In vivo base editing rescues primary hyperoxaluria type 1 in rats.

Primary hyperoxaluria type 1 (PH1) is a childhood-onset autosomal recessive disease, characterized by nephrocalcinosis, multiple recurrent urinary calcium oxalate stones, and a high risk of progressive kidney damage. PH1 is caused by inherent genetic defects of the alanine glyoxylate aminotransferase (AGXT) gene. The in vivo repair of disease-causing genes was exceedingly inefficient before the invention of base editors which can efficiently introduce precisely targeted base alterations without double-strand DNA breaks. Adenine base editor (ABE) can precisely convert A·T to G·C with the assistance of specific guide RNA. Here, we demonstrated that systemic delivery of dual adeno-associated virus encoding a split-ABE8e could artificially repair 13% of the pathogenic allele in AgxtQ84X rats, a model of PH1, alleviating the disease phenotype. Specifically, ABE treatment partially restored the expression of alanine-glyoxylate-aminotransferase (AGT), reduced endogenous oxalate synthesis and alleviated calcium oxalate crystal deposition. Western blot and immunohistochemistry confirmed that ABE8e treatment restored AGT protein expression in hepatocytes. Moreover, the precise editing efficiency in the liver remained stable six months after treatment. Thus, our findings provided a prospect of in vivo base editing as a personalized and precise medicine for PH1 by directly correcting the mutant Agxt gene.

The Evolving Role of Genetic Testing in Monogenic Kidney Stone Disease: Spotlight on Primary Hyperoxaluria.

PURPOSE: Multiple factors are thought to give rise to common, recurrent kidney stone disease, but for monogenic stone disorders a firm diagnosis is possible through genetic testing. The autosomal recessive primary hyperoxalurias (PH) are rare forms of monogenic kidney stone disease. All 3 types of PH are caused by inborn errors of glyoxylate metabolism in the liver, leading to hepatic oxalate overproduction and excessive renal urinary oxalate excretion. These conditions are characterized by kidney stones, nephrocalcinosis, progressive chronic kidney disease, and kidney failure. Systemic oxalosis, the extra-renal deposition of oxalate resulting in severe morbidity and mortality, occurs in chronic kidney disease when oxalate clearance by the kidneys declines. Novel small interfering RNA-based therapeutics targeting the liver to reduce urinary oxalate excretion have been approved, introducing precision medicine to treat primary hyperoxaluria type 1. The goal of this narrative review is to address the benefits and practicalities of genetic testing for suspected monogenic kidney stone disease and the critical roles of a multidisciplinary team. MATERIALS AND METHODS: We collated our procedures, education, training, and workflows to help other clinicians integrate genetic assessment into their diagnostic routines. RESULTS: In our experience, increased access to genetic testing facilitates early detection of PH and other monogenic causes of kidney stone disease so that individualized care can be instituted promptly. CONCLUSIONS: Alongside biochemical assessments, more widespread genetic testing may ensure more timely diagnoses so that patients with suspected monogenic kidney stone disease gain access to an expanded range of services and enrollment in clinical trials and registries.

Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

AIM: To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. METHODS: A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. RESULTS: Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5 mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6 mmol) by week 52. CONCLUSIONS: The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6 years with relatively preserved kidney function.

Modified by the Innovative Drugs and Strategies-Pattern of Selected Indications for Pediatric Liver Transplantation.

BACKGROUND: Liver transplantation (LTx) constitutes a major life-saving routine treatment for children with end-stage liver disease. However, the analysis of LTx registries in children provides much information about changes in the indication profiles in the recent years. METHODS: The article provides a comprehensive review about the successes, hopes, and challenges related to changing indications for LTx in children based on the literature review and our own experience. Retrospective review of the indications for LTx at a tertiary referral pediatric hospital was also presented. RESULTS AND CONCLUSIONS: In the context of the new therapies that have emerged, the need for LTx has decreased in patients with chronic hepatitis B and C infection and tyrosinemia type 1. In primary hyperoxaluria type 1, new RNAi-based therapy has eliminated the requirement for LTx (both isolated or combined). There is a hope that introduction of ileal bile acid transporter (IBAT) blockers reduces the need for LTx in patients with Alagille syndrome or progressive familial intrahepatic cholestasis. The number of children qualified for LTx with urea cycle disorders (UCDs) as a prophylaxis of neurodevelopmental impairment is increasing.

Nephrocalcinosis can disappear in infants receiving early lumasiran therapy.

BACKGROUND: Lumasiran is the first RNA interference (RNAi) therapy of primary hyperoxaluria type 1 (PH1). Here, we report on the rapid improvement and even disappearance of nephrocalcinosis after early lumasiran therapy. CASE-DIAGNOSIS/TREATMENT: In patient 1, PH1 was suspected due to incidental discovery of nephrocalcinosis stage 3 in a 4-month-old boy. Bilateral nephrocalcinosis stage 3 was diagnosed in patient 2 at 22 months concomitantly to acute pyelonephritis. Urinary oxalate (UOx) and glycolate (UGly) were increased in both patients allowing to start lumasiran therapy before genetic confirmation. Nephrocalcinosis started to improve and disappeared after 27 months and 1 year of treatment in patients 1 and 2, respectively. CONCLUSION: These cases illustrate the efficacy of early lumasiran therapy in infants to improve and even normalize nephrocalcinosis. As proposed in the 2023 European guidelines, the interest of starting treatment quickly without waiting for genetic confirmation may have an impact on long-term outcomes.

Unveiling atypical diagnoses: when whole-genome analysis performed for refractory infantile hypomagnesemia reveals primary hyperoxaluria.

BACKGROUND: Genetic testing is increasingly recognized as crucial in inherited nephropathies. Here, we report on an atypical presentation of a complex tubulopathy that led to an unexpected diagnosis of primary hyperoxaluria type 1 (PH1). CASE DIAGNOSIS: At 2 weeks of age, a premature boy with stunted growth was diagnosed with complex tubulopathy associating hyponatremia, hypokalemia, hypomagnesemia, hypophosphatemia, metabolic acidosis, and acute kidney injury. Despite electrolyte replacement, severe hypomagnesemia persisted while massive parallel sequencing of genes involved in hypomagnesemia yielded negative results, including HNF1ß. At 3 years of age, despite satisfactory growth, hypomagnesemia persisted and nephrocalcinosis appeared and progressed rapidly thereafter. Whole-genome analysis then revealed compound heterozygous mutations in the AGXT gene, thus leading to the diagnosis of PH1. CONCLUSION: Given the emergence of new targeted therapies, thorough genetic analysis including whole-genome analysis should be pursued, especially in case of atypical clinical presentation.

Natural history of urine and plasma oxalate in children with primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is a rare, severe genetic disease causing increased hepatic oxalate production resulting in urinary stone disease, nephrocalcinosis, and often progressive chronic kidney disease. Little is known about the natural history of urine and plasma oxalate values over time in children with PH1. METHODS: For this retrospective observational study, we analyzed data from genetically confirmed PH1 patients enrolled in the Rare Kidney Stone Consortium PH Registry between 2003 and 2018 who had at least 2 measurements before age 18 years of urine oxalate-to-creatinine ratio (Uox:cr), 24-h urine oxalate excretion normalized to body surface area (24-h Uox), or plasma oxalate concentration (Pox). We compared values among 3 groups: homozygous G170R, heterozygous G170R, and non-G170R AGXT variants both before and after initiating pyridoxine (B6). RESULTS: Of 403 patients with PH1 in the registry, 83 met the inclusion criteria. Uox:cr decreased rapidly over the first 5 years of life. Both before and after B6 initiation, patients with non-G170R had the highest Uox:cr, 24-h Uox, and Pox. Patients with heterozygous G170R had similar Uox:cr to homozygous G170R prior to B6. Patients with homozygous G170R had the lowest 24-h Uox and Uox:cr after B6. Urinary oxalate excretion and Pox tend to decrease over time during childhood. eGFR over time was not different among groups. CONCLUSIONS: Children with PH1 under 5 years old have relatively higher urinary oxalate excretion which may put them at greater risk for nephrocalcinosis and kidney failure than older PH1 patients. Those with homozygous G170R variants may have milder disease. A higher resolution version of the Graphical abstract is available as Supplementary information.

Primary hyperoxaluria type 3: from infancy to adulthood in a genetically unique cohort.

BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. METHODS: This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. RESULTS: Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63 years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74 mL/min/1.73 m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. CONCLUSIONS: A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.

Clinical characteristics, genetic profile and short-term outcomes of children with primary hyperoxaluria type 2: a nationwide experience.

BACKGROUND: Three types of primary hyperoxaluria (PH) are recognized. However, data on PH type 2 (PH2), caused by defects in the GRHPR gene, are limited. METHODS: We reviewed the medical records of patients < 18 years of age with genetically-proven PH2 from seven centres across India to identify the age of onset, patterns of clinical presentation, short-term outcomes and genetic profile, and to determine if genotype-phenotype correlation exists. RESULTS: We report 20 patients (all with nephrolithiasis or nephrocalcinosis) diagnosed to have PH2 at a median (IQR) age of 21.5 (7, 60) months. Consanguinity and family history of kidney stones were elicited in nine (45%) and eight (40%) patients, respectively. The median (IQR) serum creatinine at PH2 diagnosis was 0.45 (0.29, 0.56) mg/dL with the corresponding estimated glomerular filtration rate being 83 (60, 96) mL/1.73 m2/min. A mutational hotspot (c.494 G > A), rare in Caucasians, was identified in 12 (60%) patients. An intronic splice site variant (c.735-1G > A) was noted in five (25%) patients. Four (20%) patients required surgical intervention for stone removal. Major adverse kidney events (mortality or chronic kidney disease (CKD) stages 3-5) were noted in six (30%) patients at a median (IQR) follow-up of 12 (6, 27) months. Risk factors for CKD progression and genotype-phenotype correlation could not be established. CONCLUSIONS: PH2 should no longer be considered an innocuous disease, but rather a potentially aggressive disease with early age of presentation, and possible rapid progression to CKD stages 3-5 in childhood in some patients. A mutational hotspot (c.494 G > A variant) was identified in 60% of cases, but needs further exploration to decipher the genotype-phenotype correlation.

Diagnosis and management of primary hyperoxalurias: best practices.

The primary hyperoxalurias (PH 1, 2, and 3) are rare autosomal recessive disorders of glyoxylate metabolism resulting in hepatic overproduction of oxalate. Clinical presentations that should prompt consideration of PH include kidney stones, nephrocalcinosis, and kidney failure of unknown etiology, especially with echogenic kidneys on ultrasound. PH1 is the most common and severe of the primary hyperoxalurias with a high incidence of kidney failure as early as infancy. Until the recent availability of a novel RNA interference (RNAi) agent, PH care was largely supportive of eventual need for kidney/liver transplantation in PH1 and PH2. Together with the Oxalosis and Hyperoxaluria Foundation, the authors developed a diagnostic algorithm for PH1 and in this report outline best clinical practices related to its early diagnosis, supportive treatment, and long-term management, including the use of the novel RNAi. PH1-focused approaches to dialysis and kidney/liver transplantation for PH patients with progression to chronic kidney disease/kidney failure and systemic oxalosis are suggested. Therapeutic advances for this devastating disease heighten the importance of early diagnosis and informed treatment.

Comprehensive evaluation of patients with primary hyperoxaluria type 1: A nationwide study.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are nephrocalcinosis/nephrolithiasis, causing impaired kidney function. We aimed to evaluate the clinical characteristics and overall outcomes of paediatric PH1 patients in Turkey. METHODS: This is a nationwide, multicentre, retrospective study evaluating all available paediatric PH1 patients from 15 different paediatric nephrology centres in Turkey. Detailed patient data was collected which included demographic, clinical and laboratory features. Patients were classified according to their age and characteristics at presentation: patients presenting in the first year of life with nephrocalcinosis/nephrolithiasis (infantile oxalosis, Group 1), cases with recurrent nephrolithiasis diagnosed during childhood (childhood-onset PH1, Group 2), and asymptomatic children diagnosed with family screening (Group 3). RESULTS: Forty-eight patients had a mutation consistent with PH1. The most common mutation was c.971_972delTG (25%). Infantile oxalosis patients had more advanced chronic kidney disease (CKD) or kidney failure necessitating dialysis (76.9% vs. 45.5%). These patients had much worse clinical course and mortality rates seemed to be higher (23.1% vs. 13.6%). Patients with fatal outcomes were the ones with significant comorbidities, especially with cardiovascular involvement. Patients in Group 3 were followed with better outcomes, with no kidney failure or mortality. CONCLUSION: PH1 is not an isolated kidney disease but a systemic disease. Family screening helps to preserve kidney function and prevent systemic complications. Despite all efforts made with traditional treatment methods including transplantation, our results show devastating outcomes or mortality.

Second transplantation after kidney graft loss in primary hyperoxaluria type 2: a pedigree study and mutation analysis.

BACKGROUND: Primary hyperoxaluria type 2 (PH2) is a rare disorder caused by GRHPR mutations. Research on the mutation spectrum and pedigree of PH2 helps in comprehending its pathogenesis and clinical outcomes, guiding clinical diagnosis and treatment. METHODS: We report a case of PH2 with a three-generational pedigree. The GRHPR genotypes of the family members were confirmed by Sanger sequencing. Urine and blood samples were collected for biochemical analysis. Computational analysis was performed to assess the pathogenicity of the mutations. Cellular experiments based on site-directed mutagenesis were conducted to confirm the effect of mutations on GRHPR expression, activity, and subcellular localization. RESULTS: The proband underwent her first kidney transplantation in 2015, and experienced recurrent urinary tract infections and urolithiasis postoperatively. Graft failure occurred in 2018. Whole exome sequencing identified compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7. The patient underwent a second kidney transplantation in 2019 and maintained good graft function with urine dilution measures. Notably, her brother and sister carried the same mutations; however, only the proband progressed to renal failure. Computational analysis suggested that p.G160E reduced the affinity of GRHPR for coenzymes. Cellular experiments indicated that p.G160E reduced GRHPR activity (p < 0.001), whereas p.P203Rfs*7 not only suppressed expression (p < 0.001) and reduced activity (p < 0.001), but also facilitated protein aggregation. Based on our results, the variant p.G160E was classified as 'pathogenic' according to ACMG guidelines. CONCLUSIONS: Our findings suggest that treatment strategies for the long-term prevention of oxalate nephropathy should be developed for patients with PH2 receiving isolated kidney transplantation. Moreover, the pathogenicity of the compound heterozygous GRHPR mutations p.G160E/p.P203Rfs*7 was also validated.

Infant primary hyperoxaluria type 1: A case report and literature review. / å©´å„¿åŽŸå‘æ€§é«˜è‰é ¸å°¿ç—‡1型1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Primary hyperoxaluria (PH) is a rare autosomal recessive disorder, with PH type 1 (PH1) being the most common. It is primarily characterized by recurrent renal calculi, renal calcification, and can lead to acute renal failure. In infants, PH1 often results in early end-stage renal disease (ESRD) with a high mortality rate. This paper reports a case of an infant with acute renal failure in the Second Hospital of Shandong University who was diagnosed as PH1 using whole-exome sequencing, revealing a homozygous mutation in the AGXT gene (c.596-2A>G), which is reported here for the first time in the Chinese population. Previous literature indicates that urinary oxalate levels and stone composition can suggest PH1, with the gold standard for diagnosis being liver biopsy combined with alanine-glyoxylate aminotransferase (AGT) enzyme activity assessment. However, due to its convenience, AGXT gene sequencing has increasingly become the preferred diagnostic method. Conservative treatments for PH1 include adequate fluid intake, citrate, vitamin B6, and continuous renal replacement therapy, while liver transplantation is the only curative treatment. Infants with unexplained acute renal failure should be evaluated for PH1, with early detection of the level of urine oxalate and screening for genetic testing recommended.

Pediatric combined living donor liver and kidney transplantation for primary hyperoxaluria type 2.

We report the case of a 12-year-old boy with primary hyperoxaluria type 2 (PH2) presenting with end-stage renal disease and systemic oxalosis who underwent a combined living donor liver and kidney transplant from 3 donors, 1 of whom was a heterozygous carrier of the mutation. Plasma oxalate and creatinine levels normalized immediately following the transplant and remain normal after 18 months. We recommend combined liver and kidney transplantation as the preferred therapeutic option for children with primary hyperoxaluria type 2 with early-onset end-stage renal disease.

Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.

Lumasiran for Advanced Primary Hyperoxaluria Type 1: Phase 3 ILLUMINATE-C Trial.

RATIONALE & OBJECTIVE: Lumasiran reduces urinary and plasma oxalate (POx) in patients with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. ILLUMINATE-C evaluates the efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with PH1 and advanced kidney disease. STUDY DESIGN: Phase 3, open-label, single-arm trial. SETTING & PARTICIPANTS: Multinational study; enrolled patients with PH1 of all ages, estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (if age ≥12 months) or increased serum creatinine level (if age <12 months), and POx ≥20 µmol/L at screening, including patients with or without systemic oxalosis. INTERVENTION: Lumasiran administered subcutaneously; 3 monthly doses followed by monthly or quarterly weight-based dosing. OUTCOME: Primary end point: percent change in POx from baseline to month 6 (cohort A; not receiving hemodialysis at enrollment) and percent change in predialysis POx from baseline to month 6 (cohort B; receiving hemodialysis at enrollment). Pharmacodynamic secondary end points: percent change in POx area under the curve between dialysis sessions (cohort B only); absolute change in POx; percent and absolute change in spot urinary oxalate-creatinine ratio; and 24-hour urinary oxalate adjusted for body surface area. RESULTS: All patients (N = 21; 43% female; 76% White) completed the 6-month primary analysis period. Median age at consent was 8 (range, 0-59) years. For the primary end point, least-squares mean reductions in POx were 33.3% (95% CI, -15.2% to 81.8%) in cohort A (n = 6) and 42.4% (95% CI, 34.2%-50.7%) in cohort B (n = 15). Improvements were also observed in all pharmacodynamic secondary end points. Most adverse events were mild or moderate. No patient discontinued treatment or withdrew from the study. The most commonly reported lumasiran-related adverse events were injection-site reactions, all of which were mild and transient. LIMITATIONS: Single-arm study without placebo control. CONCLUSIONS: Lumasiran resulted in substantial reductions in POx with acceptable safety in patients with PH1 who have advanced kidney disease, supporting its efficacy and safety in this patient population. FUNDING: Alnylam Pharmaceuticals. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT04152200 and at EudraCT with study number 2019-001346-17. PLAIN-LANGUAGE SUMMARY: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive hepatic oxalate production that frequently causes kidney failure. Lumasiran is an RNA interference therapeutic that is administered subcutaneously for the treatment of PH1. Lumasiran has been shown to reduce oxalate levels in the urine and plasma of patients with PH1 who have relatively preserved kidney function. In the ILLUMINATE-C study, the efficacy and safety of lumasiran were evaluated in patients with PH1 and advanced kidney disease, including a cohort of patients undergoing hemodialysis. During the 6-month primary analysis period, lumasiran resulted in substantial reductions in plasma oxalate with acceptable safety in patients with PH1 complicated by advanced kidney disease.

Primary hyperoxaluria: Comprehensive mutation screening of the disease causing genes and spectrum of disease-associated pathogenic variants.

The primary hyperoxalurias are rare disorders of glyoxylate metabolism. Accurate diagnosis is essential for therapeutic and management strategies. We conducted a molecular study on patients suffering from recurrent calcium-oxalate stones and nephrocalcinosis and screened primary hyperoxaluria causing genes in a large cohort of early-onset cases. Disease-associated pathogenic-variants were defined as missense, nonsense, frameshift-indels, and splice-site variants with a reported minor allele frequency <1% in controls. We found pathogenic-variants in 34% of the cases. Variants in the AGXT gene causing PH-I were identified in 81% of the mutation positive cases. PH-II-associated variants in the GRHPR gene are found in 15% of the pediatric PH-positive population. Only 3% of the PH-positive cases have pathogenic-variants in the HOGA1 gene, responsible to cause PH-III. A population-specific AGXT gene variant c.1049G>A; p.Gly350Asp accounts for 22% of the PH-I-positive patients. Pathogenicity of the identified variants was evaluated by in-silico tools and ACMG guidelines. We have devised a rapid and low-cost approach for the screening of PH by using targeted-NGS highlighting the importance of an accurate and cost-effective screening platform. This is the largest study in Pakistani pediatric patients from South-Asian region that also expands the mutation spectrum of the three known genes.

HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships.

PURPOSE: The aim of our study is to describe the genetic features and correlation between the genotype and phenotype of Chinese patients with primary hyperoxaluria type 3 (PH3). METHODS: The genetic and clinical data of PH3 patients in our cohort were collected and analyzed retrospectively. All published studies of Chinese PH3 populations between January 2010 and November 2022 were searched and enrolled based on inclusive standards. RESULTS: A total of 60 Chinese PH3 patients (21 cases from our cohort and 39 cases from previous studies) were included. The mean age of onset was 1.62 ± 1.35 (range 0.4-7) years. A total of 29 different variants in the HOGA1 gene were found. The mutations were most commonly clustered in exons 1, 6, and 7. Among the genotypes, exon 6 skipping (c.834G > A and c.834_834 + 1GG > TT mutations) was the most common, followed by c.769 T > G; the allele frequencies (AFs) were 48.76% and 12.40%, respectively. Patients homozygous for exon 6 skipping exhibited a median age of onset of 0.67 (0.58-1) years, which was significantly lower than that observed among heterozygotes and nonexon 6 skipping patients (p = 0.021). A total of 22.5% (9/40) of PH3 patients had a decreased estimated glomerular filtration rate, and one patient with homozygous exon 6 skipping developed end-stage renal disease. CONCLUSIONS: A hotspot mutation, potential hotspot mutation and genotype-phenotype correlation were found in Chinese PH3 patients. This study expands the mutational spectrum and contributes to the understanding of genotypic profiles of PH3, which may provide a potential diagnostic and therapeutic target.

Clinical and molecular characterization of a large primary hyperoxaluria cohort from Saudi Arabia: a retrospective study.

BACKGROUND: Primary 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. METHODS: A 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. RESULTS: The 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%). CONCLUSIONS: Characterization of the genetic and clinical aspects of PH in this unique population provides direction for improved patient management and further research. A higher resolution version of the Graphical abstract is available as Supplementary information.

Three Tesla magnetic resonance imaging detects oxalate osteopathy in patients with primary hyperoxaluria type I.

BACKGROUND: With declining kidney function and therefore increasing plasma oxalate, patients with primary hyperoxaluria type I (PHI) are at risk to systemically deposit calcium-oxalate crystals. This systemic oxalosis may occur even at early stages of chronic kidney failure (CKD) but is difficult to detect with non-invasive imaging procedures. METHODS: We tested if magnetic resonance imaging (MRI) is sensitive to detect oxalate deposition in bone. A 3 Tesla MRI of the left knee/tibial metaphysis was performed in 46 patients with PHI and in 12 healthy controls. In addition to the investigator's interpretation, signal intensities (SI) within a region of interest (ROI, transverse images below the level of the physis in the proximal tibial metaphysis) were measured pixelwise, and statistical parameters of their distribution were calculated. In addition, 52 parameters of texture analysis were evaluated. Plasma oxalate and CKD status were correlated to MRI findings. MRI was then implemented in routine practice. RESULTS: Independent interpretation by investigators was consistent in most cases and clearly differentiated patients from controls. Statistically significant differences were seen between patients and controls (p < 0.05). No correlation/relation between the MRI parameters and CKD stages or Pox levels was found. However, MR imaging of oxalate osteopathy revealed changes attributed to clinical status which differed clearly to that in secondary hyperparathyroidism. CONCLUSIONS: MRI is able to visually detect (early) oxalate osteopathy in PHI. It can be used for its monitoring and is distinguished from renal osteodystrophy. In the future, machine learning algorithms may aid in the objective assessment of oxalate deposition in bone. Graphical Abstract A higher resolution version of the Graphical abstract is available as Supplementary information.