Primary Hyperoxaluria Type 1 (PH1)

Genetic and Molecular Basis

AGXT

The AGXT Gene and Its Function

The AGXT gene, located on chromosome 2q37.3 (HGNC ID: HGNC:341), encodes the enzyme alanine–glyoxylate aminotransferase (AGT). This enzyme is found in liver cell organelles called peroxisomes, where it converts glyoxylate into glycine, a harmless amino acid.

When mutations occur in AGXT, this conversion is disrupted. Instead of being neutralized, glyoxylate is converted into oxalate, which accumulates and triggers the symptoms of PH1.

Disease Overview

Pathophysiology

Under normal conditions, glyoxylate is processed into glycine by the AGT enzyme. In PH1, a weak or absent AGT enzyme leads to excessive oxalate production.

Since oxalate cannot be metabolized, it must be excreted by the kidneys. Excessive oxalate binds to calcium, forming calcium oxalate crystals, which leads to kidney stones, nephrocalcinosis (calcium deposits in kidney tissue), and, in severe cases, systemic oxalosis, where oxalate accumulates in multiple organs.

Epidemiology

PH1 is extremely rare, affecting approximately 1 in 100,000 to 1 in 1.5 million people, depending on the region.

It accounts for about 80% of all hyperoxaluria cases and is more prevalent in North Africa, the Middle East, and the Canary Islands, regions where genetic consanguinity is more common.

In some areas, PH1 represents around 10% of pediatric end-stage kidney disease (ESKD) cases. Because symptoms can mimic more common conditions, PH1 is frequently misdiagnosed, especially when it appears later in life.

Etiology

Inheritance and Mutations

PH1 is inherited in an autosomal recessive pattern, meaning both copies of the AGXT gene must carry pathogenic variants for the disease to manifest.

Over 200 different pathogenic mutations have been identified, including:

• Missense mutations: errors in amino acid coding
  
• Nonsense mutations: premature termination of protein production
  
• Splice-site mutations: errors in how gene segments are joined
  
• Frameshift mutations: disruption of the genetic reading frame
  

Common Mutations and Their Impact

Some well-documented mutations include:

• p.Gly170Arg (p.G170R): usually milder; often responsive to vitamin B6 (pyridoxine) therapy
  
• p.Phe152Ile (p.F152I): sometimes B6-responsive
  
• p.Ile244Thr (p.I244T): frequently observed in Morocco and the Canary Islands
  

These mutations may result in incorrect enzyme folding, failure to localize to the peroxisomes, enzyme instability, or total loss of enzyme activity.

Symptoms

In Infants (Under 12 Months)

• Growth failure and lethargy
  
• Nephrocalcinosis detectable on imaging
  
• Rapid progression to end-stage kidney disease
  

In Children and Adolescents

• Recurrent kidney stones
  
• Hematuria (blood in urine)
  
• Urinary tract infections
  

In Adults

• Recurrent kidney stones that may go undiagnosed for years
  
• Progressive chronic kidney disease
  
• Symptoms of systemic oxalosis, such as:
  
  • Bone: fractures, growth delays, skeletal fragility
    
  • Eyes: retinal fibrosis and vision loss
    
  • Heart: cardiomyopathy, arrhythmias
    
  • Vascular and nerve issues: gangrene, numbness, poor circulation
    
  • Bone marrow: anemia and weakened immunity
    

Testing and Diagnosis

When to Suspect PH1

• Children or young adults with recurrent calcium kidney stones
  
• Nephrocalcinosis on ultrasound
  
• Chronic kidney disease of unknown origin
  
• Family history of kidney stones or metabolic disorders
  

Diagnostic Tests

• 24-hour urine oxalate: >0.5 mmol/1.73 m²/day suggests PH1 in patients producing urine
  
• Plasma oxalate: >50 µmol/L is strongly indicative in advanced kidney damage
  
• Urinary glycolic acid: sometimes helpful, though not definitive
  
• Stone composition analysis: typically calcium oxalate monohydrate
  
• Genetic testing:
  
  • Confirms diagnosis when both AGXT gene copies carry mutations
    
  • Multi-gene panels help distinguish PH1 from PH2 and PH3
    
  • Detection rates exceed 97%
    

Treatment and Management

Vitamin B6 (Pyridoxine) Therapy

• Dose: 5–10 mg/kg/day
  
• Particularly effective in p.G170R and p.F152I mutations
  
• A reduction of urinary oxalate by more than 30% indicates a good response
  

RNA Interference (RNAi) Therapy

• Lumasiran: suppresses glycolate oxidase (GO)
  
  • Suitable for all ages
    
  • Reduces oxalate levels by ~65%
    
• Nedosiran: targets lactate dehydrogenase A (LDHA)
  
  • Approved for patients 9 years and older with functioning kidneys
    
  • Currently under study for other hyperoxaluria types
    

Transplant Options

• Liver transplant: corrects the enzyme defect at the source
  
• Combined liver-kidney transplant (CLKT): preferred for end-stage kidney disease
  
• Kidney transplant alone: reserved for patients with proven response to vitamin B6
  

Supportive Care

• Maintain high fluid intake: 2–3 L/1.73 m² per day
  
• Citrate therapy: prevents calcium oxalate crystal formation
  
• Dietary adjustments: limit high-oxalate foods and avoid excessive vitamin C
  
• Avoid nephrotoxic medications such as NSAIDs and loop diuretics
  

Dialysis

• Initiated if plasma oxalate exceeds 30–45 µmol/L
  
• May require four or more sessions per week
  
• Serves as a bridge to transplantation rather than a long-term solution
  

Prognosis

Infant-onset PH1 typically progresses rapidly, and delayed treatment often leads to severe outcomes.

Patients who respond to vitamin B6 often experience slower kidney deterioration. RNAi therapies are increasingly reducing the need for transplants in some cases.

Early detection and appropriate therapy greatly improve quality of life and help maintain kidney function for longer.

References

Milliner DS, Harris PC, Sas DJ, et al. Primary Hyperoxaluria Type 1. GeneReviews®, University of Washington, Seattle; 1993–2025. https://www.ncbi.nlm.nih.gov/books/NBK1283/

Fargue S, Acquaviva Bourdain C. Primary Hyperoxaluria Type 1: Pathophysiology and Genetics. Clinical Kidney Journal. 2022;15(Suppl 1):i4–8. https://doi.org/10.1093/ckj/sfab217

Wannous H. Primary hyperoxaluria type 1 in children: clinical and laboratory manifestations and outcome. Pediatr Nephrol. 2023;38:2643–2648. https://doi.org/10.1007/s00467-023-05917-x

Hoppe B, Martin-Higueras C. Improving Treatment Options for Primary Hyperoxaluria. Drugs. 2022;82:1077–1094. https://doi.org/10.1007/s40265-022-01735-x

Keywords

Primary Hyperoxaluria, PH1, AGXT, Alanine–glyoxylate aminotransferase, Oxalate, Glyoxylate metabolism, Urinary tract stones, Nephrocalcinosis, Systemic oxalosis, Calcium oxalate, Vitamin B6, Pyridoxine, RNA interference, Lumasiran, Nedosiran, Liver transplant, Kidney transplant, End-stage kidney disease, Autosomal recessive inheritance, Metabolic disorder, Genetic diagnosis