Child Kidney Dis > Volume 23(2); 2019 > Article
Choe, Lee, Kim, Cho, Kim, Lee, Park, Kang, Ha, and Cheong: Primary Hyperoxaluria in Korean Pediatric Patients

Abstract

Background

Primary hyperoxaluria (PH), a rare inborn error of glyoxylate meta bolism causing overproduction of oxalate, is classified into three genetic subgroups: type 1–3 (PH1–PH3) caused by AGXT, GRHPR, and HOGA1 gene mutations, respectively. We performed a retrospective case series study of Korean pediatric patients with PH.

Methods

In total, 11 unrelated pediatric patients were recruited and their phenotypes and genotypes were analyzed by a retrospective review of their medical records.

Results

Mutational analyses revealed biallelic AGXT mutations (PH1) in nine patients and a single heterozygous GRHPR and HOGA1 mutation in one patient each. The c.33dupC was the most common AGXT mutation with an allelic frequency of 44%. The median age of onset was 3 months (range, 2 months–3 years), and eight patients with PH1 presented with end stage renal disease (ESRD). Patients with two truncating mutations showed an earlier age of onset and more frequent retinal involvement than patients with one truncating mutation. Among eight PH1 patients presenting with ESRD, five patients were treated with intensive dialysis followed by liver transplantation (n=5) with/without subsequent kidney transplantation (n=3).

Conclusion

Most patients presented with severe infantile forms of PH. Patients with two truncating mutations displayed more severe phenotypes than those of patients with one truncating mutation. Sequential liver and kidney transplantation was adopted for PH1 patients presenting with ESRD. A larger nation-wide multicenter study is needed to confirm the genotype-phenotype correlations and outcomes of organ transplantation.

Introduction

Primary hyperoxaluria (PH) is a rare autosomal recessive inborn error of glyoxylate metabolism that results in endogenous overproduction of oxalate [1]. PH is a genetically and clinically heterogeneous disease and is classified into three subgroups.
PH type 1 (PH1), the most frequent and severe subgroup accounting for the majority of cases, is caused by mutations in AGXT, which encodes the peroxisomal liver-specific enzyme alanine-glyoxylate aminotransferase (AGT) [2]. AGT catalyzes the conversion of glyoxylate to glycine. Defective function of AGT results in conversion of glyoxylate to oxalate, which accumulates in the kidneys and other organs by forming insoluble calcium oxalate salts. Progressive renal deposition of calcium oxalate results in urolithiasis and/or nephrocalcinosis, followed by renal failure. Excessive blood levels of oxalate may lead to systemic oxalosis with oxalate deposition predominantly in the bone, skin, retina, myocardium, vessel walls, and the central nervous system. PH type 2 (PH2) is caused by mutations in GRHPR , which encodes glyoxylate reductasehydroxypyruvate reductase (GRHPR) [3]. GRHPR catalyzes the reduction of glyoxylate to glycolate. Functional deficiency of GRHPR results in abnormally increased metabolism of glyoxylate to oxalate by lactate dehydrogenase. PH type 3 (PH3) is caused by mutations in HOGA1 , which encodes the liver-specific mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (HOGA) [4]. It is unclear why defective HOGA causes oxalate accumulation.
Combined liver and kidney transplantation is the treatment of choice in patients with PH1, whereas isolated kidney transplantation is recommended for patients with PH2. Neither kidney nor liver transplantation is required in patients with PH3, as none of the patients with PH3 have been reported to develop end-stage renal disease (ESRD) [5].
Although there have been several case reports of PH in Korea [6,7], systematic studies have not been reported yet. Herein we report 11 cases of Korean patients with PH, with retrospective analyses of genotype-phenotype correlations and the outcome of combined liver and kidney transplantation in five patients.

Materials and methods

In total, 11 pediatric patients who were diagnosed with PH during the period from December 2008 to July 2018 at three tertiary care centers (Seoul National University Children’s Hospital Seoul, Korea, Asan Medical Center, Seoul, Korea, and Pusan University Children’s Hospital, Yangsan, Korea) were recruited. All patients were non-consanguineous Koreans, except for one patient (Patient 8) who had a Korean mother and Taiwanese father. Diagnosis of PH was based on increased urinary excretion levels of oxalate [5] and/or presence of genetic mutations in one of the three candidate genes, i.e., AGXT for PH1, GRHPR for PH2, and HOGA1 for PH3. Genomic DNAs of the patients and their available family members were isolated from their peripheral blood leukocytes. Entire coding regions of the three genes were amplified via polymerase chain reaction and sequenced directly. All the primers for polymerase chain reaction were designed to start from intronic sequences, and the primer sequences are available upon request.
1. Ethics statement
This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. 0812-002-264). The patients and/or their parents provided informed consent to participate in this study.

Results

1. Genotypes

Mutational analyses revealed compound heterozygous or homozygous mutations in AGXT in nine patients. The remaining two patients carried a single heterozygous mutation in GRHPR and HOGA1 , respectively. Among 10 different AGXT mutations, 6 were truncating mutations. The c.33dupC mutation in AGXT was common with an allele frequency of 8/18 (44.4%) (Table 1).

2. Phenotypes

The clinical features and disease courses of the patients are summarized in Table 2. Among 11 patients in this study, 10 patients were boys and one patient with AGXT mutation was a girl. The median age of onset was 3 months (range, 2 months–3 years), and eight patients developed renal symptoms at the age of 5 months or younger. Eight patients with PH1 already had ESRD at initial presentation, and three patients presented with nephrolithiasis with/without gross hematuria. A family history of renal diseases was positive in two patients: Patient 7 had a grand-uncle who had ESRD of unknown causes, and Patient 9 had a grand-uncle who had an episode of spontaneous passage of a urinary stone. Urinary oxalate excretion levels were higher in two non-PH1 patients than in patients with PH1. This difference may be caused by different renal functions between both groups of patients. Nephrocalcinosis was detected in all patients on kidney ultrasonography and/or CT scan., except for Patient 9 who presented with nephrolithiasis, and nephrolithiasis was accompanied in five patients (Fig.1). Six patients with PH1 had retinal involvement (Fig.2), indicating systemic oxalosis.

3. Genotype-phenotype correlations

Among the nine patients with PH1, five patients (Patients 1, 3–5, and 7) had truncating mutations in both alleles, and four patients (Patients 2, 6, 8, and 9) had one truncating mutation in one allele and one missense mutation in the other allele. All patients with two truncating mutations showed early onset ages (≤5 months of age), whereas two of four patients with one truncating mutation showed older ages of onset at 2 years and 3 years, respectively. Retinal involvement indicating systemic oxalosis was detected in all patients with two truncating mutations, but in two of four patients with one truncating mutation. All patients with PH1 had ESRD at onset, except for Patient 9 who had one truncating mutation and presented with recurrent nephrolithiasis without renal functional impairment.

4. Disease courses

In four patients (Patients 1–3, and 7), pyridoxine therapy was initially started with dialysis, but was discontinued after the genetic diagnosis, which showed that their genotypes were expected to indicate pyridoxine non-responsiveness.
Among the eight PH1 patients who presented with ESRD, five patients were initially treated with combined hemodialysis and nocturnal peritoneal dialysis to maximize oxalate removal, and three patients were treated with hemodialysis or peritoneal dialysis. Later, five patients (Patients 1–5) underwent liver transplantation with/without subsequent kidney transplantation (n=3). Patient 1 underwent deceaseddonor liver transplantation at the age of 4 months. However, he developed fulminant sepsis due to surgical wound problems and died on the 51st postoperative day. Patient 2 underwent deceased-donor liver transplantation at the age of 6 years but developed primary graft non-function. He received a second liver transplantation from his mother soon thereafter. He is currently waiting for kidney transplantation while on hemodialysis. Patient 3 received deceased-donor liver transplantation at the age of 3 years followed by a living-donor kidney transplantation from his mother 3 months later. However, the graft kidney was lost due to primary graft non-function and again underwent a second kidney transplantation from a deceaseddonor. Currently, he has chronic kidney disease (CKD) stage 3 without dialysis. Patient 4 received deceased-donor liver transplantation at the age of 1 year followed by a deceased-donor kidney transplantation at the age of 5 years. Currently, his estimated glomerular filtration rate (eGFR calculated using the Schwartz formula) is 90.3 ml/min/1.73 m2. Patient 5 received deceased-donor liver transplantation followed by a deceased-donor kidney transplantation at the age of 6 months and 2 years, respectively. Currently, he has CKD stage 2. Among the remaining four patients with PH1, three patients (Patients 6–8) are waiting for organ transplantation while on dialysis. Patient 9 maintains normal renal function although he had recurrent episodes of nephrolithiasis despite oral potassium citrate medication.
Patient 10 with non-PH1 presented with gross hematuria on the diaper at the age of 2 years. Kidney ultrasonography showed medullary nephrocalcinosis with multiple renal stones. He was prescribed high fluid intake and oral potassium citrate, and the latest kidney ultrasonography showed persistent medullary nephrocalcinosis without recurrence of nephrolithiasis. Patient 11 with non-PH1 presented with a staghorn stone in the right kidney with hydrouretronephrosis. He underwent percutaneous nephrostomy, and chemical analysis revealed that the stone was composed of 80% calcium oxalate, 10% carbonate apatite, and 10% struvite. Nephrolithiasis did not recur on oral potassium citrate medication and his renal function is maintained normally.

Discussion

This study showed a case series of 11 Korean pediatric cases, including nine cases with a genetic diagnosis of PH1. The estimated prevalence of PH1 has been reported to be 1–3 per million populations in Europe,8,9 and PH1 accounts for 0.5–2% of pediatric ESRD in Europe, North America, and Japan [10-12]. The prevalence of PH1 is higher in Mediterranean consanguineous populations, and the proportion of PH1 as a cause of pediatric ESRD is 10% in Kuwait [13] and 13% in Tunisia [14]. There have been no data on large cohorts except a few case reports of PH in Korea so far [6,7]. Although we did not analyze the prevalence of PH1, given that the patients in our study were limited to pediatric cases from three tertiary centers in Korea with a total population of approximately 50 million, the prevalence of PH1 in Korea might be similar to that in Western countries. In addition, PH1 accounts for 0.9% of pediatric ESRD according to the data of the chronic kidney disease registry of the Korean Society of Pediatric Nephrology (not published data). The marked male preponderance in our study is not explained.
In our study, 10 different AGXT mutations were detected, including a novel mutation, c.681-1G>A in intron 6. The GRHPR mutation (c.181G>A, p.Asp61Asn, rs371660673) detected in Patient 10 was predicted to be disease-causing by MutationTaster (http://www.mutationtaster.org/), and the minor allele frequency was reported to be 0.00005/6 on ExAC Browser (http://exac.broadinstitute.org/), 0.00008/1 on GO-ESP (http://evs.gs.washington.edu/EVS/), and 0.000008/1 on TOPMED (https://www.nhlbi.nih.gov/science/trans-omics-precision-medicine-topmed-program). The HOGA1 mutation (c.812G>A, p.Arg271His) detected in Patient 11 was also predicted to be diseasecausing by MutationTaster, and the minor allele frequency was reported to be 2/7524 in East Asians and 4/103800 in the total population on the ExAC Browser. However, a genetic diagnosis of Patients 10 and 11 was not confirmed because they only carried a single heterozygous mutation.
The most commonly detected AGXT mutation in our study was c.33dupC mutation with an allelic frequency of 44%. The run of eight cytosine residues (c.26_33) in exon 1 is known to be particularly prone to deletion/insertion mutations. Accordingly, c.33dupC mutation has been known as one of the three most common mutations across populations, p.Gly170Arg, c.33dupC, and p.Ile244Thr. However, the allele frequency of the c.33dupC mutation in our study was much higher than that in other studies (11–15% of total AGXT mutant alleles) [15,16]. In addition, the p.Gly170Arg mutation, which is the most common mutation occurring at a frequency of approximately 30% [15,16] and shows responsiveness to pyridoxine [17,18], was not detected in our study.
Several studies have reported the possible association of homozygous c.33dupC mutation with poor prognosis, including earlier onset and more rapid progression to ESRD, in accordance with the complete lack of AGT protein [15,18-20]. However, there is a marked intra- and inter-familial phenotypic heterogeneity in families with homozygous c.33dupC mutation from ESRD in infancy to PH diagnosed in the second or third decade of life [21,22]. In our study, although the number of total patients was too small, patients with two truncating mutations including c.33dupC mutation, showed earlier ages of onset and more frequent retinal involvement than patients with one truncating mutation.
There has been no clear genotype–phenotype correlation in PH1, except for pyridoxine responsiveness in some patients with PH1, particularly in those with homozygous p.Gly170Arg or Phe152Ile mutations [17,19]. Pyridoxine, vitamin B6, is a known cofactor of AGT and is effective in reducing urine oxalate excretion in about a third of PH1 patients [23]. Unfortunately, none of the patients in our study had p.Gly170Arg or p.Phe152Ile mutations.
Renal damage is inevitable in most patients with PH1 and ultimately progresses to ESRD. When the GFR drops to 30–45 mL/min/1.73 m2, the kidney is unable to excrete the oxalate load effectively and oxalate is subsequently deposited in all tissues (systemic oxalosis) [24]. Since conventional hemodialysis and peritoneal dialysis do not eliminate sufficient amounts of oxalate, more intensive strategies such as short daily sessions of high-flux dialysis, nocturnal dialysis, or combinations of hemodialysis and nocturnal peritoneal dialysis, must be used to avert a continuous positive balance of oxalate and to limit systemic oxalosis [25]. For patients before reaching CKD stage 4, preemptive liver transplantation to avoid the complications of systemic oxalosis would be a logical approach [26]. However, this approach raises ethical issues given the risk of graft failure and death associated with the procedure [27]. Isolated kidney transplantation to correct ESRD in PH1 is frequently followed by recurrence of the disease in the graft kidney since the liver is the site of the metabolic defect. Therefore, combined liver and kidney transplantation is a reasonable choice for these patients, although kidney transplantation alone may be considered on an individual basis such as in adults with confirmed responsiveness to pyridoxine [1,10]. While dual transplantation is a reasonable choice for patients with CKD stage 4, sequential liver and kidney transplantation for patients with CKD stage 5 has the advantage that it provides sufficient time for the use of aggressive dialysis, which may mobilize some of the systemic oxalate burden and protect the kidney to be transplanted subsequently [1,28,29]. In our study, we adopted sequential liver and kidney transplantation for eight patients presenting with ESRD: three patients have already undergone this procedure and the rest are waiting for organ donation. According to the European pediatric registry [10], the 5-year survival rate for kidney transplantation alone and dual kidney and liver transplantation in children with PH was 14% and 76%, respectively
There is a limited experience with organ transplantation in patients with PH2. Although the ubiquitous tissue distribution of GRHPR favors kidney transplantation, some transplant recipients have undergone oxalate-related graft loss [5]. PH3 has not been associated with ESRD thus far, but there have been a couple of cases with impaired renal function [30].
In conclusion, the estimated prevalence of PH1 in Korea was similar to that reported in other studies from Europe, North America, and Japan. The c.33dupC was the most common AGXT mutation with an allelic frequency of 44%. The median age of onset was 3 months, and eight patients with PH1 already had ESRD at initial presentation. Although the number of total patients was too small, patients with two truncating mutations showed earlier ages of onset and more frequent retinal involvement than patients with one truncating mutation. Sequential liver and kidney transplantation was adopted for PH1 patients presenting with ESRD. A major limitation of this study was the small number of subjects. Therefore, a larger, nation-wide, multicenter study is needed.

Notes

Author Contributions
Conceptualization: Cheong HI. Methodology: Choe Y, Kim JH, Lee JH, Park YS, Kang HG, Ha IS. Formal analysis: Choe Y, Lee JM, Kim JH, Kim SH, Lee JH, Kang HG. Data curation: Lee JM, Cho MH, Park YS. Validation: Cho MH, Kim SH, Park YS, Ha IS, Cheong HI. Investigation: Kim JH, Cho MH, Cheong HI. Writing - original draft preparation: Choe Y, Lee JM. Writing - review and editing: Kim SH, Lee JH, Park YS, Kang HG, Ha IS, Cheong HI. Approval of final manuscript: all authors.
Patient consent
This study was approved by the institutional review board (IRB), and the consent was waived due to the nature of the retrospective study [IRB number 1812-002-264].
Conflict of interest
No potential conflict of interest relevant to this article was reported.

Acknowledgement

This research was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number : HI18C0013).

References

1. Cochat P, Rumsby G. Primary hyperoxaluria. N Engl J Med 2013;369:649-58.
crossref pmid
2. Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 1990;111(6 Pt 1):2341-51.
crossref pmid pmc
3. Cramer SD, Ferree PM, Lin K, Milliner DS, Holmes RP. The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II. Hum Mol Genet 1999;8:2063-9.
crossref pmid
4. Belostotsky R, Seboun E, Idelson GH, Milliner DS, Becker-Cohen R, Rinat C, et al. Mutations in DHDPSL are responsible for primary hyperoxaluria type III. Am J Hum Genet 2010;87:392-9.
crossref pmid pmc
5. Hoppe B. An update on primary hyperoxaluria. Nat Rev Nephrol 2012;8:467-7.
crossref pmid pdf
6. Kim HH, Koh HI, Ku BI, Lee HS. Late-onset primary hyperoxaluria diagnosed after renal transplantation presented with early recurrence of disease. Nephrol Dial Transplant 2005;20:1738-40.
crossref pmid pdf
7. Kim SE, Kim SJ, Chu ST, Yang SH, Kim YS, Cha RH. A rare case of hyperoxaluria presenting with acute liver injury and stone-free kidney injury. Kidney Res Clin Pract 2015;34:113-6.
crossref pmid pmc
8. Cochat P, Deloraine A, Rotily M, Olive F, Liponski I, Deries N. Epidemiology of primary hyperoxaluria type 1. Nephrol Dial Transplant 1995;10 Suppl 8:3-7.
crossref pmid pdf
9. van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA. Primary hyperoxaluria type 1 in the Netherlands: prevalence and outcome. Nephrol Dial Transplant 2003;18:273.
crossref pmid pdf
10. Harambat J, van Stralen KJ, Espinosa L, Groothoff JW, Hulton SA, Cerkauskiene R, et al. Characteristics and outcomes of children with primary oxalosis requiring renal replacement therapy. Clin J Am Soc Nephrol 2012;7:458-65.
crossref pmid pmc
11. North American Pediatric Renal Trials and Collaborative Studies. NAPRTCS 2011 Annual Dialysis Report. https://web.emmes.com/study/ped/annlrept/annualrept20pdf

12. Hattori S, Yosioka K, Honda M, Ito H. Japanese Society for Pediatric Nephrology. The 1998 report of the Japanese national registry data on pediatric end-stage renal disease patients. Pediatr Nephrol 2002;17:456-61.
crossref pmid pdf
13. Al-Eisa AA, Samhan M, Naseef M. End-stage renal disease in Kuwaiti children: an 8-year experience. Transplant Proc 2004;36:1788-91.
crossref pmid
14. Kamoun A, Lakhoua R. End-stage renal disease of the Tunisian child: epidemiology, etiologies, and outcome. Pediatr Nephrol 1996;10:479-82.
crossref pmid pdf
15. Williams EL, Acquaviva C, Amoroso A, Chevalier F, Coulter-Mackie M, Monico CG, et al. Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene. Hum Mutat 2009;30:910-7.
crossref pmid
16. Hopp K, Cogal AG, Bergstralh EJ, Seide BM, Olson JB, Meek AM, et al. Rare Kidney Stone Consortium. Phenotype-genotype correlations and estimated carrier frequencies of primary hyperoxaluria. J Am Soc Nephrol 2015;26:2559-70.
crossref pmid pmc
17. Monico CG, Rossetti S, Olson JB, Milliner DS. Pyridoxine effect in type I primary hyperoxaluria is associated with the most common mutant allele. Kidney Int 2005;67:1704-9.
crossref pmid
18. Harambat J, Fargue S, Acquaviva C, Gagnadoux MF, Janssen F, Liutkus A, et al. Genotype-phenotype correlation in primary hyperoxaluria type 1: the p.Gly170Arg AGXT mutation is associated with a better outcome. Kidney Int 2010;77:443-9.
crossref pmid
19. van Woerden CS, Groothoff JW, Wijburg FA, Annink C, Wanders RJ, Waterham HR. OxalEurope Consortium. Clinical implications of mutation analysis in primary hyperoxaluria type 1. Kidney Int 2004;66:746-52.
crossref pmid
20. Mandrile G, van Woerden CS, Berchialla P, Beck BB, Acquaviva Bourdain C, Hulton SA, et al. Data from a large European study indicate that the outcome of primary hyperoxaluria type 1 correlates with the AGXT mutation type. Kidney Int 2014;86:1197-204.
crossref pmid
21. Rumsby G, Williams E, Coulter-Mackie M. Evaluation of mutation screening as a first line test for the diagnosis of the primary hyperoxalurias. Kidney Int 2004;66:959-63.
crossref pmid
22. Frishberg Y, Rinat C, Shalata A, Khatib I, Feinstein S, Becker-Cohen R, et al. Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel. Am J Nephrol 2005;25:269-75.
crossref pmid
23. Milliner DS, Eickholt JT, Bergstralh EJ, Wilson DM, Smith LH. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. N Engl J Med 1994;331:1553-8.
crossref pmid
24. Hoppe B, Kemper MJ, Bökenkamp A, Portale AA, Cohn RA, Langman CB. Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure. Kidney Int 1999;56:268-74.
crossref pmid
25. Illies F, Bonzel KE, Wingen AM, Latta K, Hoyer PF. Clearance and removal of oxalate in children on intensified dialysis for primary hyperoxaluria type 1. Kidney Int 2006;70:1642-8.
crossref pmid
26. Kemper MJ, Nolkemper D, Rogiers X, Timmermann K, Sturm E, Malago M, et al. Preemptive liver transplantation in primary hyperoxaluria type 1: timing and preliminary results. J Nephrol 1998;11 Suppl 1:46-8.
pmid
27. Cochat P, Groothoff J. Primary hyperoxaluria type 1: practical and ethical issues. Pediatr Nephrol 2013;28:2273-81.
crossref pmid pdf
28. Malla I, Lysy PA, Godefroid N, Smets F, Malaise J, Reding R, et al. Two-step transplantation for primary hyperoxaluria: cadaveric liver followed by living donor related kidney transplantation. Pediatr Transplant 2009;13:782-4.
crossref pmid
29. Mor E, Nesher E, Ben-Ari Z, Weissman I, Shaharabani E, Eizner S, et al. Sequential liver and kidney transplantation from a single living donor in two young adults with primary hyperoxaluria type 1. Liver Transpl 2013;19:646-8.
crossref pmid
30. Allard L, Cochat P, Leclerc AL, Cachat F, Fichtner C, De Souza VC, et al. Renal function can be impaired in children with primary hyperoxaluria type 3. Pediatr Nephrol 2015;30:1807-13.
crossref pmid pdf

Fig. 1.
Imaging studies in patients with primary hyperoxaluria. (A) Kidney ultrasonography shows diffuse increased echogenicity indicating nephrocalcinosis and loss of corticomedullary differentiation of both kidneys in patient 1. (B) Kidney ultrasonography shows multiple stones (arrows) in patient 9. (C) Abdomen CT scan shows a staghorn stone (arrow) with hydronephrosis in the right kidney of patient 11.
ckd-23-2-59f1.jpg
Fig. 2.
Retina of primary hyperoxaluria patients indicating systemic oxalosis. (A) Calcium oxalate crystal deposition in patient 1. B) Central geographic macular lesion surrounded by flecks in patient 2.
ckd-23-2-59f2.jpg
Table 1.
Genotypes of 11 Primary Hyperoxaluria Patients
Patients Genes Mutation 1 Mutation 2
1 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs c.577dupC, p.Leu(CTT)193Pro(CCT)fs
2 AGXT c.33delC, p.Lys(AAG)12Arg(AGG)fs*34 c.335C>A, p.Ala(GCC)112Asp(GAC)
3 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs Homozygote
4 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs c.681-1G>A in intron 6a
5 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs Homozygote
6 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs c.346G>C, p.Gly(GGG)116Arg(CGG)
7 AGXT c.331C>T, p.Arg(CGA)111*(TGA) Homozygote
8 AGXT c.187G>C, p.Gly(GGC)63Arg(CGC) c.823_824dupAG, p.Ser(AGC)275Arg(AGA)fs
9 AGXT c.33dupC, p.Lys(AAG)12Gln(CAA)fs c.568G>A, p.Gly(GGG)190Arg(AGG)
10 GRHPR c.181G>A, p.Asp(GAC)61Asn(AAC)* not detected
11 HOGA1 c.812G>A, p.Arg(CGC)271His(CAC)* not detected

* novel mutations.

Table 2.
Clinical Features of the Patients
Patient/Gender GA/Birth weight Height/weight percentile at Dx Age (months) at onset/Dx Initial presentation NL/NC urinary Ox/Cr (reference range) Initial Scr/eGFR Retinal lesion Disease course (ages [years] at the last F-U)
1/male 40 wks/3.7 kg 10-25p/10-25p 2/3 ESRD -/+ 544 (<325-360) 5.40/5.2 + PD→LT→death (0.5)
2/male 39+6 wks/3.24 kg 10-25p/10-25p 4/4 ESRD -/+ 632 (<325-360) 3.45/8.2 - PD+HD→LT→LT→HD (7)
3/male 40+2 wks/3.36 kg 25-50p/25-50p 3/3 ESRD -/+ 263 (<325-360) 6.27/4.4 + PD+HD→LT→KT→eGFR 32 (6)
4/male 40+5 wks/3.5 kg 5-10p/5-10p 2/3 ESRD -/+ 800 (<325-360) 5.74/4.5 + PD+HD→LT→KT→eGFR 90 (6)
5/male 39+5 wks/2.9 6kg 25-50p/10-25p 3/3 ESRD -/+ 161 (<325-360) 7.61/3.7 + PD+HD→LT→KT→eGFR 66 (5)
6/male Fullterm/3 kg 10-25p/10-25p 36/118 ESRD +/+ n. c. 9.8/9.1 + HD→PD (16)
7/female 40 wks/2.78 kg 10-25p/25p 5/5 ESRD +/+ n. c. 6.19/4.0 - PD+HD→PD (0.6)
8/male 37+6 wks/2.97 kg 10-25p/25-50p 2/2 ESRD -/+ 540 (<325-360) 3.78/8.2 + HD (0.3)
9/male Fullterm/3.34 kg 15-25p/25-50p 25/61 NL +/- 292 (<70-82) 0.46/104.9 n. c. eGFR 103 (8)
10/male Fullterm/2.9 kg 10-15p/10-15p 23/34 GHU, NL +/+ 824 (<98-101) 0.35/111 n. c. eGFR 105 (5)
11/male 27 wks/1.08 kg <3p/<3p 2/4 NL +/+ 2845 (<325-360) 0.17/130 - eGFR 123 (2)

GA, gestational age; Dx, diagnosis; eGFR, estimated glomerular filtration rate calculated using the Schwartz formula (ml/min/1.73 m2); ESRD, end-stage renal disease; F-U, follow-up; GHU, gross hematuria; HD, hemodialysis; PD, peritoneal dialysis; RRT, renal replacement therapy; KT, kidney transplantation; LT, liver transplantation; NL, nephrolithiasis; NC, nephrocalcinosis; n.c., not checked; Ox/Cr, oxalate to creatinine ratio (mmol/mol) in spot urine; Scr, serum creatinine (mg/dL).


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