Diagnostic policies on nephrolithiasis/nephrocalcinosis of possible genetic origin by Italian nephrologists: a survey by the Italian Society of Nephrology with an emphasis on primary hyperoxaluria.

BACKGROUND: Primary hyperoxaluria is a genetic disorder of the metabolism of glyoxylate, the precursor of oxalate. It is characterized by high endogenous production and excessive urinary excretion of oxalate, resulting in the development of calcium oxalate nephrolithiasis, nephrocalcinosis, and, in severe cases, end-stage kidney disease and systemic oxalosis. Three different forms of primary hyperoxaluria are currently known, each characterized by a specific enzymatic defect: type 1 (PH1), type 2 (PH2), and type 3 (PH3). According to currently available epidemiological data, PH1 is by far the most common form (about 80% of cases), and is caused by a deficiency of the hepatic enzyme alanine:glyoxylate aminotransferase. METHODS: A survey on rare forms of nephrolithiasis and nephrocalcinosis with a focus on primary hyperoxaluria in the setting of Italian Nephrology and Dialysis Centers, using an online questionnaire, was recently conducted by the Project Group "Rare Forms of Nephrolithiasis and Nephrocalcinosis" of the Italian Society of Nephrology, with the aim of assessing the impact and management of this disorder in clinical practice in Italy. RESULTS: Forty-five public and private Italian Centers participated in the survey, and responses to the questionnaire were provided by 54 medical professionals. The survey results indicate that 21 out of the 45 participating Centers are managing or have managed primary hyperoxaluria patients, most of whom are on dialysis, or are recipients of kidney transplants. CONCLUSIONS: The data of this survey indicate the need to implement genetic testing in suspected cases of primary hyperoxaluria, not only in the setting of dialysis or transplantation, but also with the aim of encouraging early diagnosis of PH1, which is the only type of primary hyperoxaluria for which specific drug therapy is currently available.

Healthcare utilization, quality of life, and work productivity associated with primary hyperoxaluria: a cross-sectional web-based US survey.

Primary hyperoxaluria (PH) is a family of ultra-rare, autosomal recessive, metabolic disorders associated with frequent kidney stones, chronic kidney disease and kidney failure, and serious complications due to systemic oxalosis, resulting in significant morbidity. We investigated the burden of PH among affected patients and caregivers. This cross-sectional, web-based survey was used to quantify the burden of PH, in terms of healthcare resource utilization, health-related quality of life, and work productivity and activity impairment among adults (≥ 18 years) with PH and caregivers of children (≤ 17 years) with PH in the US. Among the 20 respondents, there were 7 adults with PH and 13 caregivers of children with PH. Adherence to hyperhydration was noted as the most, or one of the most, difficult aspects of PH by 56% of respondents. Most patients (95%) had experienced painful kidney stone events, one-third had visited the emergency room, and 29% were hospitalized for complications due to PH. Of the 24% of patients on dialysis, all found the procedure burdensome. Adult patients' quality of life was negatively affected across several domains. Most respondents (81%) reported that PH had a negative effect on their finances. Employed adult patients and caregivers, and children with PH, had moderate impairment in work productivity, school attendance, and activity. Anxiety about future PH-related sequelae was moderate to high. These findings highlight the need for improvements in PH medical management. A plain language summary is available in the supplementary information.

Characterization of Stone Events in Patients With Type 3 Primary Hyperoxaluria.

PURPOSE: Hallmarks of primary hyperoxaluria type 3 are nephrolithiasis and hyperoxaluria. However, little is known about factors influencing stone formation in this disease. We characterized stone events and examined associations with urine parameters and kidney function in a primary hyperoxaluria type 3 population. MATERIALS AND METHODS: We retrospectively analyzed clinical, and laboratory data of 70 primary hyperoxaluria type 3 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry. RESULTS: Kidney stones occurred in 65/70 primary hyperoxaluria type 3 patients (93%). Among the 49 patients with imaging available, the median (IQR) number of stones was 4 (2, 5), with largest stone 7 mm (4, 10) at first imaging. Clinical stone events occurred in 62/70 (89%) with median number of events per patient 3 (2, 6; range 1-49). Age at first stone event was 3 years (0.99, 8.7). Lifetime stone event rate was 0.19 events/year (0.12, 0.38) during follow-up of 10.7 (4.2, 26.3) years. Among 326 total clinical stone events, 139 (42.6%) required surgical intervention. High stone event rates persisted for most patients through the sixth decade of life. Analysis was available for 55 stones: pure calcium oxalate accounted for 69%, with mixed calcium oxalate and phosphate in 22%. Higher calcium oxalate supersaturation was associated with increased lifetime stone event rate after adjusting for age at first event (IRR [95%CI] 1.23 [1.16, 1.32]; P < .001). By the fourth decade, estimated glomerular filtration rate was lower in primary hyperoxaluria type 3 patients than the general population. CONCLUSIONS: Stones impose a lifelong burden on primary hyperoxaluria type 3 patients. Reducing urinary calcium oxalate supersaturation may reduce event frequency and surgical intervention.

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.

Clinical and molecular characterization of primary hyperoxaluria in Egypt.

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.

Primary hyperoxaluria and genetic linkages: an insight into the disease burden from Pakistan.

Autosomal recessive disorders are prevalent in Pakistan, a developing South Asian country where consanguineous marriages are common. This study seeks to determine the prevalence of monogenic causes in children presenting with nephrocalcinosis and nephrolithiasis at a dialysis and transplant center in Karachi, Pakistan. A retrospective analysis was conducted in children aged 1-18 years presenting with nephrocalcinosis, between 2010 and 2019. Demographic information, clinical profile, laboratory parameters and stone analysis were collected, on a pre-designed questionnaire. One hundred and twenty-six children were included, with 11 and 3 diagnosed with renal tubular acidosis and Bartter's syndrome respectively. Next-generation sequencing and Sanger sequencing was performed on 112 children. Eighty-seven patients were diagnosed with primary hyperoxaluria, with mutations in alanine-glyoxylate-aminotransferase gene found in 73, followed by glyoxylate reductase/hydroxy-pyruvate reductase in 13, and 4-hydroxy-2-oxaloglutarate aldolase in 1. Twenty-five patients reported negative for mutations. Sixty-four percent were males, with a statistically significant difference (p < 0.05). History of parental consanguineous marriage was found in 98% of the cohort. Fifty-four and 40 patients presented to the clinic with Chronic Kidney Disease Stage 1 and Stage 5, respectively, with a statistically significant difference p = 0.007. Mutations noted in our cohort are different and more severe than those reported in the developed world. The disease poses a major disease burden in developing world context with the only treatment option of combined liver-kidney transplantation not available in Pakistan.

Primary hyperoxaluria in Italy: the past 30 years and the near future of a (not so) rare disease.

BACKGROUND: Primary hyperoxalurias (PHs) are rare autosomal recessive diseases of the glyoxylate metabolism; PH1 is caused by mutations in the AGXT gene, PH2 in GRHPR and PH3 in HOGA1. METHODS: Here we report the first large multi-center cohort of Italian PH patients collected over 30 years (1992-2020 median follow-up time 8.5 years). Complete genotype was available for 94/95 PH1 patients and for all PH2 (n = 3) and PH3 (n = 5) patients. Symptoms at onset were mainly nephrolithiasis (46.3%) and nephrocalcinosis (33.7%). Median age at onset of symptoms and diagnosis were 4.0 years and 9.9 years, respectively. RESULTS: Fifty-four patients (56.8%) were diagnosed after chronic kidney disease. Sixty-three patients (66.3%) developed end stage kidney disease (median age 14.0 years). Twenty-one patients had a kidney-only transplant and, among them, seven had a second kidney transplant combined with liver transplant. A combined kidney-liver transplant was carried out in 29 patients and a sequential kidney-liver transplant was performed in two. In five cases a preemptive liver transplant was performed. Those receiving a liver-only transplant tended to have lower kidney function at last follow-up. CONCLUSION: Our study of PHs in Italy underlines a considerable diagnostic delay, which has only slightly decreased in recent years. Therefore, we suggest a more extensive use of both metabolic screening among patients with recurrent kidney stones and genotyping, including unambiguous assignment of minor/major allele status in order to promptly begin appropriate treatment. This will be fundamental in order to have access to the new therapies, which are mainly focused on substrate reduction for the oxalate-producing enzymes using RNA-interference.

Clinical and economic impact of primary hyperoxaluria: a retrospective claims analysis.

BACKGROUND: Primary hyperoxaluria (PH) is a family of rare, life-threatening genetic liver disorders characterized by elevated production and excretion of oxalate. To date, the clinical and economic burden associated with PH has not been well characterized due to the rarity of the disease and previous challenges with diagnostic coding that prevented proper identification of patients with PH in claims data. OBJECTIVE: To characterize the clinical and economic costs, as well as health care resource utilization (HCRU), associated with PH relative to a matched cohort of patients without PH. METHODS: Data from the IQVIA PharMetrics Plus Database were used to conduct a retrospective matched-cohort study to compare differences in clinical characteristics, HCRU, and pharmacy and medical costs in patients with PH compared with a matched cohort of patients without PH from January 2014 to December 2019. RESULTS: Overall, 324 patients were included in the PH cohort and 1,620 patients were in the non-PH cohort. The mean age of PH patients was 48.1 years, and approximately 58% of the sample were male. Significantly more patients in the PH cohort than the non-PH cohort were diagnosed with stage 2 chronic kidney disease (CKD; 3.1% vs 0.4%, respectively; P < 0.001), stage 3 CKD (4.6% vs 0.5%; P < 0.001), stage 4 CKD (2.5% vs 0.1%; P < 0.001), and stage 5 CKD or end-stage renal disease (ESRD; 2.2% vs 0.1%; P < 0.001). PH patients had a significantly higher mean Charlson Comorbidity Index composite score than patients in the non-PH cohort (0.79 vs 0.37; P < 0.001). HCRU was significantly higher in patients with PH. The PH cohort had a significantly higher proportion of patients with at least 1 visit to clinicians specializing in nephrology (19% vs 0.4%, respectively; P < 0.001), cardiology (22% vs 12%; P < 0.001), ophthalmology (16% vs 7%; P < 0.001), general surgery (9% vs 6%; P = 0.011), and urology (65% vs 6%; P < 0.001) compared with patients without PH. Mean total annual health care costs in the PH cohort were 65% higher than in the non-PH cohort ($22,549 vs $7,852, respectively; P < 0.001). Similar results were found for total prescription drug costs ($4,125 vs $2,464; P = 0.012). CONCLUSIONS: Despite the rarity of PH, patients with this disease incur substantial clinical and economic burden and may cause financial strain on the health care system. Additional research is warranted to understand the economic and clinical burden of PH stratified by the 3 subtypes of the disease. DISCLOSURES: Funding for this research was provided by Dicerna Pharmaceuticals. Mucha and Hoppe are employed by Dicerna Pharmaceuticals. Silber Miyasoto, Skaar, and Wang are employed by Trinity Life Sciences, which was contracted by Dicerna Pharmaceuticals to conduct the study analysis. Langman is consultant to Dicerna Pharmaceuticals. This study was presented as a poster at the AMCP Nexus 2020 (virtual), October 19-23, 2020, and American Society of Nephrology 2020 (virtual), October 19-25, 2020.

Posttransplant recurrence of calcium oxalate crystals in patients with primary hyperoxaluria: Incidence, risk factors, and effect on renal allograft function.

Primary hyperoxaluria (PH) is a metabolic defect that results in oxalate overproduction by the liver and leads to kidney failure due to oxalate nephropathy. As oxalate tissue stores are mobilized after transplantation, the transplanted kidney is at risk of recurrent disease. We evaluated surveillance kidney transplant biopsies for recurrent calcium oxalate (CaOx) deposits in 37 kidney transplants (29 simultaneous kidney and liver [K/L] transplants and eight kidney alone [K]) in 36 PH patients and 62 comparison transplants. Median follow-up posttransplant was 9.2 years (IQR: [5.3, 15.1]). The recurrence of CaOx crystals in surveillance biopsies in PH at any time posttransplant was 46% overall (41% in K/L, 62% in K). Higher CaOx crystal index (which accounted for biopsy sample size) was associated with higher plasma and urine oxalate following transplant (p < .01 and p < .02, respectively). There was a trend toward higher graft failure among PH patients with CaOx crystals on surveillance biopsies compared with those without (HR 4.43 [0.88, 22.35], p = .07). CaOx crystal deposition is frequent in kidney transplants in PH patients. The avoidance of high plasma oxalate and reduction of CaOx crystallization may decrease the risk of recurrent oxalate nephropathy following kidney transplantation in patients with PH. This study was approved by the IRB at Mayo Clinic.

A report from the European Hyperoxaluria Consortium (OxalEurope) Registry on a large cohort of patients with primary hyperoxaluria type 3.

Outcome data in primary hyperoxaluria type 3 (PH3), described as a less severe form of the PH's with a low risk of chronic kidney disease, are scarce. To investigate this, we retrospectively analyzed the largest PH3 cohort reported so far. Of 95 patients, 74 were followed over a median of six years. Median age of first symptoms and diagnosis were 1.9 and 6.3 years, respectively. Urolithiasis was the major clinical feature observed in 70% of pediatric and 50% of adult patients. At most recent follow-up available for 56 of the 95 patients, 21.4% were in chronic kidney disease stages 2 or more. For better characterization, samples from 49 patients were analyzed in a single laboratory and compared to data from patients with PH1 and PH2 from the same center. Urinary oxalate excretion was not significantly different from PH1 and PH2 (median: 1.37, 1.40 and 1.16 mmol/1.73m2/24hours for PH1 not responsive to vitamin B6, PH2, and PH3, respectively) but was significantly higher than in vitamin B6 responsive patients with PH1. Urinary oxalate excretion did not correlate to stone production rate nor to estimated glomerular filtration rate. Normocitraturia was present even without alkalinisation treatment; hypercalciuria was found rarely. Median plasma oxalate was significantly different only to the vitamin B6-unresponsive PH1 group. Thus, PH3 is more comparable to PH1 and PH2 than so far inferred from smaller studies. It is the most favorable PH type, but not a benign entity as it constitutes an early onset, recurrent stone disease, and kidney function can be impaired.

Clinical analysis of 13 children with primary hyperoxaluria type 1.

A retrospective statistical analysis of primary hyperoxaluria type 1 (PH1) in children from June 2016 to May 2019 was carried out to discover its clinical and molecular biological characteristics. Patients were divided into two groups (infant and noninfant) according to clinic type. There were 13 pediatric patients (male:female = 6:7) with PH1 in the cohort from 11 families (four of which were biological siblings from two families), whose median age of symptom onset was 12 months and median confirmed diagnosis age was 14 months. Infant type (6 patients) was the most common type. The infant type mortality rate (100%) was higher than the noninfant (14.3%) (p = 0.029). The incidence of renal failure in infant patients was 67%, while the noninfant was 14.3%. 8 of 10 patients with nephrocalcinosis (NC) (76.92%, 10/13) were diagnosed by radiological imaging examinations, including X-ray (3 patients), CT (4 patients) and MRI (1 patient). NC was an independent risk factor for renal insufficiency [OR 3.33, 95% CI (0.7-1.2)], p < 0.05). Nine types of AGXT gene mutations were found; 1 type, c.190A > T, were first reported here. The most common AGXT gene mutation was c.679_680del, which occurred in exon 6 (5 patients). The infant type is the most common type of pediatric PH, with a relatively higher ratio of renal failure at symptom onset and poor prognosis. NC is an independent risk factor leading to renal failure, and radiological imaging examination is recommended for patients with abnormal ultrasound examination to identify NC. AGXT gene detection is important for the diagnosis and treatment of PH1 in children.

Still diagnosed too late and under-recognized? The first comprehensive report on primary hyperoxaluria in Poland.

INTRODUCTION: Primary hyperoxalurias (PHs) are rare disorders leading to overproduction and increased urinary excretion of oxalate. Three monogenic forms (PH1-PH3) were classified. PHs lead to urolithiasis and chronic kidney disease. There are only sparse data on patients with PH from Eastern European countries including Poland. OBJECTIVES: The aim of the study was to evaluate the prevalence, genetic background, and clinical course of PH in the Polish population. PATIENTS AND METHODS: This was a retrospective multicenter study including data of all identified and genetically confirmed Polish patients with PH. RESULTS: Between 1998 and 2019, 21 patients with PH were identified, including 13 patients with PH1 (62%), 2 with PH2 (9%), and 6 with PH3 (29%). In those with PH1, the most common mutation was c.508G>A in AGXT and in PH3, c.700+5G>T in HOGA1. Nine patients (69%) developed end­stage renal disease at a median age of 13 years and 2 died. In 6 (46%) PH1 cases, the diagnosis was made only after patients had progressed to end­stage renal disease and received isolated kidney transplantation, followed by graft failure. Combined liver­kidney transplantation was performed in 6 patients with PH1. Two siblings with PH2 showed a milder course with slightly decreased renal function in one, at age of 11 years. Despite infantile onset of urolithiasis, all patients with PH3 at a median age of 10 years maintained normal renal function. CONCLUSIONS: The prevalence of PH1 and PH2 in Poland seems to be much lower than in Western countries with PH3 constituting about 30% of all cases. The molecular findings and clinical course are typical, but the underdiagnosis is of concern.

NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results - a pilot study.

BACKGROUND: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). METHODS: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary. RESULTS: Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West. CONCLUSION: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.

Clinical features of genetically confirmed patients with primary hyperoxaluria identified by clinical indication versus familial screening.

Primary hyperoxaluria is a rare monogenic disorder characterized by excessive hepatic production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis, and progressive kidney damage. Most patients with primary hyperoxaluria are diagnosed after clinical suspicion based on symptoms. Since some patients are detected by family screening following detection of an affected family member, we compared the clinical phenotype of these two groups. Patients with primary hyperoxaluria types 1, 2, and 3 enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria Registry were retrospectively analyzed following capture of clinical and laboratory results in the Registry. Among 495 patients with primary hyperoxaluria, 47 were detected by family screening. After excluding 150 patients with end stage kidney disease at diagnosis, 300 clinical suspicion and 45 family screening individuals remained. Compared to patients with clinical suspicion, those identified by family screening had significantly fewer stones at diagnosis (mean 1.2 vs. 3.6), although initial symptoms occurred at a similar age (median age 6.1 vs. 7.6 years). Urinary oxalate did not differ between these groups. The estimated glomerular filtration rate at diagnosis and its decline over time were similar for the two groups. Altogether, five of 45 in family screening and 67 of 300 of clinical suspicion individuals developed end stage kidney disease at last follow-up. Thus, patients with primary hyperoxaluria identified through family screening have significant disease despite no outward clinical suspicion at diagnosis. Since promising novel treatments are emerging, genetic screening of family members is warranted because they are at significant risk for disease progression.

Patients with primary hyperoxaluria type 2 have significant morbidity and require careful follow-up.

Primary hyperoxaluria type 2 is a rare inherited disorder of glyoxylate metabolism causing nephrocalcinosis, renal stone formation and ultimately kidney failure. Previously, primary hyperoxaluria type 2 was considered to have a more favorable prognosis than primary hyperoxaluria type 1, but earlier reports are limited by low patient numbers and short follow up periods. Here we report on the clinical, genetic, and biochemical findings from the largest cohort of patients with primary hyperoxaluria type 2, obtained by a retrospective record review of genetically confirmed cases in the OxalEurope registry, a dataset containing 101 patients from eleven countries. Median follow up was 12.4 years. Median ages at first symptom and diagnosis for index cases were 3.2 years and 8.0 years, respectively. Urolithiasis was the most common presenting feature (82.8% of patients). Genetic analysis revealed 18 novel mutations in the GRHPR gene. Of 238 spot-urine analyses, 23 (9.7%) were within the normal range for oxalate as compared to less than 4% of 24-hour urine collections. Median intra-individual variation of 24-hour oxalate excretion was substantial (34.1%). At time of review, 12 patients were lost to follow-up; 45 of the remaining 89 patients experienced chronic kidney disease stage 2 or greater and 22 patients had reached stage 5. Median renal survival was 43.3 years, including 15 kidney transplantations in 11 patients (1 combined with liver transplantation). Renal outcome did not correlate with genotype, biochemical parameters or initially present nephrocalcinosis. Thus, primary hyperoxaluria type 2 is a disease with significant morbidity. Accurate diagnosis by 24-hour urine analysis and genetic testing are required with careful follow-up.

Mutation Hot Spot Region in the HOGA1 Gene Associated with Primary Hyperoxaluria Type 3 in the Chinese Population.

BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder that affects glyoxylate metabolism. PH3 is caused by defects in 4-hydroxy-2-oxoglutarate aldolase, which is encoded by the HOGA1 gene. However, only 3 cases of PH3 have been described in Asians until today. This study aimed to determine the clinical and mutation spectra of patients from mainland China with PH3. METHODS: We applied targeted next-generation sequencing to four non-consanguineous, unrelated Chinese families with PH3 to identify the genes hosting disease-causing mutations. This approach was confirmed by Sanger sequencing. RESULTS: Five patients (2 boys and 3 girls) from four unrelated Chinese families were admitted because of kidney stones. Five HOGA1 gene sequence mutations were detected, including two novel mutations, c.811C>T (p.R271C) and c.812G>A (p.R271H). These compound heterozygous mutations were detected in a female PH3 patient (patient 4). Other patients included 2 boys who had heterozygous c.834_834+1GG>TT and c.834G>A (p.A278A) mutations (patients 1 and 2), a girl with homozygous c.834G>A (p.A278A) mutation (patient 3), and a girl with heterozygous c.834_834+1GG>TT and c.346C>T (p.Q116X) mutations (patient 5). The mutations in the c.834_834+1 region, including c.834G>A, c.834+1G>T, and c.834_834+1GG>TT, account for 5/8 of alleles in our study and 3/4 of alleles reported among Chinese patients. All patients in this study received hyperhydration and urine alkalinization treatment. CONCLUSION: Five PH3 cases were reported. Potential mutation hot spot region (c.834_834+1) in the Chinese population and two novel mutations were found.

[Genetic aspects of primary hyperoxaluria: epidemiology, ethiology, pathogenesis, and clinical signs of the disorder].

Primary hyperoxaluria is a group of rare inherited diseases characterized by impaired oxalate metabolism with the early manifestation of urolithiasis and the development of the chronic kidney disease. The mutations in the AGXT, GRHPR, HOGA1 genes are attributable for different types of primary hyperoxaluria leading to the dysfunction of specific enzymes involved in the oxalate metabolism. The article summary the current data on the epidemiology, genetic and biochemical aspects of pathogenesis of the primary hyperoxaluria types 1-3. The variety of clinical signs and disease severity depend on the type of hyperoxaluria.

Congenital and acquired diseases related to stone formation.

PURPOSE OF REVIEW: To summarize the latest findings of congenital and acquired diseases related to stone formation and help understanding the multitude of cofactors related to urolithiasis. RECENT FINDINGS: Urolithiasis is related to a broad spectrum of congenital and acquired diseases and its management varies according to the stone type, underlying disease or recurrence rate, but it also changes according to recent findings and developments. As prevalence of urolithiasis is constantly increasing, identification of high-risk stone formers and early treatment is essential. Therefore, genetic evaluation like whole exome sequencing becomes a pertinent part of further diagnostics. SUMMARY: Stone formation is a very heterogeneous pathomechanism. This prompt us to look at every patient individually particularly in high-risk patients, including stone and 24-h-urine analysis and additional diagnostic work-up based on stone type or underlying disease.

Mutational analysis of AGXT gene in Libyan children with primary hyperoxaluria type 1 at Tripoli Children Hospital.

Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism. It results from genetic mutation of the AGXT gene. The study objective was to verify the clinical and epidemiological patterns of PH1 in Libyan children at Tripoli Children Hospital confirmed by AGXT gene mutation. A descriptive case series study of 53 children with PH1 diagnosed between 1994 and 2015 was carried out in the Nephrology Unit at Tripoli Children Hospital. Diagnosis of PH1 was based on the clinical presentation (renal stones or nephrocalcinosis), positive family history of PH1, and high 24 h urinary oxalate. Sampling for AGXT gene mutation was collected from April 2012 to December. 2015. Among the 53 children included, males composed of 62.3% of patients. Their age at presentation ranged between two months and 20 years with a mean age of 55.4 ± 48 months. The parents of 81.1% of these patients had positive consanguinity. Forty (75.5%) patients were from South West (mountain area), and 16 (40%) of them were from Yefrin. The most common mutation found in this study was c.731T>C (p.lle244thr) seen in 32 (71%) of children, and interestingly, among these patients, 87.1% were homozygous in gene typing, 86.2% had positive history of consanguinity, 71.4% were from South West (mountain area), 96.6% had family history of PH1, and 20% presented with impaired renal function. The patients with this mutation were younger at presentation than that with other genes, and it was more prevalent among boys (61.3%). Thus, the most common gene mutation found in Libyan children with PH1 was c.731T>C (p.lle244thr) and this is more likely due to the strong genetic pooling caused by the high consanguinity rate which requires an extensive genetic counseling.

Primary hyperoxaluria in populations of Pakistan origin: results from a literature review and two major registries.

Primary hyperoxalurias (PH) are devastating, autosomal recessive diseases causing renal stones. Undifferentiated hyperoxaluria is seen in up to 43% of Pakistani paediatric stone patients. High rates of consanguinity in Pakistan suggest significant local prevalence. There is no detailed information regarding number of cases, clinical features, and genetics in Pakistan-origin (P-o) patients. We reviewed available information on P-o PH patients recorded in the literature as well as from two major PH registries (the Rare Kidney Stone Consortium PH Registry (RKSCPHR) and the OxalEurope PH Registry (OxER); and the Aga Khan University Hospital in Pakistan. After excluding overlaps, we noted 217 P-o PH subjects (42 in OxER and 4 in RKSCPHR). Presentations were protean. Details of mutations were available for 94 patients of 201 who had genetic analyses. Unique mutations were noted. Mutation [c.508G>A (p. Gly170Arg)] (present in up to 25% in the West) was reported in only one case. In one series, only 30% had mutations on exons 1,4,7 of AGXT. Of 42 P-o patients in OxER, 52.4% were PH1, 45.2% PH2, and 2.4% PH3. Of concern is that diagnosis was made after renal transplant rejection (four cases) and on bone-marrow aspiration (in five). Lack of consideration of PH as a diagnosis, late diagnosis, and loss of transplanted kidneys mandates that PH be searched for diligently. Mutation analysis will need to extend to all exons and include PH 1,2,3. There is a need to spread awareness and identify patients through a scoring or screening system that alerts physicians to consider a diagnosis of PH.