Clinical burden, genetic heterogeneity, and diagnostic implications in primary hyperoxaluria type 2

Area of Science:

• Nephrology
• Genetics
• Pediatrics

Background:

• Primary hyperoxaluria type 2 (PH2) is a rare genetic disorder affecting oxalate metabolism due to glyoxalate reductase/hydroxypyruvate reductase (GRHPR) enzyme defects.
• This study focuses on characterizing the clinical presentation and outcomes of pediatric PH2 patients in Pakistan.

Purpose of the Study:

• To describe the demographic, clinical, and genetic characteristics of pediatric PH2 patients.
• To evaluate disease progression and identify predictors of advanced chronic kidney disease (CKD) in this cohort.

Main Methods:

• Retrospective analysis of 52 pediatric patients diagnosed with PH2 at a single center in Pakistan (2010-2022).
• Data included clinical features, laboratory findings, imaging, family history, and genetic testing (NGS, Sanger sequencing) for GRHPR mutations.
• Patients were followed for 24 months to monitor CKD progression.

Main Results:

• Fifty-two pediatric patients with PH2 were identified, predominantly males (56%) from the Sindh province (62%).
• Seventeen distinct GRHPR mutations were found, including six novel variants; Gly165Asp was the most common.
• At diagnosis, 30% of patients had CKD stage 5, increasing to 42% at 24 months; male sex and higher baseline creatinine predicted progression.

Conclusions:

• This is the first reported PH2 cohort from Pakistan, revealing a substantial disease burden.
• Diverse GRHPR mutations contribute to PH2, with a significant proportion of patients presenting with advanced CKD stage 5.
• Early identification and monitoring are crucial for managing PH2 progression in pediatric patients.