Orphanet Journal of Rare Diseases | Clinical Presentation, Genetic Mutations, and Transplantation Outcomes of Primary Hyperoxaluria in the Saudi Pediatric Population

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This study systematically reviews the genotypic and phenotypic characteristics of primary hyperoxaluria in Saudi pediatric patients, revealing its genetic variants, clinical manifestations, and transplant efficacy. The research emphasizes the importance of early diagnosis and intervention, while exploring the potential of RNA interference therapies like Lumasiran to reduce transplant requirements.

 

Literature Overview
The article titled Primary hyperoxaluria: insights into its clinical presentation, genetic mutations, and transplantation outcomes in a pediatric population in a tertiary care center, published in the Orphanet Journal of Rare Diseases, reviews clinical, genetic, and treatment outcomes of 21 pediatric patients diagnosed with primary hyperoxaluria (PH) at Saudi tertiary healthcare centers between 2014 and 2023. The study shows PH1 as the most common subtype, closely linked to AGXT gene mutations. The high rate of consanguinity and positive family history highlights the significant genetic basis of PH in Saudi populations.

Background Knowledge
Primary hyperoxaluria (PH) is a rare autosomal recessive metabolic disorder primarily caused by dysfunction of hepatic glyoxylate and hydroxypyruvate reductase (AGT), leading to excessive oxalate production that deposits in kidneys and other organs, causing severe clinical manifestations including nephrolithiasis, nephrocalcinosis, and chronic kidney disease. PH1 results from AGXT mutations, PH2 from GRHPR mutations, and PH3 from HOGA1 mutations. PH1 is the most severe and common subtype, particularly in children, often progressing to end-stage renal disease without timely intervention.
This study reveals NM_000030.3:c.33dup (p.Lys12GlnfsTer156) as the most prevalent AGXT mutation in Saudi patients, suggesting a founder effect. Certain AGXT mutations like c.481G>A (p.Gly161Ser) and c.346G>A (p.Gly116Arg) correlate with poorer renal prognosis, underscoring the clinical value of genotype-phenotype association studies.
Due to its global rarity but increased prevalence in high-consanguinity regions like Saudi Arabia, understanding regional mutation spectra and clinical features is critical for early screening, diagnosis, and personalized treatment. The study also emphasizes liver transplantation in advanced stages and highlights RNA interference therapies as promising alternatives for PH1 management.

 

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Research Methods and Experiments
This retrospective case series analyzed medical records of 21 pediatric PH patients diagnosed at King Faisal Specialist Hospital & Research Centre (KFSHRC), Riyadh, Saudi Arabia between 2014-2023. Inclusion criteria required diagnosis before age 18, excluding incomplete phenotypic or genotypic data. PH diagnosis was confirmed through clinical evaluation, biochemical markers, and genetic testing. REDCap database collected demographic data, medical history, laboratory findings, and genetic results. Genetic testing used targeted gene sequencing or whole exome sequencing. Pathogenicity of variants was assessed per ACMG guidelines.

Key Findings

• 20/21 patients had PH1 (AGXT mutations), 1 PH2 (GRHPR mutation), with 6 families having multiple affected children.
• Median diagnosis age: 36 months. Male 47.6%, female 52.4%. 90.5% had consanguineous parents, 81% family history of PH.
• Most common AGXT mutation: NM_000030.3:c.33dup (p.Lys12GlnfsTer156) at 38.1% prevalence, also observed in Chinese populations indicating possible founder effect.
• Median serum oxalate: 89 µmol/L, urine oxalate/creatinine ratio: 52 mg/g - both significantly exceeding normal ranges.
• 71.4% presented with nephrolithiasis, 47.6% nephrocalcinosis, 42.9% progressed to CKD V, 38.1% showed developmental delays.
• All patients received conservative treatment. 38.1% (n=8) underwent liver transplantation, 9.5% (n=2) combined liver-kidney transplantation.
• Mortality rate: 14.3% (n=3), including 2 liver-transplanted patients.
• Early liver transplantation improved renal function, while late transplantation still required dialysis due to end-stage renal disease progression.
• AGXT mutations like c.481G>A and c.346G>A may correlate with poorer renal prognosis but insufficient sample size prevented statistical analysis.
• Novel GRHPR mutation NM_012203.2:c.64G>A (p.Ala22Thr) discovered, requiring functional validation.

Research Significance and Prospects
The study provides Saudi-specific genetic and clinical profiles of PH, emphasizing early screening and intervention for better prognosis. Newborn genetic screening could enable early diagnosis. RNAi therapies like Lumasiran offer non-transplant alternatives for PH1 patients, warranting prospective studies. The complex genotype-phenotype relationship in PH1 necessitates multi-center large-scale research to validate mutation-prognosis correlations.

 

Assesses pathogenicity of genetic variants for functional analysis

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Conclusion
This systematic analysis of 21 Saudi pediatric PH patients shows 95.2% prevalence of PH1 caused by AGXT mutations, particularly c.33dup. High consanguinity and family history highlight genetic factors' epidemiological significance. Major clinical manifestations include nephrolithiasis, nephrocalcinosis, and chronic kidney disease, with 42.9% progressing to end-stage renal disease. 14.3% mortality rate underscores severe risks without timely intervention. Liver transplantation improved renal function while RNAi therapy Lumasiran initiated in 6 patients offers non-transplant options. Despite retrospective design and small sample size, this study provides critical references for clinical management and genetic screening in Saudi and Middle Eastern regions, supporting future exploration of newborn screening and RNAi therapies.

 

Bayan Sayed, Raghad Alhuthil, Sermin Saadeh, Ibrahim Alhassoun, and Essam Al-Sabban. Primary hyperoxaluria: insights into its clinical presentation, genetic mutations, and transplantation outcomes in a pediatric population in a tertiary care center. Orphanet Journal of Rare Diseases.