologically crossreacting enzyme protein. In all CRM+ individuals, which included three controls, a PH1 heterozygote and a PH1 homozygote immunoreactive AGT protein was confined to peroxisomes, where it was randomly dispersed throughout the peroxisomal matrix with no obvious association with the peroxisomal membrane. No AGT protein could be detected in the peroxisomes or other cytoplasmic compartments in the livers of CRM- PH1 patients (homozygotes). The peroxisomal labeling density in the CRM+ PH1 patient, who was completely deficient in AGT enzyme activity, was similar to that of the controls. In addition, in the PH1 heterozygote, who had one third normal AGT enzyme activity, peroxisomal labeling density was reduced to 50% of normal.

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Hou, Shurong, Franck Madoux, Louis Scampavia, Jo Ann Janovick, P. Michael Conn y Timothy P. Spicer. "Drug Library Screening for the Identification of Ionophores That Correct the Mistrafficking Disorder Associated with Oxalosis Kidney Disease". SLAS DISCOVERY: Advancing the Science of Drug Discovery 22, n.º 7 (31 de enero de 2017): 887–96. http://dx.doi.org/10.1177/2472555217689992.

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Primary hyperoxaluria is the underlying cause of oxalosis and is a life-threatening autosomal recessive disease, for which treatment may require dialysis or dual liver-kidney transplantation. The most common primary hyperoxaluria type 1 (PH1) is caused by genetic mutations of a liver-specific enzyme alanine:glyoxylate aminotransferase (AGT), which results in the misrouting of AGT from the peroxisomes to the mitochondria. Pharmacoperones are small molecules with the ability to modify misfolded proteins and route them correctly within the cells, which may present an effective strategy to treat AGT misrouting in PH1 disorders. We miniaturized a cell-based high-content assay into 1536-well plate format and screened ~4200 pharmacologically relevant compounds including Food and Drug Administration, European Union, and Japanese-approved drugs. This assay employs CHO cells stably expressing AGT-170, a mutant that predominantly resides in the mitochondria, where we monitor for its relocation to the peroxisomes through automated image acquisition and analysis. The miniaturized 1536-well assay yielded a Z′ averaging 0.70 ± 0.07. Three drugs were identified as potential pharmacoperones from this pilot screen, demonstrating the applicability of this assay for large-scale high-throughput screening.

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Dindo, Mirco, Silvia Grottelli, Giannamaria Annunziato, Giorgio Giardina, Marco Pieroni, Gioena Pampalone, Andrea Faccini et al. "Cycloserine enantiomers are reversible inhibitors of human alanine:glyoxylate aminotransferase: implications for Primary Hyperoxaluria type 1". Biochemical Journal 476, n.º 24 (20 de diciembre de 2019): 3751–68. http://dx.doi.org/10.1042/bcj20190507.

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Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5′-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate stones deposition in the urinary tract as a consequence of glyoxylate accumulation. Most missense mutations cause AGT misfolding, as in the case of the G41R, which induces aggregation and proteolytic degradation. We have investigated the interaction of wild-type AGT and the pathogenic G41R variant with d-cycloserine (DCS, commercialized as Seromycin), a natural product used as a second-line treatment of multidrug-resistant tuberculosis, and its synthetic enantiomer l-cycloserine (LCS). In contrast with evidences previously reported on other PLP-enzymes, both ligands are AGT reversible inhibitors showing inhibition constants in the micromolar range. While LCS undergoes half-transamination generating a ketimine intermediate and behaves as a classical competitive inhibitor, DCS displays a time-dependent binding mainly generating an oxime intermediate. Using a mammalian cellular model, we found that DCS, but not LCS, is able to promote the correct folding of the G41R variant, as revealed by its increased specific activity and expression as a soluble protein. This effect also translates into an increased glyoxylate detoxification ability of cells expressing the variant upon treatment with DCS. Overall, our findings establish that DCS could play a role as pharmacological chaperone, thus suggesting a new line of intervention against PH1 based on a drug repositioning approach. To a widest extent, this strategy could be applied to other disease-causing mutations leading to AGT misfolding.

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Poyah, Penelope, Joel Bergman, Laurette Geldenhuys, Glenda Wright, Noreen M. Walsh, Peter Hull, Kristina Roche y Michael L. West. "Primary Hyperoxaluria Type 1 (PH1) Presenting With End-Stage Kidney Disease and Cutaneous Manifestations in Adulthood: A Case Report". Canadian Journal of Kidney Health and Disease 8 (enero de 2021): 205435812110589. http://dx.doi.org/10.1177/20543581211058931.

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Rationale: Primary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation. Case Presentation: A 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis. Diagnosis: A diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis. Interventions: She was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities. Outcomes: After 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation. Teaching Points: This case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.

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Fargue, Sonia, Dawn S. Milliner, John Knight, Julie B. Olson, W. Todd Lowther y Ross P. Holmes. "Hydroxyproline Metabolism and Oxalate Synthesis in Primary Hyperoxaluria". Journal of the American Society of Nephrology 29, n.º 6 (27 de marzo de 2018): 1615–23. http://dx.doi.org/10.1681/asn.2017040390.

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Background Endogenous oxalate synthesis contributes to calcium oxalate stone disease and is markedly increased in the inherited primary hyperoxaluria (PH) disorders. The incomplete knowledge regarding oxalate synthesis complicates discovery of new treatments. Hydroxyproline (Hyp) metabolism results in the formation of oxalate and glycolate. However, the relative contribution of Hyp metabolism to endogenous oxalate and glycolate synthesis is not known.Methods To define this contribution, we performed primed, continuous, intravenous infusions of the stable isotope [15N,13C5]-Hyp in nine healthy subjects and 19 individuals with PH and quantified the levels of urinary 13C2-oxalate and 13C2-glycolate formed using ion chromatography coupled to mass detection.Results The total urinary oxalate-to-creatinine ratio during the infusion was 73.1, 70.8, 47.0, and 10.6 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3 and controls, respectively. Hyp metabolism accounted for 12.8, 32.9, and 14.8 mg oxalate/g creatinine in subjects with PH1, PH2, and PH3, respectively, compared with 1.6 mg oxalate/g creatinine in controls. The contribution of Hyp to urinary oxalate was 15% in controls and 18%, 47%, and 33% in subjects with PH1, PH2, and PH3, respectively. The contribution of Hyp to urinary glycolate was 57% in controls, 30% in subjects with PH1, and <13% in subjects with PH2 or PH3.Conclusions Hyp metabolism differs among PH types and is a major source of oxalate synthesis in individuals with PH2 and PH3. In patients with PH1, who have the highest urinary excretion of oxalate, the major sources of oxalate remain to be identified.

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Danpure, C. J., P. J. Cooper, P. J. Wise y P. R. Jennings. "An enzyme trafficking defect in two patients with primary hyperoxaluria type 1: peroxisomal alanine/glyoxylate aminotransferase rerouted to mitochondria." Journal of Cell Biology 108, n.º 4 (1 de abril de 1989): 1345–52. http://dx.doi.org/10.1083/jcb.108.4.1345.

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Most patients with the autosomal recessive disease primary hyperoxaluria type 1 (PH1) have a complete deficiency of alanine/glyoxylate aminotransferase (AGT) enzyme activity and immunoreactive protein. However a few possess significant residual activity and protein. In normal human liver, AGT is entirely peroxisomal, whereas it is entirely mitochondrial in carnivores, and both peroxisomal and mitochondrial in rodents. Using the techniques of isopycnic sucrose and Percoll density gradient centrifugation and quantitative protein A-gold immunoelectron microscopy, we have found that in two PH1 patients, possessing 9 and 27% residual AGT activity, both the enzyme activity and immunoreactive protein were largely mitochondrial and not peroxisomal. In addition, these individuals were more severely affected than expected from the levels of their residual AGT activity. In these patients, the PH1 appears to be due, at least in part, to a unique trafficking defect, in which peroxisomal AGT is diverted to the mitochondria. To our knowledge, this is the first example of a genetic disease caused by such interorganellar rerouting.

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Wang, Wenying, Yi Liu, Lulu Kang, Ruxuan He, Jinqing Song, Yanhan Li, Jun Li y Yanling Yang. "Mutation Hot Spot Region in the HOGA1 Gene Associated with Primary Hyperoxaluria Type 3 in the Chinese Population". Kidney and Blood Pressure Research 44, n.º 4 (2019): 743–53. http://dx.doi.org/10.1159/000501458.

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Background: Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder that affects glyoxylate metabolism. PH3 is caused by defects in 4-hydroxy-2-oxoglutarate aldolase, which is encoded by the HOGA1 gene. However, only 3 cases of PH3 have been described in Asians until today. This study aimed to determine the clinical and mutation spectra of patients from mainland China with PH3. Methods: We applied targeted next-generation sequencing to four non-consanguineous, unrelated Chinese families with PH3 to identify the genes hosting disease-causing mutations. This approach was confirmed by Sanger sequencing. Results: Five patients (2 boys and 3 girls) from four unrelated Chinese families were admitted because of kidney stones. Five HOGA1 gene sequence mutations were detected, including two novel mutations, c.811C>T (p.R271C) and c.812G>A (p.R271H). These compound heterozygous mutations were detected in a female PH3 patient (patient 4). Other patients included 2 boys who had heterozygous c.834_834+1GG>TT and c.834G>A (p.A278A) mutations (patients 1 and 2), a girl with homozygous c.834G>A (p.A278A) mutation (patient 3), and a girl with heterozygous c.834_834+1GG>TT and c.346C>T (p.Q116X) mutations (patient 5). The mutations in the c.834_834+1 region, including c.834G>A, c.834+1G>T, and c.834_834+1GG>TT, account for 5/8 of alleles in our study and 3/4 of alleles reported among Chinese patients. All patients in this study received hyperhydration and urine alkalinization treatment. Conclusion: Five PH3 cases were reported. Potential mutation hot spot region (c.834_834+1) in the Chinese population and two novel mutations were found.

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Purdue, P. E., Y. Takada y C. J. Danpure. "Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1." Journal of Cell Biology 111, n.º 6 (1 de diciembre de 1990): 2341–51. http://dx.doi.org/10.1083/jcb.111.6.2341.

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We have previously shown that in some patients with primary hyperoxaluria type 1 (PH1), disease is associated with mistargeting of the normally peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT) to mitochondria (Danpure, C.J., P.J. Cooper, P.J. Wise, and P.R. Jennings. J. Cell Biol. 108:1345-1352). We have synthesized, amplified, cloned, and sequenced AGT cDNA from a PH1 patient with mitochondrial AGT (mAGT). This identified three point mutations that cause amino acid substitutions in the predicted AGT protein sequence. Using PCR and allele-specific oligonucleotide hybridization, a range of PH1 patients and controls were screened for these mutations. This revealed that all eight PH1 patients with mAGT carried at least one allele with the same three mutations. Two were homozygous for this allele and six were heterozygous. In at least three of the heterozygotes, it appeared that only the mutant allele was expressed. All three mutations were absent from PH1 patients lacking mAGT. One mutation encoding a Gly----Arg substitution at residue 170 was not found in any of the control individuals. However, the other two mutations, encoding Pro----Leu and Ile----Met substitutions at residues 11 and 340, respectively, cosegregated in the normal population at an allelic frequency of 5-10%. In an individual homozygous for this allele (substitutions at residues 11 and 340) only a small proportion of AGT appeared to be rerouted to mitochondria. It is suggested that the substitution at residue 11 generates an amphiphilic alpha-helix with characteristics similar to recognized mitochondrial targeting sequences, the full functional expression of which is dependent upon coexpression of the substitution at residue 170, which may induce defective peroxisomal import.

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Huang, Amadeus, Julia Burke, Richard D. Bunker, Yee-Foong Mok, Michael D. Griffin, Edward N. Baker y Kerry M. Loomes. "Regulation of human 4-hydroxy-2-oxoglutarate aldolase by pyruvate and α-ketoglutarate: implications for primary hyperoxaluria type-3". Biochemical Journal 476, n.º 21 (15 de noviembre de 2019): 3369–83. http://dx.doi.org/10.1042/bcj20190548.

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4-hydroxy-2-oxoglutarate aldolase (HOGA1) is a mitochondrial enzyme that plays a gatekeeper role in hydroxyproline metabolism. Its loss of function in humans causes primary hyperoxaluria type 3 (PH3), a rare condition characterised by excessive production of oxalate. In this study, we investigated the significance of the associated oxaloacetate decarboxylase activity which is also catalysed by HOGA1. Kinetic studies using the recombinant human enzyme (hHOGA1) and active site mutants showed both these dual activities utilise the same catalytic machinery with micromolar substrate affinities suggesting that both are operative in vivo. Biophysical and structural studies showed that pyruvate was a competitive inhibitor with an inhibition constant in the micromolar range. By comparison α-ketoglutarate was a weak inhibitor with an inhibition constant in the millimolar range and could only be isolated as an adduct with the active site Lys196 in the presence of sodium borohydride. These studies suggest that pyruvate inhibits HOGA1 activity during gluconeogenesis. We also propose that loss of HOGA1 function could increase oxalate production in PH3 by decreasing pyruvate availability and metabolic flux through the Krebs cycle.

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Williams, Emma y Gill Rumsby. "Selected Exonic Sequencing of the AGXT Gene Provides a Genetic Diagnosis in 50% of Patients with Primary Hyperoxaluria Type 1". Clinical Chemistry 53, n.º 7 (1 de julio de 2007): 1216–21. http://dx.doi.org/10.1373/clinchem.2006.084434.

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Abstract Background: Definitive diagnosis of primary hyperoxaluria type 1 (PH1) requires analysis of alanine:glyoxylate aminotransferase (AGT) activity in the liver. We have previously shown that targeted screening for the 3 most common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) can provide a molecular diagnosis in 34.5% of PH1 patients, eliminating the need for a liver biopsy. Having reviewed the distribution of all AGXT mutations, we have evaluated a diagnostic strategy that uses selected exon sequencing for the molecular diagnosis of PH1. Methods: We sequenced exons 1, 4, and 7 for 300 biopsy-confirmed PH1 patients and expressed the identified missense mutations in vitro. Results: Our identification of at least 1 mutation in 224 patients (75%) and 2 mutations in 149 patients increased the diagnostic sensitivity to 50%. We detected 29 kinds of sequence changes, 15 of which were novel. Four of these mutations were in exon 1 (c.2_3delinsAT, c.30_32delCC, c.122G>A, c.126delG), 7 were in exon 4 (c.447_454delGCTGCTGT, c.449T>C, c.473C>T, c.481G>A, c.481G>T, c.497T>C, c.424-2A>G), and 4 were in exon 7 (c.725insT, c.737G>A, c.757T>C, c.776 + 1G>A). The missense changes were associated with severely decreased AGT catalytic activity and negative immunoreactivity when expressed in vitro. Missense mutation c.26C>A, previously described as a pathological mutation, had activity similar to that of the wild-type enzyme. Conclusions: Selective exon sequencing can allow a definitive diagnosis in 50% of PH1 patients. The test offers a rapid turnaround time (15 days) with minimal risk to the patient. Demonstration of the expression of missense changes is essential to demonstrate pathogenicity.

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Donini, Stefano, Manuela Ferrari, Chiara Fedeli, Marco Faini, Ilaria Lamberto, Ada Serena Marletta, Lara Mellini et al. "Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism". Biochemical Journal 422, n.º 2 (13 de agosto de 2009): 265–72. http://dx.doi.org/10.1042/bj20090748.

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PH1 (primary hyperoxaluria type 1) is a severe inborn disorder of glyoxylate metabolism caused by a functional deficiency of the peroxisomal enzyme AGXT (alanine-glyoxylate aminotransferase), which converts glyoxylate into glycine using L-alanine as the amino-group donor. Even though pre-genomic studies indicate that other human transaminases can convert glyoxylate into glycine, in PH1 patients these enzymes are apparently unable to compensate for the lack of AGXT, perhaps due to their limited levels of expression, their localization in an inappropriate cell compartment or the scarcity of the required amino-group donor. In the present paper, we describe the cloning of eight human cytosolic aminotransferases, their recombinant expression as His6-tagged proteins and a comparative study on their ability to transaminate glyoxylate, using any standard amino acid as an amino-group donor. To selectively quantify the glycine formed, we have developed and validated an assay based on bacterial GO (glycine oxidase); this assay allows the detection of enzymes that produce glycine by transamination in the presence of mixtures of potential amino-group donors and without separation of the product from the substrates. We show that among the eight enzymes tested, only GPT (alanine transaminase) and PSAT1 (phosphoserine aminotransferase 1) can transaminate glyoxylate with good efficiency, using L-glutamate (and, for GPT, also L-alanine) as the best amino-group donor. These findings confirm that glyoxylate transamination can occur in the cytosol, in direct competition with the conversion of glyoxylate into oxalate. The potential implications for the treatment of primary hyperoxaluria are discussed.

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Nishiyama, K., T. Funai, S. Yokota y A. Ichiyama. "ATP-dependent degradation of a mutant serine: pyruvate/alanine:glyoxylate aminotransferase in a primary hyperoxaluria type 1 case." Journal of Cell Biology 123, n.º 5 (1 de diciembre de 1993): 1237–48. http://dx.doi.org/10.1083/jcb.123.5.1237.

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Primary hyperoxaluria type 1 (PH 1), an inborn error of glyoxylate metabolism characterized by excessive synthesis of oxalate and glycolate, is caused by a defect in serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT). This enzyme is peroxisomal in human liver. Recently, we cloned SPT/AGT-cDNA from a PH 1 case, and demonstrated a point mutation of T to C in the coding region of the SPT/AGT gene encoding a Ser to Pro substitution at residue 205 (Nishiyama, K., T. Funai, R. Katafuchi, F. Hattori, K. Onoyama, and A. Ichiyama. 1991. Biochem. Biophys. Res. Commun. 176:1093-1099). In the liver of this patient, SPT/AGT was very low with respect to not only activity but also protein detectable on Western blot and immunoprecipitation analyses. Immunocytochemically detectable SPT/AGT labeling was also low, although it was detected predominantly in peroxisomes. On the other hand, the level of translatable SPT/AGT-mRNA was higher than normal, indicating that SPT/AGT had been synthesized in the patient's liver at least as effectively as in normal liver. Rapid degradation of the mutant SPT/AGT was then demonstrated in transfected COS cells and transformed Escherichia coli, accounting for the low level of immunodetectable mutant SPT/AGT in the patient's liver. The mutant SPT/AGT was also degraded much faster than normal in an in vitro system with a rabbit reticulocyte extract, and the degradation in vitro was ATP dependent. These results indicate that a single amino acid substitution in SPT/AGT found in the PH1 case leads to a reduced half-life of this protein. It appears that the mutant SPT/AGT is recognized in cells as an abnormal protein to be eliminated by degradation.

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Webster, Kylie E., Patrick M. Ferree, Ross P. Holmes y Scott D. Cramer. "Identification of missense, nonsense, and deletion mutations in the GRHPR gene in patients with primary hyperoxaluria type II (PH2)". Human Genetics 107, n.º 2 (agosto de 2000): 176–85. http://dx.doi.org/10.1007/s004390000351.

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Leiper, J. M., P. B. Oatey y C. J. Danpure. "Inhibition of alanine:glyoxylate aminotransferase 1 dimerization is a prerequisite for its peroxisome-to-mitochondrion mistargeting in primary hyperoxaluria type 1." Journal of Cell Biology 135, n.º 4 (15 de noviembre de 1996): 939–51. http://dx.doi.org/10.1083/jcb.135.4.939.

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Peroxisome-to-mitochondrion mistargeting of the homodimeric enzyme alanine:glyoxylate aminotransferase 1 (AGT) in the autosomal recessive disease primary hyperoxaluria type 1 (PH1) is associated with the combined presence of a normally occurring Pro(11)Leu polymorphism and a PH1-specific Gly170Arg mutation. The former leads to the formation of a novel NH2-terminal mitochondrial targeting sequence (MTS), which although sufficient to direct the import of in vitro-translated AGT into isolated mitochondria, requires the additional presence of the Gly170Arg mutation to function efficiently in whole cells. The role of this mutation in the mistargeting phenomenon has remained elusive. It does not interfere with the peroxisomal targeting or import of AGT. In the present study, we have investigated the role of the Gly170Arg mutation in AGT mistargeting. In addition, our studies have led us to examine the relationship between the oligomeric status of AGT and the peroxisomal and mitochondrial import processes. The results obtained show that in vitro-translated AGT rapidly forms dimers that do not readily exchange subunits. Although the presence of the Pro(11)Leu or Gly170Arg substitutions alone had no effect on dimerization, their combined presence abolished homodimerization in vitro. However, AGT containing both substitutions was still able to form heterodimers in vitro with either normal AGT or AGT containing either substitution alone. Expression of various combinations of normal and mutant, as well as epitope-tagged and untagged forms of AGT in whole cells showed that normal AGT rapidly dimerizes in the cytosol and is imported into peroxisomes as a dimer. This dimerization prevents mitochondrial import, even when the AGT possesses an MTS generated by the Pro(11)Leu substitution. The additional presence of the Gly170Arg substitution impairs dimerization sufficiently to allow mitochondrial import. Pharmacological inhibition of mitochondrial import allows AGT containing both substitutions to be imported into peroxisomes efficiently, showing that AGT dimerization is not a prerequisite for peroxisomal import.

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Giafi, C. F. y G. Rumsby. "Kinetic Analysis and Tissue Distribution of Human D-Glycerate Dehydrogenase/Glyoxylate Reductase and its Relevance to the Diagnosis of Primary Hyperoxaluria Type 2". Annals of Clinical Biochemistry: International Journal of Laboratory Medicine 35, n.º 1 (enero de 1998): 104–9. http://dx.doi.org/10.1177/000456329803500114.

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The enzyme D-glycerate dehydrogenase (D-GDH; EC 1.1.1.29), which is also believed to have glyoxylate reductase (GR; EC 1.1.1.26/79) activity, plays a role in serine catabolism and glyoxylate metabolism and deficiency of this enzyme is believed to be the cause of primary hyperoxaluria type 2 (PH2). The pH optima and kinetic parameters of D-GDH and GR in human liver have been determined and assays developed for their measurement. Maximal activities were observed at pH 6.0, 8.0 and 7.6 for the D-GDH forward, D-GDH reverse and GR reactions, respectively. The apparent Km values for the substrates in these reactions were as follows: D-GDH forward reaction, 0.5 mmol/L hydroxypyruvate and 0.08 mmol/L NADPH; D-GDH reverse reaction, 20 mmol/L D-glycerate and 0.03 mmol/L NADP and for the GR reaction 1.25 mmol/L glyoxylate and 0.33 mmol/L NADPH. The forward D-GDH and GR assays were adopted for routine use, the low activity of the reverse D-GDH reaction being of little use for routine analyses. D-GDH and GR activity in 13 normal livers ranged from 350–940 nmol per min per mg protein (median 547) and 129–209 nmol per min per mg protein (median 145), respectively. D-GDH activity in kidney, lymphocytes and fibroblasts fell within the range of values seen in the liver but GR activity was approximately 30% in the kidney and barely detectable in lymphocytes and fibroblasts. Analysis of liver and lymphocyte samples from patients with PH2 showed that GR activity was either very low or undetectable while D-GDH activity was reduced in liver but within the normal range in lymphocytes. These results suggest that there is more than one enzyme with D-GDH activity in human tissues but only one of these has significant GR activity. We conclude that a definitive diagnosis of PH2 requires measurement of GR and D-GDH in a liver biopsy.

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Danese, D., R. Murray, A. Monpara, R. Ben-David, T. Crockett, M. Holloway, K. Barr, S. Doyle y K. Howie. "The Importance of evaluating for potential underlying causes of kidney stones: A survey of physician experiences in diagnosing Primary Hyperoxaluria type 1 (PH1)". European Urology Supplements 18, n.º 7 (octubre de 2019): e2796. http://dx.doi.org/10.1016/s1569-9056(19)32989-6.

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Neira, Jose L., Athi N. Naganathan, Noel Mesa-Torres, Eduardo Salido y Angel L. Pey. "Phosphorylation of Thr9 Affects the Folding Landscape of the N-Terminal Segment of Human AGT Enhancing Protein Aggregation of Disease-Causing Mutants". Molecules 27, n.º 24 (10 de diciembre de 2022): 8762. http://dx.doi.org/10.3390/molecules27248762.

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The mutations G170R and I244T are the most common disease cause in primary hyperoxaluria type I (PH1). These mutations cause the misfolding of the AGT protein in the minor allele AGT-LM that contains the P11L polymorphism, which may affect the folding of the N-terminal segment (NTT-AGT). The NTT-AGT is phosphorylated at T9, although the role of this event in PH1 is unknown. In this work, phosphorylation of T9 was mimicked by introducing the T9E mutation in the NTT-AGT peptide and the full-length protein. The NTT-AGT conformational landscape was studied by circular dichroism, NMR, and statistical mechanical methods. Functional and stability effects on the full-length AGT protein were characterized by spectroscopic methods. The T9E and P11L mutations together reshaped the conformational landscape of the isolated NTT-AGT peptide by stabilizing ordered conformations. In the context of the full-length AGT protein, the T9E mutation had no effect on the overall AGT function or conformation, but enhanced aggregation of the minor allele (LM) protein and synergized with the mutations G170R and I244T. Our findings indicate that phosphorylation of T9 may affect the conformation of the NTT-AGT and synergize with PH1-causing mutations to promote aggregation in a genotype-specific manner. Phosphorylation should be considered a novel regulatory mechanism in PH1 pathogenesis.

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37

Dindo, Mirco, Giulia Ambrosini, Elisa Oppici, Angel L. Pey, Peter J. O’Toole, Joanne L. Marrison, Ian E. G. Morrison et al. "Dimerization Drives Proper Folding of Human Alanine:Glyoxylate Aminotransferase But Is Dispensable for Peroxisomal Targeting". Journal of Personalized Medicine 11, n.º 4 (6 de abril de 2021): 273. http://dx.doi.org/10.3390/jpm11040273.

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Peroxisomal matrix proteins are transported into peroxisomes in a fully-folded state, but whether multimeric proteins are imported as monomers or oligomers is still disputed. Here, we used alanine:glyoxylate aminotransferase (AGT), a homodimeric pyridoxal 5′-phosphate (PLP)-dependent enzyme, whose deficit causes primary hyperoxaluria type I (PH1), as a model protein and compared the intracellular behavior and peroxisomal import of native dimeric and artificial monomeric forms. Monomerization strongly reduces AGT intracellular stability and increases its aggregation/degradation propensity. In addition, monomers are partly retained in the cytosol. To assess possible differences in import kinetics, we engineered AGT to allow binding of a membrane-permeable dye and followed its intracellular trafficking without interfering with its biochemical properties. By fluorescence recovery after photobleaching, we measured the import rate in live cells. Dimeric and monomeric AGT displayed a similar import rate, suggesting that the oligomeric state per se does not influence import kinetics. However, when dimerization is compromised, monomers are prone to misfolding events that can prevent peroxisomal import, a finding crucial to predicting the consequences of PH1-causing mutations that destabilize the dimer. Treatment with pyridoxine of cells expressing monomeric AGT promotes dimerization and folding, thus, demonstrating the chaperone role of PLP. Our data support a model in which dimerization represents a potential key checkpoint in the cytosol at the crossroad between misfolding and correct targeting, a possible general mechanism for other oligomeric peroxisomal proteins.

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38

Motley, A., M. J. Lumb, P. B. Oatey, P. R. Jennings, P. A. De Zoysa, R. J. Wanders, H. F. Tabak y C. J. Danpure. "Mammalian alanine/glyoxylate aminotransferase 1 is imported into peroxisomes via the PTS1 translocation pathway. Increased degeneracy and context specificity of the mammalian PTS1 motif and implications for the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1." Journal of Cell Biology 131, n.º 1 (1 de octubre de 1995): 95–109. http://dx.doi.org/10.1083/jcb.131.1.95.

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Alanine/glyoxylate aminotransferase 1 (AGT) is peroxisomal in most normal humans, but in some patients with the hereditary disease primary hyperoxaluria type 1 (PH1), AGT is mislocalized to the mitochondria. In an attempt to identify the sequences in AGT that mediate its targeting to peroxisomes, and to determine the mechanism by which AGT is mistargeted in PH1, we have studied the intracellular compartmentalization of various normal and mutant AGT polypeptides in normal human fibroblasts and cell lines with selective deficiencies of peroxisomal protein import, using immunofluorescence microscopy after intranuclear microinjection of AGT expression plasmids. The results show that AGT is imported into peroxisomes via the peroxisomal targeting sequence type 1 (PTS1) translocation pathway. Although the COOH-terminal KKL of human AGT was shown to be necessary for its peroxisomal import, this tripeptide was unable to direct the peroxisomal import of the bona fide peroxisomal protein firefly luciferase or the reporter protein bacterial chloramphenicol acetyltransferase. An ill-defined region immediately upstream of the COOH-terminal KKL was also found to be necessary for the peroxisomal import of AGT, but again this region was found to be insufficient to direct the peroxisomal import of chloramphenicol acetyltransferase. Substitution of the COOH-terminal KKL of human AGT by the COOH-terminal tripeptides found in the AGTs of other mammalian species (SQL, NKL), the prototypical PTS1 (SKL), or the glycosomal PTS1 (SSL) also allowed peroxisomal targeting, showing that the allowable PTS1 motif in AGT is considerably more degenerate than, or at least very different from, that acceptable in luciferase. AGT possessing the two amino acid substitutions responsible for its mistargeting in PH1 (i.e., Pro11-->Leu and Gly170-->Arg) was targeted mainly to the mitochondria. However, AGTs possessing each amino acid substitution on its own were targeted normally to the peroxisomes. This suggests that Gly170-->Arg-mediated increased functional efficiency of the otherwise weak mitochondrial targeting sequence (generated by the Pro11-->Leu polymorphism) is not due to interference with the peroxisomal targeting or import of AGT.

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39

Martinez-Turrillas, Rebeca, Saray Rodriguez-Diaz, Paula Rodriguez-Marquez, Angel Martin-Mallo, Eduardo Salido, Bodo B. Beck, Felipe Prosper y Juan R. Rodriguez-Madoz. "Generation of an induced pluripotent stem cell line (CIMAi001-A) from a compound heterozygous Primary Hyperoxaluria Type I (PH1) patient carrying p.G170R and p.R122* mutations in the AGXT gene." Stem Cell Research 41 (diciembre de 2019): 101626. http://dx.doi.org/10.1016/j.scr.2019.101626.

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40

RINAT, CHONI, RONALD J. A. WANDERS, ALFRED DRUKKER, DAVID HALLE y YAACOV FRISHBERG. "Primary Hyperoxaluria Type I". Journal of the American Society of Nephrology 10, n.º 11 (noviembre de 1999): 2352–58. http://dx.doi.org/10.1681/asn.v10112352.

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Abstract. Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprissing at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.

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41

Quan, Kara J. y Lee A. Biblo. "Type I Primary Hyperoxaluria". Cardiology in Review 11, n.º 6 (noviembre de 2003): 318–19. http://dx.doi.org/10.1097/01.crd.0000065421.50549.21.

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42

Cochat, Pierre. "Primary hyperoxaluria type 1". Kidney International 55, n.º 6 (junio de 1999): 2533–47. http://dx.doi.org/10.1046/j.1523-1755.1999.00477.x.

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43

Bastani, Bahar y George Nahass. "Type I Primary Hyperoxaluria". New England Journal of Medicine 341, n.º 26 (23 de diciembre de 1999): 1979. http://dx.doi.org/10.1056/nejm199912233412605.

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44

Ajzensztejn, M. J., N. J. Sebire, R. S. Trompeter y S. D. Marks. "Primary hyperoxaluria type 1". Archives of Disease in Childhood 92, n.º 3 (1 de marzo de 2007): 197. http://dx.doi.org/10.1136/adc.2006.107334.

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45

Latta, K. y J. Brodehl. "Primary hyperoxaluria type I". European Journal of Pediatrics 149, n.º 8 (mayo de 1990): 518–22. http://dx.doi.org/10.1007/bf01957682.

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46

Mansell, M. A. "Primary hyperoxaluria type 2". Nephrology Dialysis Transplantation 10, supp8 (1 de enero de 1995): 58–60. http://dx.doi.org/10.1093/ndt/10.supp8.58.

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47

Abukhatwah, Mohamed W., Samia H. Almalki, Mohammed S. Althobaiti, Abdulla O. Alharbi, Najla K. Almalki y Naglaa M. Kamal. "Primary hyperoxaluria Type 1". Medicine 99, n.º 25 (19 de junio de 2020): e20371. http://dx.doi.org/10.1097/md.0000000000020371.

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48

Kemper, M. J., S. Conrad y D. E. Müller-Wiefel. "Primary hyperoxaluria type 2". European Journal of Pediatrics 156, n.º 7 (26 de junio de 1997): 509–12. http://dx.doi.org/10.1007/s004310050649.

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49

Harambat, Jérôme, Sonia Fargue, Justine Bacchetta, Cécile Acquaviva y Pierre Cochat. "Primary Hyperoxaluria". International Journal of Nephrology 2011 (2011): 1–11. http://dx.doi.org/10.4061/2011/864580.

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Primary hyperoxalurias (PH) are inborn errors in the metabolism of glyoxylate and oxalate. PH type 1, the most common form, is an autosomal recessive disorder caused by a deficiency of the liver-specific enzyme alanine, glyoxylate aminotransferase (AGT) resulting in overproduction and excessive urinary excretion of oxalate. Recurrent urolithiasis and nephrocalcinosis are the hallmarks of the disease. As glomerular filtration rate decreases due to progressive renal damage, oxalate accumulates leading to systemic oxalosis. Diagnosis is often delayed and is based on clinical and sonographic findings, urinary oxalate assessment, DNA analysis, and, if necessary, direct AGT activity measurement in liver biopsy tissue. Early initiation of conservative treatment, including high fluid intake, inhibitors of calcium oxalate crystallization, and pyridoxine in responsive cases, can help to maintain renal function in compliant subjects. In end-stage renal disease patients, the best outcomes have been achieved with combined liver-kidney transplantation which corrects the enzyme defect.

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50

Rao, Neal M., Anil Yallapragada, Kellen D. Winden, Jeffrey Saver y David S. Liebeskind. "Stroke in Primary Hyperoxaluria Type I". Journal of Neuroimaging 24, n.º 4 (2 de abril de 2013): 411–13. http://dx.doi.org/10.1111/jon.12020.

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