Disorder of glyoxylate metabolism

Disorder of glyoxylate metabolism (Orphanet code 308998) is a grouping term that encompasses a set of rare inherited metabolic conditions in which the body's ability to properly handle glyoxylate is impaired. Glyoxylate is a small organic acid intermediate in several metabolic pathways, and when its metabolism is disrupted, it can be converted to oxalate in excessive amounts. The accumulation of oxalate leads to the formation of calcium oxalate crystals, which deposit primarily in the kidneys and urinary tract, causing recurrent kidney stones (nephrolithiasis) and progressive kidney damage (nephrocalcinosis). Over time, as kidney function declines, oxalate can accumulate systemically and deposit in bones, eyes, skin, heart, and other organs — a condition known as systemic oxalosis. The most well-characterized conditions within this group are the primary hyperoxalurias (types 1, 2, and 3), each caused by deficiency of a specific enzyme involved in glyoxylate metabolism. Primary hyperoxaluria type 1 (PH1), caused by mutations in the AGXT gene encoding alanine-glyoxylate aminotransferase, is the most common and severe form. Primary hyperoxaluria type 2 (PH2) results from deficiency of glyoxylate reductase/hydroxypyruvate reductase (GRHPR gene), and type 3 (PH3) is caused by mutations in the HOGA1 gene encoding 4-hydroxy-2-oxoglutarate aldolase. Key symptoms across these disorders include recurrent calcium oxalate kidney stones, nephrocalcinosis, progressive chronic kidney disease, and in advanced cases, systemic oxalosis with bone pain, fractures, anemia, and cardiac complications. Treatment depends on the specific subtype and severity. Conservative management includes high fluid intake, pyridoxine (vitamin B6) supplementation (effective in a subset of PH1 patients), and crystallization inhibitors such as citrate. For patients with end-stage kidney disease, combined liver-kidney transplantation has been the definitive treatment for PH1, as the liver is the site of the deficient enzyme. More recently, lumasiran (an RNA interference therapy targeting glycolate oxidase) has been approved for PH1, and nedosiran is under investigation for PH1 and PH2, representing a significant advance in the treatment landscape for these conditions.

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