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BackgroundPrimary hyperoxalurias (PHs) constitute rare disorders resulting in abnormal glyoxalate metabolism. PH-associated phenotypes range from progressive nephrocalcinosis and/or recurrent urolithiasis to early kidney failure.MethodsA retrospective study was conducted for patients with confirmed PH diagnoses from three tertiary centers in Saudi Arabia. Detailed clinical molecular diagnosis was performed for 25 affected individuals. Whole exome sequencing (WES)–based molecular diagnosis was performed for all affected individuals.ResultsThe male:female ratio was 52% male (n = 13) and 48% female (n = 12), and consanguinity was present in 88%. Nephrolithiasis and/or nephrocalcinosis were present in all patients. Kidney stones were present in 72%, nephrocalcinosis in 60%, hematuria in 32%, proteinuria in 16%, abdominal pain in 36%, developmental delay in 8%, and chronic kidney disease stage 5 (CKD stage 5) was observed in 28% of the patients. The most common PH disorder was type I caused by variants in the AGXT gene, accounting for 56%. The GRHPR gene variants were identified in 4 patients, 16% of the total cases. Seven patients did not reveal any associated variants. Missense variants were the most commonly observed variants (48%), followed by frame-shift duplication variants (28%).ConclusionsCharacterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research.

Abstract Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.

The rapid development of therapies for severe and rare genetic conditions underlines the need to incorporate first-tier genetic testing into newborn screening (NBS) programs. A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes. The prospective observational BabyDetect pilot project was launched in September 2022 in a maternity ward of a public hospital in the Liege area, Belgium. In this ongoing observational study, 4,260 families have been informed of the project, and 3,847 consented to participate. To date, 71 disease cases have been identified, 30 of which were not detected by conventional NBS. Glucose-6-phosphate dehydrogenase deficiency was the most frequent disorder detected, with 44 positive individuals. Of the remaining 27 cases, 17 were recessive disorders. We also identified one false-positive case in a newborn in whom two variants in the AGXT gene were identified, which were subsequently shown to be located on the maternal allele. Nine heterozygous variants were identified in genes associated with dominant conditions. Results from the BabyDetect project demonstrate the importance of integrating biochemical and genomic methods in NBS programs. Challenges must be addressed in variant interpretation within a presymptomatic population and in result reporting and diagnostic confirmation. The BabyDetect project offered expanded newborn genomic screening covering more than 400 genes to 4,260 families, leading to 71 clinical diagnoses.

Primary hyperoxaluria type 1 displays a heterogeneous phenotype, likely to be affected by genetic and non-genetic factors, including timeliness of diagnosis and quality of care. As previous genotype-phenotype studies were hampered by limited patient numbers the European OxalEurope Consortium was constituted. This preliminary retrospective report is based on 526 patients of which 410 have the AGXT genotype defined. We grouped mutations by the predicted effect as null, missense leading to mistargeting (G170R), and other missense, and analyzed their phenotypic correlations. Median age of end-stage renal disease increased from 9.9 for 88 homozygous null patients, 11.5 for 42 heterozygous null/missense, 16.9 for 116 homozygous missense patients, 25.1 for 61 G170R/null patients, 31.2 for 32 G170R/missense patients, and 33.9 years for 71 homozygous G170R patients. The outcome of some recurrent missense mutations (p.I244T, p.F152I, p.M195R, p.D201E, p.S81L, p.R36C) and an unprecedented number of G170R homozygotes is described in detail. Diagnosis is still delayed and actions aimed at increasing awareness of primary hyperoxaluria type 1 are recommended. Thus, in addition to G170R, other causative mutations are associated with later onset of end-stage renal disease. The OxalEurope registry will provide necessary tools for characterizing those genetic and non-genetic factors through a combination of genetic, functional, and biostatistical approaches.

Background Primary hyperoxaluria (PH) is a rare heterogeneous, autosomal recessive disorder of glyoxylate metabolism. It is characterized by excessive hepatic production of oxalate resulting in a wide spectrum of clinical, imaging, and functional presentation. The characteristic features of PH comprise of recurrent urolithiasis, renal stones, and/or nephrocalcinosis. Three known types of PH have been identified PH1, PH2, and PH3. Pathogenic variants in AGXT, GRHPR, and HOGA1 cause the phenotypic expression of PH. Methods In this study, we describe the clinical and genetic findings of 22 patients from 21 unrelated Egyptian families with the distinctive clinical features of PH. A thorough clinical evaluation followed by an NGS custom panel of AGXT, GRHPR, and HOGA1 genes was done. Results Two novel mutations (p.Gly27Glu and p.Gln256Serfs*17) and six previously reported mutations (p.Lys12Glnfs*156, p.Lys12Argfs*34, p.Ile244Thr, p.Asn22Ser, p.Pro11Leu, and p.Ile340Met) were identified in AGXT gene. The NGS panel results were validated thereafter using Sanger sequencing. Conclusion Our results extend the number of AGXT mutations identified so far and emphasize the important role of genetic testing in providing proper counseling and patients management. Primary hyperoxaluria (PH) is a rare heterogeneous, autosomal recessive disorder of glyoxylate metabolism. It is characterized by excessive hepatic production of oxalate resulting in wide spectrum of clinical, imaging and functional presentation. The characteristic features of PH comprise of recurrent urolithiasis, renal stones and/or nephrocalcinosis. Three known types of PH have been identified PH1, PH2 and PH3. Pathogenic variants in AGXT, GRHPR and HOGA1 cause the phenotypic expression of PH.

Background Characterization of the molecular basis of primary hyperoxaluria type 1 (PH-1) in Syria has been accomplished through the analysis of 90 unrelated chromosomes from 45 Syrians patients with PH-1 from different regions. Methods Alanine glyoxylate aminotransferase (AGXT) gene mutations have been analyzed by using molecular detection methods based on the direct DNA sequencing for all exons of the AGXT gene. Results Seventeen pathogenic mutations were detected in our patients. Six mutations were novels. The three most frequent mutations were c.33_34insC (p.Lys12fs) in Exon 1, c.584 T < G; p.Met195Arg in exon 5 and c.1007 T > A (p.Val336Asp) in exon 10, with a frequency of 33.3%, 12.2%, and 11.1%, respectively. Conclusion DNA sequencing used in this study can offer a useful method to investigate the mutations in Syrian PH-1 patients, and could offer an accurate tool for prenatal diagnosis and genetic counseling.

Based on the single-center case reports and all reported patients with primary hyperoxaluria type 1 (PH1) in China, this study discussed the clinical and genetic characteristics of this disease retrospectively. We reported and validated a novel genetic variation c.302 T > G: the clinical phenotypes of the two siblings were similar, in which both had onset in infancy, mainly manifested as renal insufficiency, and died within 6 months out of end-stage renal disease. The literature review is the first to summarize the Chinese patients with PH1 up to now. Forty-eight Chinese patients were included, containing 7 adults and 41 children. The median onset age was 51 months, and the ratio of male to female was 2.69:1. It showed a poor prognosis: 51.1% of Chinese primary hyperoxaluria type 1 patients suffered from end-stage renal disease, and 38.9% of patients died. Urolithiasis was the most common clinical manifestation both in adults and children, while infant-onset patients generally presented with renal insufficiency and had a higher mortality of 75.0%. One hundred and forty-nine AGXT mutant alleles are currently known in the Chinese population, c.33dupC and c.815_816insGA were the most common AGXT genes, accounting for 12.0% and 10.1% of allele frequencies, respectively. The exons 1, 2, 6, and 8 were the most common locations of gene variants, accounting for 78% of all variants, which will be promising targets of DNA sequencing for primary hyperoxaluria type 1.

Background Primary hyperoxaluria type 1 (PH 1) is a rare genetic condition due to mutations in the AGXT gene. This leads to an overproduction of oxalate in the liver. Hyperoxaluria often causes kidney stones, nephrocalcinosis, and chronic kidney disease. Lumasiran is a recently approved drug that reduces the hepatic oxalate production by mRNA interference. Methods In this multicenter study, we evaluated the response to lumasiran treatment in PH 1 patients ( n  = 8) with a median age of 10.9 years (range 1.2–17.9 years), including two patients on hemodialysis. We retrospectively analyzed the reduction of urinary and plasma oxalate levels as well as changes in kidney stone events, nephrocalcinosis, and kidney function. Results In patients without kidney failure, the median reduction of urinary oxalate was 64% (range 10–80%) and 71% (61–86%) at 6 and 12 months, respectively. However, only one patient reached urinary oxalate levels within the age-specific normal range. Two patients did not respond to lumasiran and treatment was stopped. In one of the two patients on hemodialysis, the frequency of sessions could be reduced. The only notable side effects were injection site reactions. Conclusion There was a variable response to lumasiran in PH 1. Despite a reduction of hyperoxaluria in many patients with PH 1, only one patient reached normal values and 2 of 8 patients did not respond. Regular monitoring of urinary oxalate values and registry data collection seems mandatory to monitor the efficacy and the long-term outcome of PH 1 treated with lumasiran. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary Materials .

Primary hyperoxaluria (PH) is an autosomal recessive disorder of oxalate metabolism caused by pathogenic variants in either of three genes ( AGXT , GRHPR or HOGA1 ). The study aimed at characterizing the clinical phenotypes as well as the genotypic spectrum of PH in Egypt. We screened 25 Egyptian patients suspected of PH for the three responsible genes by Sanger sequencing. We diagnosed 20 patients from 18 unrelated families, in which the natural history, family history, clinical features and genotypes were evaluated. PH patients were 15 males and 5 females ranging in age from 4 months to 31 years (median 8 years). Fifteen families were consanguineous (83%) and familial clustering was reported in six families (33%). Pathogenic variants in all 40 alleles were in AGXT , with none detected in GRHPR or HOGA1 . We detected two novel pathogenic variants c.166-1_172dupGATCATGG (p.Asp58Glyfs*65) and c.766delC (p.Gln256fs*16) and seven previously reported variants in our cohort. This is the first study reporting the genotype of a considerable number of PH1 patients from Egypt. Our detected variants in the AGXT gene could form the basis for future genetic counseling and prenatal diagnosis in Egypt and surrounding populations.

Background Primary hyperoxaluria (PH) is a rare inherited disorder characterized by excessive oxalate accumulation in blood and urine due to defects in glyoxylate metabolism, leading to significant clinical consequences. As genetic and phenotypic heterogeneity contribute to the morbidity of PH, this study examined the phenotypes and genotypes of PH among confirmed pediatric patients (< 18 years) diagnosed with PH at a tertiary care center in Saudi Arabia between 2014 and 2023. Results Twenty-one patients from 14 families, including 10 boys (47.6%) and 11 girls (52.4%), were included. Six families had more than one affected child. The median age at diagnosis was 36 months (interquartile range = 6–84). All but one patient had PH type 1 [due to alanine–glyoxylate aminotransferase gene variant ( AGXT )], with the remaining patient having PH type 2 [associated with glyoxylate and hydroxypyruvate reductase gene (GRHPR)]. The most frequent variant in the AGXT gene was NM_000030.3: c.33dup (p.Lys12GlnfsTer156), which was detected in 38.1% of patients. High parental consanguinity (90.5%) and positive family history (81%) were notable. The major clinical manifestations were kidney stones (71.4%), nephrocalcinosis (47.6%), failure to thrive (38.1%), stage V chronic kidney disease (42.9%), and hematuria (33.3%). All patients received conservative management, in addition to liver transplantation in eight patients and combined liver–kidney transplantation in two patients. The mortality rate was 14.3% (3/21). AGXT variants such as NM_000030.3:c.481G > A(p.(Gly161Ser) and NM_000030.3: c.346G > A (p.(Gly116Arg) displayed potential trends with worse renal prognosis. Conclusions PH type 1 is the predominant form of hyperoxaluria among Saudi patients. High consanguinity might contribute to its disease burden. Early diagnosis and intervention are critical for improving outcomes. Recently approved RNA interference-based therapies offer promising outcomes, potentially reducing the need for organ transplantation in patients with PH type 1. Clinical trail number Not applicable.