Potential mechanisms of marked hyperoxaluria not due to primary hyperoxaluria I or II

Background. Hyperoxaluria may be idiopathic, secondary, or due to primary hyperoxaluria (PH). Hepatic alanine:glyoxylate aminotransferase (AGT) or glyoxylate/hydroxypyruvate reductase (GR/HPR) deficiency causes PHI or PHII, respectively. Hepatic glycolate oxidase (GO) is a candidate enzyme for a third form of inherited hyperoxaluria. Methods. Six children were identified with marked hyperoxaluria, urolithiasis, and normal hepatic AGT (N = 5) and GR/HPR (N = 4). HPR was below normal and GR not measured in one. Of an affected sibling pair, only one underwent biopsy. GO mutation screening was performed, and dietary oxalate (Diet_ox), enteric oxalate absorption (EOA) measured using [¹³C₂] oxalate, renal clearance (GFR), fractional oxalate excretion (FE_ox) in the children, and urine oxalate in first- degree relatives (FDR) to understand the etiology of the hyperoxaluria. Results. Mean presenting age was 19.2 months and urine oxalate 1.3 ± 0.5 mmol/1.73 m²/24 h (mean ± SD). Two GO sequence changes (T754C, IVS3 - 49 C>G) were detected which were not linked to the hyperoxaluria. Diet_ox was 42 ± 31 mg/day. EOA was 9.4 ± 3.6%, compared with 7.6 > 1.2% in age-matched controls (P = 0.33). GFR was 90 ± 19 mL/min/1.73 m² and FE_ox 4.2 ± 1.4. Aside from the two brothers, hyperoxaluria was not found in FDR. Conclusions. These patients illustrate a novel form of hyperoxaluria and urolithiasis, without excess Diet_ox, enteric hyper-absorption, or hepatic AGT, GR/HPR deficiency. Alterations in pathways of oxalate synthesis, in liver or kidney, or in renal tubular oxalate handling are possible explanations. The affected sibling pair suggests an inherited basis.