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Prenatal Diagnosis Jul 1996Primary hyperoxaluria type 1 (PH1) is a potentially lethal autosomal recessive disorder of glyoxylate metabolism caused by a deficiency of the liver-specific peroxisomal... (Comparative Study)
Comparative Study Review
Primary hyperoxaluria type 1 (PH1) is a potentially lethal autosomal recessive disorder of glyoxylate metabolism caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). Over the past 13 years, various strategies have been adopted for its prenatal diagnosis, including (1) glyoxylate metabolite analysis of amniotic fluid in the second trimester; (2) AGT enzyme assay, immunoassay, and immuno-electron microscopy of fetal liver biopsies also in the second trimester; and (3) linkage and mutation analysis of DNA isolated from chorionic villus samples in the first trimester. These methods have evolved in parallel with our increased understanding of the molecular aetiology and pathogenesis of the disease. Although the usefulness of metabolite analysis remains unproven, all the other methods have been successfully applied to the prenatal diagnosis of PH1. In this review, examples of the use of the available methodologies are provided, and their pros and cons are discussed with reference to specific cases.
Topics: Alleles; Female; Fetal Diseases; Genetic Linkage; Humans; Hyperoxaluria, Primary; Liver; Male; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Pregnancy; Prenatal Diagnosis; Transaminases
PubMed: 8843467
DOI: 10.1002/(SICI)1097-0223(199607)16:7<587::AID-PD925>3.0.CO;2-9 -
Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.Kidney International Dec 2019Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure....
Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.
Topics: Adolescent; Adult; Age of Onset; Child; Child, Preschool; Europe; Female; Humans; Hyperoxaluria, Primary; Infant; Kidney Failure, Chronic; Kidney Transplantation; Male; Registries; Retrospective Studies; Young Adult
PubMed: 31685312
DOI: 10.1016/j.kint.2019.08.018 -
Nephrologie 1995Primary hyperoxalurias are inborn errors of metabolism with recessive autosomal transmission. Type 1 is due to the deficiency of the hepatic-specific peroxisomal enzyme... (Review)
Review
Primary hyperoxalurias are inborn errors of metabolism with recessive autosomal transmission. Type 1 is due to the deficiency of the hepatic-specific peroxisomal enzyme alanine: glyoxylate aminotransferase, and type 2 to that of the glyoxylate reductase/D-glycerate dehydrogenase, present in the cytosol of hepatocytes and leucocytes. Type 3 is due to increased intestinal absorption of oxalate of unknown pathophysiology. In the 3 types, increased oxalate load may lead to systemic oxalosis when glomerular filtration rate decreases below 30 ml/min/1.73 m2, calcium oxalate saturation occurring in plasma when oxalate level approximates 50 mumol/l. High fluid intake and long-term co-administration of pyridoxine and orthophosphate could perhaps efficiently prevent renal failure in a majority of patients. However, combined liver-kidney transplantation presently constitutes the most adequate therapy of end-stage renal failure in type 1 and perhaps in type 2 hyperoxaluria.
Topics: Child; Child, Preschool; Humans; Hyperoxaluria, Primary; Infant; Kidney Transplantation; Liver Transplantation; Prenatal Diagnosis; Renal Dialysis
PubMed: 8524446
DOI: No ID Found -
Pediatric Nephrology (Berlin, Germany) Sep 2021Loss-of-function mutations in three genes, involved in the metabolic pathway of glyoxylate, result in increased oxalate production and its crystallization in the form of... (Review)
Review
Loss-of-function mutations in three genes, involved in the metabolic pathway of glyoxylate, result in increased oxalate production and its crystallization in the form of calcium oxalate. This leads to three forms of primary hyperoxaluria-an early-onset inherited kidney disease with wide phenotypic variability ranging from isolated kidney stone events to stage 5 chronic kidney disease in infancy. This review provides a description of metabolic processes resulting in oxalate overproduction and summarizes basic therapeutic approaches. Unfortunately, current treatment of primary hyperoxaluria does not allow the prevention of loss of kidney function or to substantially diminish other symptoms in most patients. However, latest breakthroughs in biotechnology provide new promising directions for drug development. Some of them have already progressed to the level of clinical trials; others are just at the stage of proof of concept. Here we review the most advanced technologies including those that have been harnessed as possible therapeutic modalities.
Topics: Humans; Hyperoxaluria, Primary
PubMed: 33156410
DOI: 10.1007/s00467-020-04817-8 -
European Journal of Pediatrics Dec 1999Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterised by an increased urinary excretion of calcium oxalate, leading to recurrent... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterised by an increased urinary excretion of calcium oxalate, leading to recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble oxalate throughout the body (oxalosis) when the glomerular filtration rate falls to below 40-20 mL/min per 1.73 m(2). The disease is due to a functional defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), the gene of which is located on chromosome 2q37.3. The diagnosis is based on increased urinary oxalate and glycollate, increased plasma oxalate and AGT measurement in a liver biopsy. AGT mistargeting may be investigated by immuno-electron microscopy and DNA analysis. End-stage renal failure is reached by the age of 15 years in 50% of PH1 patients and the overall death rate approximates 30%. The conservative treatment includes high fluid intake, pyridoxine and crystallisation inhibitors. Since the kidney is the main target of the disease, isolated kidney transplantation (Tx) has been proposed in association with vigorous peri-operative haemodialysis in an attempt to clear plasma oxalate at the time of Tx. However, because of a 100% recurrence rate, the average 3-year graft survival is 15%-25% in Europe, with a 5-10-year patient survival rate ranging from 10% to 50%. Since the liver is the only organ responsible for the detoxification of glyoxylate by AGT, deficient host liver removal is the first rationale for enzyme replacement therapy. Subsequent orthotopic liver Tx aims to supply the missing enzyme in its normal cellular and subcellular location and thus can be regarded as a form of gene therapy. Because of the usual spectrum of the disease, isolated liver Tx is limited to selected patients prior to having reached an advanced stage of chronic renal failure. Combined liver-kidney Tx has therefore become a conventional treatment for most PH1 patients: according to the European experience, patient survival approximates 80% at 5 years and 70% at 10 years. In addition, the renal function of survivors remains stable over time, between 40 and 60 mL/min per 1.73 m(2) after 5 to 10 years. In addition, liver Tx may allow the reversal of systemic storage disease (i.e. bone, heart, vessels, nerves) and provide valuable quality of life. Whatever the transplant strategy, the outcome is improved when patients are transplanted early in order to limit systemic oxalosis. According to the European experience, it appears that combined liver-kidney Tx is performed in PH1 patients with encouraging results, renal Tx alone has little role in the treatment of this disease, and liver Tx reverses the underlying metabolic defect and its clinical consequences.
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Hyperoxaluria, Primary; Infant; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Male; Quality of Life; Survival Analysis
PubMed: 10603104
DOI: 10.1007/pl00014327 -
Molecular Genetics and Metabolism 2004Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease characterized by progressive kidney failure due to renal deposition of calcium oxalate. The disease... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease characterized by progressive kidney failure due to renal deposition of calcium oxalate. The disease is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT) which catalyzes the conversion of glyoxylate to glycine. When AGT is absent, glyoxylate is converted to oxalate which forms insoluble calcium salts that accumulate in the kidney and other organs. In the most common phenotype there is a unique phenomenon wherein AGT is mis-targeted to the mitochondria instead of the peroxisomes. The diagnosis of PH1 is complicated by heterogeneity of clinical presentation, course of the disease, biochemical markers, AGT enzymatic activity and genotype. More than 50 mutations and polymorphisms have been reported in the AGT gene; three common mutations accounting for almost 50% of PH1 alleles. The mutations are of all types, with missense making up the largest fraction. There are some mutations with apparent ethnic associations and at least one that appears to be pan-ethnic. Although correlations can in some cases be made between biochemical phenotype and genotype, correlation with clinical phenotype is complicated by the involvement of other genetic and non-genetic factors that affect disease severity. A number of polymorphisms have been described in the AGT gene some of which cause missense changes and, in some cases, alter enzyme activity. As DNA testing becomes more commonly used for diagnosis it is important to correlate observed sequence changes with previously documented changes as an aid to assessing their potential significance.
Topics: Genetic Heterogeneity; Genetic Variation; Genetics, Population; Humans; Hyperoxaluria, Primary; Mutation; Phenotype; Transaminases
PubMed: 15464418
DOI: 10.1016/j.ymgme.2004.08.009 -
American Journal of Nephrology 2005Primary hyperoxaluria type 1 (PH1) is a rare autosomal-recessive disorder caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT).... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is a rare autosomal-recessive disorder caused by a deficiency of the liver-specific enzyme alanine:glyoxylate aminotransferase (AGT). AGT deficiency results in increased synthesis and excretion of the metabolic end-product oxalate and deposition of insoluble calcium oxalate in the kidney and urinary tract. Classic treatments for PH1 have tended to address the more distal aspects of the disease process (i.e. the symptoms rather than the causes). However, advances in the understanding of the molecular etiology of PH1 over the past decade have shifted attention towards the more proximal aspects of the disease process (i.e. the causes rather than the symptoms). The determination of the crystal structure of AGT has enabled the effects of some of the most important missense mutations in the AGXT gene to be rationalised in terms of AGT folding, dimerization and stability. This has opened up new possibilities for the design pharmacological agents that might counteract the destabilizing effects of these mutations and which might be of use for the treatment of a potentially life-threatening and difficult-to-treat disease.
Topics: Humans; Hyperoxaluria, Primary; Metabolism, Inborn Errors; Mutation; Nephrology; Polymorphism, Genetic; Transaminases
PubMed: 15961951
DOI: 10.1159/000086362 -
Nephrologie & Therapeutique Apr 2021Primary hyperoxalurias are rare disease with autosomal recessive inheritance; they often lead to kidney failure and can lead to life-threatening conditions, especially...
Primary hyperoxalurias are rare disease with autosomal recessive inheritance; they often lead to kidney failure and can lead to life-threatening conditions, especially in early onset forms. There are three types, responding to distinct enzyme deficits. Type 1 represents 85% of cases and results from an enzyme deficiency (alanine-glyoxylate aminotransferase) in the peroxisomes of the liver, causing hyperoxaluria leading to urolithiasis with or without nephrocalcinosis. As glomerular filtration decreases, a systemic overload appears and spares no organ. Treatment has hitherto been based on combined liver and kidney transplantation, with significant mortality and morbidity. The recent introduction of interfering RNA treatments opens up new perspectives. By blocking an enzymatic synthesis (glycolate oxidase or lacticodehydrogenase a) upstream of the deficit that causes the disease, oxaluria normalizes and the tolerance of the drug (administered by injection every 1 to 3 months) is good. This strategy will help prevent kidney failure in patients treated early and avoid liver transplantation in those who are diagnosed at an advanced stage of kidney failure.
Topics: Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Transplantation; Liver Transplantation; RNA
PubMed: 33910694
DOI: 10.1016/j.nephro.2020.02.002 -
BioMed Research International 2013Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5'-phosphate (PLP) as... (Review)
Review
Alanine-glyoxylate aminotransferase catalyzes the transamination between L-alanine and glyoxylate to produce pyruvate and glycine using pyridoxal 5'-phosphate (PLP) as cofactor. Human alanine-glyoxylate aminotransferase is a peroxisomal enzyme expressed in the hepatocytes, the main site of glyoxylate detoxification. Its deficit causes primary hyperoxaluria type I, a rare but severe inborn error of metabolism. Single amino acid changes are the main type of mutation causing this disease, and considerable effort has been dedicated to the understanding of the molecular consequences of such missense mutations. In this review, we summarize the role of protein homeostasis in the basic mechanisms of primary hyperoxaluria. Intrinsic physicochemical properties of polypeptide chains such as thermodynamic stability, folding, unfolding, and misfolding rates as well as the interaction of different folding states with protein homeostasis networks are essential to understand this disease. The view presented has important implications for the development of new therapeutic strategies based on targeting specific elements of alanine-glyoxylate aminotransferase homeostasis.
Topics: Glycine; Hepatocytes; Homeostasis; Humans; Hyperoxaluria, Primary; Mutation; Protein Folding; Protein Unfolding; Transaminases
PubMed: 23956997
DOI: 10.1155/2013/687658 -
Nefrologia : Publicacion Oficial de La... 2003
Review
Topics: Animals; DNA Mutational Analysis; Humans; Hyperoxaluria, Primary; Liver; Mice; Molecular Biology; Transaminases
PubMed: 12708368
DOI: No ID Found