PH1 follows autosomal recessive inheritance, meaning pathogenic variants must be present in both copies of the AGXT gene for the disorder to manifest. AGXT, the sole gene listed for this condition in this packet, encodes the AGT enzyme, which normally catalyzes the transamination of glyoxylate to glycine within liver peroxisomes. Deficiency or absence of functional AGT activity redirects glyoxylate through alternative metabolic pathways, most significantly oxidation by lactate dehydrogenase to produce oxalate in excess quantities. High urinary oxalate concentration leads to insoluble calcium oxalate crystal formation and deposition primarily in the kidneys. Specific AGXT variant classes have distinct biochemical and clinical consequences, including differences in pyridoxine responsiveness and severity of enzyme impairment, as characterized in the genotype-phenotype literature (GeneReviews, primary hyperoxaluria type 1 chapter). Parents of an affected individual each carry one pathogenic AGXT variant and are typically unaffected.

Clinical suspicion for PH1 arises in individuals with recurrent calcium oxalate kidney stones or nephrocalcinosis, particularly when associated with progressive chronic kidney disease or a family history of stones and renal failure. Infants presenting with rapidly progressive nephrocalcinosis represent another recognized presentation pattern. Biochemical evaluation includes 24-hour urine measurement of oxalate, glycolate, and glyoxylate; elevated levels characterize PH1 and help distinguish it from secondary hyperoxaluria. Plasma oxalate measurement is informative when kidney function is reduced. Molecular genetic testing of AGXT confirms the diagnosis and identifies the specific variant class, which carries implications for therapeutic responsiveness. Liver biopsy with enzymatic assay of AGT activity has historically been used when genetic testing is inconclusive. The differential diagnosis encompasses primary hyperoxaluria types 2 and 3, other monogenic causes of calcium oxalate stone disease, and idiopathic or secondary hyperoxaluria arising from dietary, gastrointestinal, or other systemic causes (GeneReviews, diagnosis and differential diagnosis sections).

Lumasiran (OXLUMO; generic name lumasiran), approved by the U.S. Food and Drug Administration on November 23, 2020, is the currently active pharmacological treatment for PH1 listed in this packet. Lumasiran is an RNA interference (RNAi) therapeutic that reduces hepatic oxalate production by targeting hydroxyacid oxidase 1 (HAO1), limiting the substrate available for oxalate synthesis. Prior to its availability, conservative management centered on high-volume fluid intake to dilute urinary oxalate and—for individuals with pyridoxine-responsive AGXT variants—pharmacologic doses of pyridoxine to reduce oxalate excretion. Combined liver-kidney transplantation has been performed in patients reaching end-stage renal disease, with the liver transplant component correcting the underlying metabolic defect. The GeneReviews chapter for PH1 identifies several substances capable of exacerbating the disease: intravascular volume depletion, vitamin C intake exceeding the recommended daily allowance, loop diuretics (which can increase calciuria and calcium oxalate stone production), and high-dose nonsteroidal anti-inflammatory drugs—this information is drawn from published clinical guidance and is presented here as descriptive context about known disease-exacerbating factors (GeneReviews, agents to avoid section). Among orphan-designated compounds, a BioMarin investigational agent has been withdrawn; Dicerna Pharmaceuticals holds an orphan designation for an RNAi compound targeting HAO1, which remains investigational as of this packet.

The prognosis of PH1 is closely tied to the rate of renal function decline, which depends on disease severity, AGXT genotype (particularly pyridoxine responsiveness), and the timing and effectiveness of therapeutic intervention. Without treatment, many patients progress to end-stage renal disease in childhood or early adulthood. The introduction of lumasiran has altered the treatment landscape by demonstrating reductions in urinary oxalate excretion in clinical trials. Systemic oxalosis with deposition in bones, eyes, and cardiovascular structures is a serious complication in individuals with markedly reduced kidney function and represents a significant contributor to morbidity in advanced disease. Prognosis following liver-kidney transplantation is influenced by the degree of systemic oxalate burden accumulated prior to transplant, with residual oxalate deposits in the bones and other organs continuing to pose clinical challenges in the post-transplant period.

The PH1 research landscape is actively evolving. This packet's research digest identifies 91 classified publications, with case reports and reviews predominating alongside gene therapy and biomarker research. The packet records 10 active clinical trials across multiple phases and sponsors. Phase 1 and Phase 2 studies of YOLT-203 (sponsored by YolTech Therapeutics Co., Ltd) are listed as recruiting as of this packet, targeting adult and pediatric populations. Natural history and biobank infrastructure is being built through the Mayo Clinic Prospective Research Rare Kidney Stones (ProRKS) study and the Rare Kidney Stone Consortium Biobank, both actively recruiting. Investigational strategies under evaluation as described in GeneReviews include gene editing of AGXT, HAO1, or LDHA—approaches that could potentially offer durable benefit following a single treatment by correcting the metabolic defect at its source. CRISPR/Cas9-based glycolate oxidase disruption has advanced to Phase I/II trials (referenced in GeneReviews). Small molecule chemical chaperones are also under preclinical and early clinical investigation as broadly stabilizing agents. The trial portfolio reflects a mixed sponsor profile of biopharmaceutical companies and academic medical centers, with gene therapy and biologic therapy among the active intervention categories (packet trial_intervention_summary).