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Human Mutation Jun 2009Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine:glyoxylate... (Review)
Review
Primary hyperoxaluria type 1 (PH1) is an autosomal recessive, inherited disorder of glyoxylate metabolism arising from a deficiency of the alanine:glyoxylate aminotransferase (AGT) enzyme, encoded by the AGXT gene. The disease is manifested by excessive endogenous oxalate production, which leads to impaired renal function and associated morbidity. At least 146 mutations have now been described, 50 of which are newly reported here. The mutations, which occur along the length of the AGXT gene, are predominantly single-nucleotide substitutions (75%), 73 are missense, 19 nonsense, and 18 splice mutations; but 36 major and minor deletions and insertions are also included. There is little association of mutation with ethnicity, the most obvious exception being the p.Ile244Thr mutation, which appears to have North African/Spanish origins. A common, polymorphic variant encoding leucine at codon 11, the so-called minor allele, has significantly lower catalytic activity in vitro, and has a higher frequency in PH1 compared to the rest of the population. This polymorphism influences enzyme targeting in the presence of the most common Gly170Arg mutation and potentiates the effect of several other pathological sequence variants. This review discusses the spectrum of AGXT mutations and polymorphisms, their clinical significance, and their diagnostic relevance.
Topics: Alleles; Animals; DNA Mutational Analysis; Humans; Hyperoxaluria, Primary; Polymorphism, Genetic; Transaminases; Uniparental Disomy
PubMed: 19479957
DOI: 10.1002/humu.21021 -
Current Opinion in Nephrology and... Jul 2024Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion... (Review)
Review
PURPOSE OF REVIEW
Primary hyperoxalurias (PHs) are rare disorders caused by the deficit of liver enzymes involved in glyoxylate metabolism. Their main hallmark is the increased excretion of oxalate leading to the deposition of calcium oxalate stones in the urinary tract. This review describes the molecular aspects of PHs and their relevance for the clinical management of patients.
RECENT FINDINGS
Recently, the study of PHs pathogenesis has received great attention. The development of novel in vitro and in vivo models has allowed to elucidate how inherited mutations lead to enzyme deficit, as well as to confirm the pathogenicity of newly-identified mutations. In addition, a better knowledge of the metabolic consequences in disorders of liver glyoxylate detoxification has been crucial to identify the key players in liver oxalate production, thus leading to the identification and validation of new drug targets.
SUMMARY
The research on PHs at basic, translational and clinical level has improved our knowledge on the critical factors that modulate disease severity and the response to the available treatments, leading to the development of new drugs, either in preclinical stage or, very recently, approved for patient treatment.
Topics: Humans; Hyperoxaluria, Primary; Animals; Mutation; Liver; Glyoxylates; Genetic Predisposition to Disease; Phenotype; Oxalates
PubMed: 38602143
DOI: 10.1097/MNH.0000000000000987 -
Revue Medicale de Liege Jul 2022Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate...
Primary hyperoxaluria type 1 is a rare autosomal recessive disorder leading to oxalate overproduction by deficiency in the liver-specific enzyme alanine-glyoxylate transaminase (AGT). Oxalate is a poorly soluble molecule that binds calcium and deposits in the entire organism leading to oxalosis. Its elimination is mainly carried out by kidneys. Hence the first manifestations are frequently of urinary concern and whitout any early care, progression of the disease to end-stage renal failure cannot be avoided. The only etiological treatment has long been combined liver-kidney transplantation because it restaures enzymatic function and replaces pathological kidneys. However, for a few years now, numerous studies are carried out on this subject and promising results have already been published with a new drug, lumasiran. From a clinical case, we describe the different options for the therapeutic management of primary hyperoxaluria type 1.
Topics: Humans; Hyperoxaluria, Primary; Nephrocalcinosis; Oxalates; RNA, Small Interfering
PubMed: 35924494
DOI: No ID Found -
The American Journal of Dermatopathology Dec 2022A 19-year-old girl presented to the emergency department with a progressively painful purpuric lesion on the left dorsal foot, which had initially appeared 2 days prior....
A 19-year-old girl presented to the emergency department with a progressively painful purpuric lesion on the left dorsal foot, which had initially appeared 2 days prior. Three months earlier, she had been diagnosed with end-stage renal disease. Her medical history also included recurrent urolithiasis for the past 5 years and liver failure. Biopsy revealed oxalate crystals occluding vessels with secondary epidermal and dermal ischemia. Oxalate crystals were also visualized in the vessel walls and free in the subcutis. Genetic testing confirmed the diagnosis of primary hyperoxaluria type 1. She was treated with sodium thiosulfate, apixaban, pentoxifylline, wound care, and palliative care. At 4-month follow-up, the cutaneous manifestations of oxalosis were confined to only her feet, and she was undergoing evaluation for combined liver and kidney transplant. Cutaneous oxalosis because of primary hyperoxaluria should be considered in young patients presenting with purpuric lesions, recurrent urolithiasis, and early-onset renal failure.
Topics: Humans; Female; Young Adult; Adult; Hyperoxaluria, Primary; Hyperoxaluria; Kidney Failure, Chronic; Urolithiasis; Oxalates
PubMed: 36395453
DOI: 10.1097/DAD.0000000000002307 -
Revue Medicale de Bruxelles Apr 1996Primary hyperoxaluria is a rare hereditary disease. Two types have been identified. Type 1 is due to the deficiency of the liver-specific peroxisomal enzyme... (Review)
Review
Primary hyperoxaluria is a rare hereditary disease. Two types have been identified. Type 1 is due to the deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase/serine: pyruvate amino-transferase whereas, in type 2, the deficiency concerns the glyoxylate reductase/D-glycerate dehydrogenase, a cytosolic enzyme present in the leucocytes and hepatocytes. In the elapsed decade, important progress in molecular biology led to the introduction of new strategies in the diagnosis and treatment of type 1 primary hyperoxaluria. However, the greater rarity of type 2 has so far prevented similar development. The present review recalls the normal metabolism of oxalic acid, details its deviations and their clinical consequences, and describes the methods of diagnosis and treatment to be presently recommended in primary hyperoxaluria.
Topics: Biopsy; Diet; Glycolates; Glyoxylates; Humans; Hyperoxaluria, Primary; Ilium; Metabolism, Inborn Errors; Oxalates; Oxalic Acid; Pyruvates
PubMed: 8685551
DOI: No ID Found -
Urolithiasis Aug 2022Autosomal recessive disorders are prevalent in Pakistan, a developing South Asian country where consanguineous marriages are common. This study seeks to determine the...
Autosomal recessive disorders are prevalent in Pakistan, a developing South Asian country where consanguineous marriages are common. This study seeks to determine the prevalence of monogenic causes in children presenting with nephrocalcinosis and nephrolithiasis at a dialysis and transplant center in Karachi, Pakistan. A retrospective analysis was conducted in children aged 1-18 years presenting with nephrocalcinosis, between 2010 and 2019. Demographic information, clinical profile, laboratory parameters and stone analysis were collected, on a pre-designed questionnaire. One hundred and twenty-six children were included, with 11 and 3 diagnosed with renal tubular acidosis and Bartter's syndrome respectively. Next-generation sequencing and Sanger sequencing was performed on 112 children. Eighty-seven patients were diagnosed with primary hyperoxaluria, with mutations in alanine-glyoxylate-aminotransferase gene found in 73, followed by glyoxylate reductase/hydroxy-pyruvate reductase in 13, and 4-hydroxy-2-oxaloglutarate aldolase in 1. Twenty-five patients reported negative for mutations. Sixty-four percent were males, with a statistically significant difference (p < 0.05). History of parental consanguineous marriage was found in 98% of the cohort. Fifty-four and 40 patients presented to the clinic with Chronic Kidney Disease Stage 1 and Stage 5, respectively, with a statistically significant difference p = 0.007. Mutations noted in our cohort are different and more severe than those reported in the developed world. The disease poses a major disease burden in developing world context with the only treatment option of combined liver-kidney transplantation not available in Pakistan.
Topics: Child; Cost of Illness; Female; Genetic Linkage; Humans; Hyperoxaluria; Hyperoxaluria, Primary; Kidney Calculi; Male; Nephrocalcinosis; Pakistan; Retrospective Studies
PubMed: 35678848
DOI: 10.1007/s00240-022-01338-x -
BioDrugs : Clinical Immunotherapeutics,... Jul 2022Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases...
Over the last few years, US Food and Drug Administration-approved drugs using RNA interference have come to the market. Many have treated liver-specific diseases utilizing N-acetyl galactosamine conjugation because of its effective delivery and limited off-target effects. The autosomal recessive disorder primary hyperoxaluria, specifically type 1, has benefited from these developments. Primary hyperoxaluria arises from mutations in the enzymes involved in endogenous oxalate synthesis. The severity of disease varies but can result in kidney failure and systemic oxalosis. Until recently, the treatment options were limited and focused primarily on supportive treatments, pyridoxine use in a subset of patients with primary hyperoxaluria type 1, and liver-kidney transplants in those who progressed to kidney failure. Two genes have been targeted with RNA interference; lumasiran targets glycolate oxidase and nedosiran targets lactate dehydrogenase A. Lumasiran was recently approved in the treatment of primary hyperoxaluria type 1 and nedosiran is in the approval process. Unfortunately, despite initial hopes that nedosiran may also be a treatment option for primary hyperoxaluria types 2 and 3, initial data suggest otherwise. The use of RNA interference liver-specific targeting for the treatment of primary hyperoxaluria type 1 will likely transform the natural history of the disease.
Topics: Humans; Hyperoxaluria, Primary; RNA Interference; RNA, Small Interfering; Renal Insufficiency; United States
PubMed: 35731461
DOI: 10.1007/s40259-022-00539-5 -
Kidney International Jun 1999
Review
Topics: Child; Female; Glycolates; Humans; Hyperoxaluria, Primary; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Oxalic Acid; Prognosis; Transaminases
PubMed: 10354306
DOI: 10.1046/j.1523-1755.1999.00477.x -
American Journal of Kidney Diseases :... Jan 2022Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified...
Primary hyperoxaluria (PH) is a group of genetic disorders that result in an increased hepatic production of oxalate. PH type 3 (PH3) is the most recently identified subtype and results from mutations in the mitochondrial 4-hydroxy-2-oxoglutarate aldolase gene (HOGA1). To date, there have been 2 cases of kidney failure reported in PH3 patients. We present a case of a young man with a history of recurrent urinary tract infections and voiding dysfunction who developed kidney failure at 33 years of age. He developed a bladder stone and bilateral staghorn calculi at 12 years of age. Initial metabolic evaluation revealed hyperoxaluria with very low urinary citrate excretion on multiple measurements for which he was placed on oral citrate supplements. Further investigation of the hyperoxaluria was not completed as the patient was lost to follow-up observation until he presented at 29 years of age with chronic kidney disease stage 4 (estimated glomerular filtration rate 24mL/min/1.73m). Hemodialysis 3 times a week was started at 33 years of age, and subsequent genetic testing revealed a homozygous HOGA1 mutation (C.973G>A p.Gly325Ser) diagnostic of PH3. The patient is currently being evaluated for all treatment options including possible liver/kidney transplantation. All cases of a childhood history of recurrent urinary stone disease with marked hyperoxaluria should prompt genetic testing for the 3 known PH types. Hyperhydration and crystallization inhibitors (citrate) are standard of care, but the role of RNA interference agents for all 3 forms of PH is also under active study.
Topics: Humans; Hyperoxaluria; Hyperoxaluria, Primary; Male; Oxalates; Oxo-Acid-Lyases; Renal Insufficiency
PubMed: 34245816
DOI: 10.1053/j.ajkd.2021.05.016 -
Journal of Feline Medicine and Surgery Aug 2006
Topics: Acute Kidney Injury; Animals; Cat Diseases; Cats; Diagnosis, Differential; Female; Hyperoxaluria, Primary; Oxalates
PubMed: 16603399
DOI: 10.1016/j.jfms.2006.02.001