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Drugs Mar 2024
PubMed: 38489088
DOI: 10.1007/s40265-024-02014-7 -
Pediatric Nephrology (Berlin, Germany) Jul 2024Lumasiran is the first RNA interference (RNAi) therapy of primary hyperoxaluria type 1 (PH1). Here, we report on the rapid improvement and even disappearance of...
BACKGROUND
Lumasiran is the first RNA interference (RNAi) therapy of primary hyperoxaluria type 1 (PH1). Here, we report on the rapid improvement and even disappearance of nephrocalcinosis after early lumasiran therapy.
CASE-DIAGNOSIS/TREATMENT
In patient 1, PH1 was suspected due to incidental discovery of nephrocalcinosis stage 3 in a 4-month-old boy. Bilateral nephrocalcinosis stage 3 was diagnosed in patient 2 at 22 months concomitantly to acute pyelonephritis. Urinary oxalate (UOx) and glycolate (UGly) were increased in both patients allowing to start lumasiran therapy before genetic confirmation. Nephrocalcinosis started to improve and disappeared after 27 months and 1 year of treatment in patients 1 and 2, respectively.
CONCLUSION
These cases illustrate the efficacy of early lumasiran therapy in infants to improve and even normalize nephrocalcinosis. As proposed in the 2023 European guidelines, the interest of starting treatment quickly without waiting for genetic confirmation may have an impact on long-term outcomes.
Topics: Humans; Nephrocalcinosis; Male; Infant; Hyperoxaluria, Primary; RNAi Therapeutics; Treatment Outcome; Glycolates
PubMed: 38261066
DOI: 10.1007/s00467-023-06268-3 -
FEBS Letters Feb 2024Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1-causing mutations in AGT lead to protein mistargeting...
Primary hyperoxaluria type I (PH1) is caused by deficient alanine:glyoxylate aminotransferase (AGT) activity. PH1-causing mutations in AGT lead to protein mistargeting and aggregation. Here, we use hydrogen-deuterium exchange (HDX) to characterize the wild-type (WT), the LM (a polymorphism frequent in PH1 patients) and the LM G170R (the most common mutation in PH1) variants of AGT. We provide the first experimental analysis of AGT structural dynamics, showing that stability is heterogeneous in the native state and providing a blueprint for frustrated regions with potentially functional relevance. The LM and LM G170R variants only show local destabilization. Enzymatic transamination of the pyridoxal 5-phosphate cofactor bound to AGT hardly affects stability. Our study, thus, supports that AGT misfolding is not caused by dramatic effects on structural dynamics.
Topics: Humans; Hyperoxaluria, Primary; Mutation; Polymorphism, Genetic; Transaminases
PubMed: 38243391
DOI: 10.1002/1873-3468.14800 -
Genetic Testing and Molecular Biomarkers Apr 2024Approximately 80% of primary hyperoxaluria cases are caused by primary hyperoxaluria type 1 (PH1, OMIM# 259900), which is characterized by pathogenic variants in the...
Approximately 80% of primary hyperoxaluria cases are caused by primary hyperoxaluria type 1 (PH1, OMIM# 259900), which is characterized by pathogenic variants in the gene, resulting in deficiency of the liver-specific enzyme alanine-glyoxylate aminotransferase (AGT). This leads to increased production of oxalate, which cannot be effectively eliminated from the body, resulting in its accumulation primarily in the kidneys and other organs. This study included 17 PH1 Egyptian patients from 12 unrelated families, recruited from the Inherited Kidney Disease Outpatient Clinic and the Dialysis Units, Cairo University Hospitals, during the period from January 2018 to December 2019, aiming to identify the pathogenic variants in the gene. Six different variants were detected. These included three frameshift and three missense variants, all found in homozygosity within the respective families. The most common variant was c.121G>A;p.(Gly41Arg) detected in four families, followed by c.725dup;p.(Asp243GlyfsTer12) in three families, c.33dup;p.(Lys12Glnfs156) in two families, and c.731T >C;p.(Ile244Thr), c.33delC;p.(Lys12Argfs34), and c.568G>A;p.(Gly190Arg) detected in one family each. Consanguineous Egyptian families with history of renal stones or renal disease suspicious of primary hyperoxaluria should undergo genetic sequencing, specifically targeting exons 1 and 7, as variants in these two exons account for >75% of disease-causing variants in Egyptian patients with confirmed PH1.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Male; Middle Aged; Young Adult; Egypt; Frameshift Mutation; Homozygote; Hyperoxaluria, Primary; Mutation; Mutation, Missense; Transaminases
PubMed: 38657121
DOI: 10.1089/gtmb.2023.0525 -
Journal of Inherited Metabolic Disease Mar 2024Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol....
Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.
Topics: Humans; Mitochondria, Liver; HEK293 Cells; Transaminases; Oxalates; Liver; Glyoxylates; Alcohol Oxidoreductases
PubMed: 38200664
DOI: 10.1002/jimd.12711 -
Biochimica Et Biophysica Acta.... Jan 2024N-propargylglycine prevents 4-hydroxyproline catabolism in mouse liver and kidney. N-propargylglycine is a novel suicide inhibitor of PRODH2 and induces mitochondrial...
N-propargylglycine prevents 4-hydroxyproline catabolism in mouse liver and kidney. N-propargylglycine is a novel suicide inhibitor of PRODH2 and induces mitochondrial degradation of PRODH2. PRODH2 is selectively expressed in liver and kidney and contributes to primary hyperoxaluria (PH). Preclinical evaluation of N-propargylglycine efficacy as a new PH therapeutic is warranted.
Topics: Animals; Mice; Alkynes; Glycine; Hyperoxaluria; Kidney
PubMed: 37586438
DOI: 10.1016/j.bbadis.2023.166848 -
Journal of Clinical and Experimental... 2024Primary type 2 hyperoxaluria is a very rare genetic disorder, where in the progression to renal failure was assumed to be insidious and not very common. PH2 is due to...
BACKGROUND
Primary type 2 hyperoxaluria is a very rare genetic disorder, where in the progression to renal failure was assumed to be insidious and not very common. PH2 is due to deficient glyoxylate reductase/hydroxypyruvate reductase (GRHPR), which was thought to have extra-hepatic production also. The progression to renal failure in these patient subgroups is well documented in the Literature and the role of SLK (simultaneous liver and kidney transplantation) has not been clearly established..
METHOD
We present a case report of a young girl with PH2, who successfully underwent SLK, with evidence of reduction in the urine oxalate levels post SLK.
RESULTS
PH2, though a rare genetic disease, has a proven potential to progress to chronic renal failure requiring transplantation, renal transplantation alone has not shown any benefit, these patients can be offered SLK as a primary treatment option, to improve the outcomes, this needs further validation with consensus and studies.
PubMed: 38721383
DOI: 10.1016/j.jceh.2024.101425 -
Kidney International Mar 2024The study by Chen et al. is the first to apply the revolutionary genetic engineering tool, base editing, in a rat model for the treatment of primary hyperoxaluria type...
The study by Chen et al. is the first to apply the revolutionary genetic engineering tool, base editing, in a rat model for the treatment of primary hyperoxaluria type 1, a disease that originates in the liver but in which the kidney is the main organ affected. This commentary contextualizes and describes the gene-editing technology applied by the authors, provides an interpretation and opinion of their results, and indicates possible future applications.
Topics: Rats; Animals; Gene Editing; CRISPR-Cas Systems; Genetic Engineering; Kidney Diseases; Kidney
PubMed: 38388140
DOI: 10.1016/j.kint.2024.01.004 -
Cureus Jul 2023Oxalate nephropathy represents a frequently overlooked etiology of renal failure, characterized by the deposition of calcium oxalate crystals within the renal...
Oxalate nephropathy represents a frequently overlooked etiology of renal failure, characterized by the deposition of calcium oxalate crystals within the renal parenchyma. This progressive form of kidney disease is marked by a significant increase in serum creatinine (Cr) level accompanied by evidence of oxalate crystal deposition on renal biopsy causing tubular obstruction and tubular injury leading to fibrosis. In all instances of oxalate nephropathy, examination of stones consistently exhibits multiple birefringent calcium oxalate crystals under polarized light. This case report details the clinical course of a patient who initially presented with progressively worsening renal function and ultimately developed end-stage kidney disease (ESKD) as a consequence of idiopathic hyperoxaluria.
PubMed: 37621792
DOI: 10.7759/cureus.42402 -
Cureus Oct 2023Primary hyperoxaluria type 2 (PH2) is a rare genetic disorder characterized by excessive oxalate production due to glyoxylate metabolism alterations. This case report...
Primary hyperoxaluria type 2 (PH2) is a rare genetic disorder characterized by excessive oxalate production due to glyoxylate metabolism alterations. This case report presents a 26-year-old male with PH2 who experienced recurrent nephrolithiasis since childhood, leading to end-stage renal disease (ESRD). The patient's history prompted genetic testing, which revealed a heterozygous missense variant in the gene, confirming PH2. Early genetic diagnosis is crucial for preventing ESRD and planning effective treatments. Patients with PH2 require intensive hemodialysis and may benefit from kidney transplantation. However, even after transplantation, ongoing preventive measures are essential due to the risk of hyperoxaluria-related graft damage. This case highlights the importance of early detection and genetic testing in managing PH2 to delay ESRD and improve patient outcomes.
PubMed: 37933374
DOI: 10.7759/cureus.46555