As a rare autosomal recessive disorder, primary hyperoxaluria type 3 (PH3) presents diagnostic challenges. Our comparative analysis of clinical characteristics between patients with PH3 and non-PH patients revealed distinct characteristics that may facilitate the diagnosis of PH3. Clinical data from pediatric patients with urolithiasis who had undergone whole-exome sequencing from 2016-2024 were analyzed. Patients were divided into PH3 group and non-PH group on the basis of genetic testing. Compared with non-PH patients, PH3 patients presented earlier onset (0.9 vs. 2.0 years, P = 0.021), higher incidence of nephrocalcinosis (22.22% vs. 3.17%, P = 0.008), higher serum calcium (2.55 vs. 2.49 mmol/L, P = 0.007), higher urinary oxalate levels (333.70 vs. 170.84 µg/mg, P = 0.008), higher urinary citrate levels (195.22 vs. 123.13 µg/mg, P = 0.015), lower urinary uric acid levels (838.44 vs. 1177.42 µg/mg, P = 0.040), and lower urinary calcium levels (113.27 vs. 352.21 µg/mg, P < 0.001). Subgroup analyses revealed that patients with PH3 had higher urinary oxalate levels (333.70 vs. 170.84 µg/mg, P = 0.042) than patients with cystinuria. Compared with patients in the other stone-related gene mutation groups, patients in the PH3 group presented earlier onset (0.9 vs. 2.5 years, P = 0.029), higher urinary oxalate levels (333.70 vs. 105.30 µg/mg, P = 0.045), higher urinary citrate levels (195.22 vs. 59.36 µg/mg, P < 0.001), and lower urinary calcium levels (113.27 vs. 421.24 µg/mg, P = 0.003). Patients with PH3 had greater incidence of nephrocalcinosis (22.22% vs. 0, P = 0.007), higher serum calcium levels (2.55 vs. 2.49 mmol/L, P = 0.030), higher urinary oxalate levels (333.70 vs. 182.74 µg/mg, P = 0.048) and lower urinary calcium levels (113.27 vs. 368.14 µg/mg, P = 0.004) than patients with negative molecular diagnoses. Pediatric patients with PH3 are characterized by early onset, nephrocalcinosis, increased urinary oxalate excretion and lower urinary calcium excretion, which could provide guidance for earlier diagnosis of patients with PH3.

Glyoxylate is a toxic metabolite because of its rapid conversion into oxalate, as catalyzed by the ubiquitous enzyme lactate dehydrogenase. This requires the presence of efficient glyoxylate detoxification systems in multiple subcellular compartments, as glyoxylate is produced in peroxisomes, mitochondria, and the cytosol. Alanine glyoxylate aminotransferase (AGT) and glyoxylate reductase/hydroxypyruvate reductase (GRHPR) are the key enzymes involved in glyoxylate detoxification. Bi-allelic mutations in the genes coding for these enzymes cause primary hyperoxaluria type 1 (PH1) and 2 (PH2), respectively. Glyoxylate is derived from various sources, including 4-hydroxyproline, which is degraded in mitochondria, generating pyruvate and glyoxylate, as catalyzed by the mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA); however, counterintuitively, a defect in HOGA1 is the molecular basis of primary hyperoxaluria type 3 (PH3). Irrespective of its underlying cause, hyperoxaluria in humans leads to nephrocalcinosis, recurrent urolithiasis, and kidney damage, which may culminate in kidney failure requiring combined liver-kidney transplantation in severely affected patients. In the past few years, therapeutic options, especially for primary hyperoxaluria type 1 (PH1), have greatly been improved thanks to the introduction of two RNAi-based therapies that inhibit either the production of glycolate oxidase (lumasiran) or lactate dehydrogenase (nedosiran). While lumasiran only targets PH1 patients, nedosiran was specifically developed to target all three subtypes of PH. Inspired by the findings reported in the literature that nedosiran effectively reduced urinary oxalate excretion in PH1 patients but not in PH2 or PH3 patients, we have now revisited glyoxylate metabolism in humans and performed a thorough literature study which revealed that glyoxylate/oxalate metabolism is not confined to the liver but instead involves multiple different organs. This new view on glyoxylate/oxalate metabolism in humans may well explain the disappointing results of nedosiran in PH2 and PH3, and provides new clues for the future generation of new therapeutic strategies for PH2 and PH3.

Primary hyperoxaluria type 3 (PH3) is caused by mutations in Hoga1 gene. PH3 individuals develop nephrolithiasis, but the mechanism underlying hyperoxaluria is unclear and a mouse model recapitulating the human disease can provide insights into the pathogenesis of PH3. Hoga1-/- mice do not have increased urinary oxalate excretion, probably due to the murine mitochondrial alanine-glioxylate-aminotransferase (AGT) activity, which in humans is only expressed in peroxisomes. However, Hoga1-/-/Agxt-/- mice with AGT installed on peroxisome and not on mitochondria did not show increased urinary oxalate, suggesting that AGT expression in both cellular compartments is not an explanation for the lack of hyperoxaluria in Hoga1-/- mice.

Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63 years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74 mL/min/1.73 m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.