Publications by authors named "Dineke Westra"

17 Publications

  • Page 1 of 1

Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort.

Pediatr Nephrol 2021 Sep 2. Epub 2021 Sep 2.

Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.

Background: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G.

Methods: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood.

Results: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m at last follow-up.

Conclusions: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics.
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http://dx.doi.org/10.1007/s00467-021-05221-6DOI Listing
September 2021

Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.

J Neuromuscul Dis 2019 ;6(2):241-258

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials.

Objective: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms.

Methods: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results.

Results: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach.

Conclusion: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.
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http://dx.doi.org/10.3233/JND-180376DOI Listing
December 2019

Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.

Clin Genet 2019 08 6;96(2):126-133. Epub 2019 May 6.

Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

In this retrospective study, we conducted a clinico-genetic analysis of patients with autosomal recessive limb-girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand-dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3-5/LGMD2C-E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR-LGMD and MMD in the Netherlands amounted to 14.4 × 10 . Thirty-three novel mutations were identified. A wide range in age of onset (0-72 years) and loss of ambulation (5-74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non-invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes.
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http://dx.doi.org/10.1111/cge.13544DOI Listing
August 2019

Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome.

Pediatr Nephrol 2017 02 7;32(2):297-309. Epub 2016 Oct 7.

Department of Pediatric Nephrology (804), Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: The role of complement in the atypical form of hemolytic uremic syndrome (aHUS) has been investigated extensively in recent years. As the HUS-associated bacteria Shiga-toxin-producing Escherichia coli (STEC) can evade the complement system, we hypothesized that complement dysregulation is also important in infection-induced HUS.

Methods: Serological profiles (C3, FH, FI, AP activity, C3d, C3bBbP, C3b/c, TCC, αFH) and genetic profiles (CFH, CFI, CD46, CFB, C3) of the alternative complement pathway were prospectively determined in the acute and convalescent phase of disease in children newly diagnosed with STEC-HUS or aHUS. Serological profiles were compared with those of 90 age-matched controls.

Results: Thirty-seven patients were studied (26 STEC-HUS, 11 aHUS). In 39 % of them, including 28 % of STEC-HUS patients, we identified a genetic and/or acquired complement abnormality. In all patient groups, the levels of investigated alternative pathway (AP) activation markers were elevated in the acute phase and normalized in remission. The levels were significantly higher in aHUS than in STEC-HUS patients.

Conclusions: In both infection-induced HUS and aHUS patients, complement is activated in the acute phase of the disease but not during remission. The C3d/C3 ratio displayed the best discrepancy between acute and convalescent phase and between STEC-HUS and aHUS and might therefore be used as a biomarker in disease diagnosis and monitoring. The presence of aberrations in the alternative complement pathway in STEC-HUS patients was remarkable, as well.
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http://dx.doi.org/10.1007/s00467-016-3496-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203860PMC
February 2017

Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration.

PLoS One 2016 23;11(3):e0152047. Epub 2016 Mar 23.

Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.8% of CD cases. To further explore the role of rare variants in CD, we performed whole exome sequencing (WES) in 14 affected members of six families and 12 sporadic cases with CD. We detected rare sequence variants in CFH and FBLN5, which previously were shown to harbor rare variants in patients with CD. In addition, we detected heterozygous rare sequence variants in several genes encoding components of the extracellular matrix (ECM), including FBLN1, FBLN3/EFEMP1, FBLN5, FBLN6/HMCN1, FBN2, and COL15A1. Two rare pathogenic variants were identified in the COL15A1 gene: one in a sporadic case and another was found to segregate in a family with six affected individuals with CD. In addition, two rare pathogenic variants were identified in the FGL1 gene in three unrelated CD cases. These findings suggest that alterations in the ECM and in the coagulation pathway may play a role in the pathogenesis of CD. The identified candidate genes require further analyses in larger cohorts to confirm their role in the CD subtype of AMD. No evidence was found of rare sequence variants in a single gene that segregate with CD in the six families, suggesting that the disease is genetically heterogeneous.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152047PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805164PMC
August 2016

Complement Factor H Serum Levels Determine Resistance to Pneumococcal Invasive Disease.

J Infect Dis 2016 06 21;213(11):1820-7. Epub 2016 Jan 21.

Laboratory of Pediatric Infectious Diseases Division of Pediatric Infectious Diseases and Immunology, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Streptococcus pneumoniae is a major cause of life-threatening infections. Complement activation plays a vital role in opsonophagocytic killing of pneumococci in blood. Initial complement activation via the classical and lectin pathways is amplified through the alternative pathway amplification loop. Alternative pathway activity is inhibited by complement factor H (FH). Our study demonstrates the functional consequences of the variability in human serum FH levels on host defense. Using an in vivo mouse model combined with human in vitro assays, we show that the level of serum FH correlates with the efficacy of opsonophagocytic killing of pneumococci. In summary, we found that FH levels determine a delicate balance of alternative pathway activity, thus affecting the resistance to invasive pneumococcal disease. Our results suggest that variation in FH expression levels, naturally occurring in the human population, plays a thus far unrecognized role in the resistance to invasive pneumococcal disease.
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http://dx.doi.org/10.1093/infdis/jiw029DOI Listing
June 2016

[Partial lipodystrophy: a spot diagnosis].

Ned Tijdschr Geneeskd 2015 ;159:A8872

Deventer Ziekenhuis, afd. Kindergeneeskunde, Deventer.

Background: Partial lipodystrophy is a rare acquired disorder characterised by gradual loss of subcutaneous adipose tissue in the upper half of the body.

Case Description: We saw a 9-year-old girl who had been referred on account of recurrent urinary tract infections. On physical examination, she was noticed to be very thin in the face. Her upper extremities were also skinny. Strikingly, the lower half of her body was normally proportioned, which immediately suggested a diagnosis of partial lipodystrophy. Additional examinations showed a low level of complement factor C3 and the presence of C3 nephritic factor.

Conclusion: Partial lipodystrophy is rare but it is important to include it in the differential diagnosis of unwanted disproportional subcutaneous fat loss because of the somatic and psychological consequences.
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May 2016

Sensitive, reliable and easy-performed laboratory monitoring of eculizumab therapy in atypical hemolytic uremic syndrome.

Clin Immunol 2015 Oct 23;160(2):237-43. Epub 2015 Jun 23.

Research Laboratory, Nordland Hospital, P. O. Box 1480, 8092 Bodø, Norway; Faculty of Health Sciences, K.G. Jebsen TREC, University of Tromsø, P. O. Box 6050 Langnes, 9037 Tromsø, Norway; Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; Department of Immunology, Oslo University Hospital, and K.G Jebsen IRC, University of Oslo, P.B. 4950 Nydalen, NO-0424 Oslo, Norway. Electronic address:

Complement C5 inhibitor eculizumab treatment in atypical hemolytic uremic syndrome is effective, but associated with high costs. Complement inhibition monitoring in these patients has not been standardized. In this study we evaluated novel functional assays for application in routine follow-up. We documented that the Wieslab® complement screen assay showed a sensitivity of 1-2% of C5 activity by adding purified C5 or normal human serum to a C5 deficient serum. All the patient samples obtained during the treatment course, were completely blocked for terminal complement pathway activity for up to four weeks after the eculizumab infusion. Levels of complexes between eculizumab and C5 were inversely correlated to the complement activity (p=0.01). Moreover, titrating serum from eculizumab-treated patients into normal serum revealed that eculizumab was present in excess up to four weeks after infusion. Thus, we demonstrate sensitive, reliable and easy-performed assays which can be used to design individual eculizumab dosage regimens.
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http://dx.doi.org/10.1016/j.clim.2015.05.018DOI Listing
October 2015

Compound heterozygous mutations in the C6 gene of a child with recurrent infections.

Mol Immunol 2014 Apr 30;58(2):201-5. Epub 2013 Dec 30.

Department of Pediatric Infectious Diseases & Immunology (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands; Nijmegen Institute for Infection, Immunity and Inflammation (HP 804), Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address:

The complement system plays an important role in both the innate and adaptive immune system. Patients with inherited complement deficiencies have an increased risk of systemic bacterial infections. Deficiencies of the terminal complement pathway are especially associated with invasive meningococcal disease. Here, we report a case of a boy that presented with arthritis and recurrent bacterial and viral infections. Extensive analyses revealed decreased complement activity of both classical and alternative pathway, indicating a deficiency of C3 or one of the factors of the terminal complement pathway. Mutational analysis of the C6 gene identified two compound heterozygous mutations. An unknown missense aberration was found that involves the loss of a cysteine, possibly affecting the 3D structure of the protein. Furthermore, a known splice site variation was identified that results in a 14% shorter protein, due to transcription of amino acids that are normally intronic until a stop codon is reached (exon-intron boundary defect). It is known that the protein with this latter aberration is still functionally active when present with other C6 mutations and therefore, the consequences of the combination of the identified variations have been studied. Quantitative ELISAs showed that at least one allele produced a circulating C6 molecule that can be incorporated in the membrane attack complex, likely the truncated protein. In the present case we observed relapsing bacterial and viral infections, but no meningococcal disease. The reduced complement activity can be explained by the identified genetic variations in C6, as recombinant C6 supplementation corrected complement function in vitro.
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http://dx.doi.org/10.1016/j.molimm.2013.11.023DOI Listing
April 2014

Severe infantile Bordetella pertussis pneumonia in monozygotic twins with a congenital C3 deficiency.

Eur J Pediatr 2014 Dec 21;173(12):1591-4. Epub 2013 Aug 21.

Department of Pediatric Nephrology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands,

Unlabelled: Bordetella pertussis or whooping cough is a vaccine-preventable disease that still remains a serious infection in neonates and young infants. We describe two young infants, monozygotic twins, with a severe B. pertussis pneumonia of whom one needed extracorporeal membrane oxygenation. Diagnostic work-up of unexplained hematuria and proteinuria during the illness revealed low serum complement component 3 (C3) levels. During follow-up, C3 levels remained low (400-600 mg/L). Extensive analysis of the persistent low C3 levels revealed an unknown heterozygous mutation in the C3 gene in both siblings and their mother. This C3 mutation in combination with the specific virulence mechanisms of B. pertussis probably contributed to the severe disease course in these cases.

Conclusion: We propose that genetically caused complement disorders should be considered when confronted with severe cases of B. pertussis infection.
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http://dx.doi.org/10.1007/s00431-013-2107-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087018PMC
December 2014

Combined pulmonary hypertension and renal thrombotic microangiopathy in cobalamin C deficiency.

Pediatrics 2013 Aug 8;132(2):e540-4. Epub 2013 Jul 8.

Department of Pediatric Nephrology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, Netherlands.

Pulmonary arterial hypertension (PAH) and renal thrombotic microangiopathy (rTMA) are rare diseases in childhood, frequently leading to death and end-stage renal disease, respectively. Their combined occurrence has been reported anecdotally. We investigated the clinical, biochemical, and genetic aspects of 5 children with the rare combination of PAH and rTMA. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, PAH was preceded by rTMA from age 2.5 to 7 years. Three patients presenting at ≤ 3 years of age died of right ventricular failure secondary to progressive PAH. In 2 patients, cobalamin C (cblC) deficiency was diagnosed postmortem. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 patient exhibited progressive pulmonary vasculopathy, and 1 patient is currently in stable condition. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Genetic analysis confirmed mutations in MMACHC in all patients; 4 patients were compound heterozygous, with all having base-pair substitutions (G>A or G>T) at nucleotide 276 in addition to frame-shift mutations. One patient had homozygous nonsense mutations of MMACHC. We established cblC deficiency as the denominator in the rare combination of PAH and rTMA in these children. Early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may beneficially affect the course of this devastating disease.
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http://dx.doi.org/10.1542/peds.2012-2581DOI Listing
August 2013

The challenge of managing hemophilia A and STEC-induced hemolytic uremic syndrome.

Pediatr Nephrol 2013 Feb 23;28(2):349-52. Epub 2012 Sep 23.

Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.

Background: The hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy leading to acute kidney injury in children. In most cases it is triggered by an infection caused by Shiga-like toxin-producing Escherichia coli (STEC). Endothelial damage plays a central role in the pathogenesis of disease. Hemophilia A is a genetic disorder leading to factor VIII (FVIII) deficiency, an important factor in the coagulation system.

Case: Here we describe a hemophilia A patient who developed HUS due to a STEC O26 infection. The patient developed not only acute kidney injury, but also severe gastro-intestinal and neurological complications. Increased amounts of recombinant FVIII (rFVIII) had to be administered during the acute phase of the disease to reach acceptable blood levels of FVIII, in order to control the hemorrhagic colitis and to prevent severe neurological complications.

Conclusion: The patient's treatment schedule of rFVIII during the HUS period was a serious challenge, and we cannot exclude that it contributed to the severity of the HUS by enhancing the thrombotic microangiopathic process. The role of factor VIII administration in the severe outcome of this disease is discussed.
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http://dx.doi.org/10.1007/s00467-012-2312-8DOI Listing
February 2013

Novel C3 mutation p.Lys65Gln in aHUS affects complement factor H binding.

Pediatr Nephrol 2012 Sep 6;27(9):1519-24. Epub 2012 Jun 6.

Department of Pediatric Nephrology (804), Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations affecting complement proteins and regulators and with autoantibodies against complement factor H (CFH). Approximately half of the aHUS patients progress to end-stage renal disease. DNA analysis of the risk factor genes is important for prognosis of aHUS recurrence after renal transplantation.

Methods: Mutational screening of C3 encoding the central complement component was performed by Sanger sequencing in 70 aHUS patients. Mutated and wild type recombinant C3b proteins were produced and their affinity to CFH was analyzed by ELISA.

Results: A single novel missense change p.Lys65Gln in C3 was found in 3 aHUS patients. The alteration leads to decreased binding of C3b to CFH in vitro. All three patients acquired the illness as adults and had a first aHUS episode after renal transplantation or suffered recurrence of the disease after transplantation.

Conclusions: The novel C3 change was found in 3 aHUS patients. It results in decreased C3b binding to CFH and thus might lead to impaired C3b inactivation in vivo. The p.Lys65Gln is likely to be associated with aHUS after kidney transplantation and, therefore, might be an important prognostic factor.
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http://dx.doi.org/10.1007/s00467-012-2183-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407361PMC
September 2012

Atypical hemolytic uremic syndrome and genetic aberrations in the complement factor H-related 5 gene.

J Hum Genet 2012 Jul 24;57(7):459-64. Epub 2012 May 24.

Department of Pediatric Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands.

Atypical hemolytic uremic syndrome (aHUS) is a severe renal disorder that is associated with mutations in genes encoding proteins of the alternative complement pathway. Previously, we identified pathogenic variations in genes encoding complement regulators (CFH, CFI and MCP) in our aHUS cohort. In this study, we screened for mutations in the alternative pathway regulator CFHR5 in 65 aHUS patients by means of PCR on genomic DNA and sequence analysis. Potential pathogenicity of genetic alterations was determined by published data on CFHR5 variants, evolutionary conservation and in silico mutation prediction programs. Detection of serum CFHR5 was performed by western blot analysis and enzyme-linked immunosorbent assay. A potentially pathogenic sequence variation was found in CFHR5 in three patients (4.6%). All variations were located in short consensus repeats that might be involved in binding to C3b, heparin or C-reactive protein. The identified CFHR5 mutations require functional studies to determine their relevance to aHUS, but they might be candidates for an altered genetic profile predisposing to the disease.
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http://dx.doi.org/10.1038/jhg.2012.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407369PMC
July 2012

Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics.

Pediatr Nephrol 2012 Aug 13;27(8):1283-91. Epub 2012 Mar 13.

Department of Pediatric Nephrology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Background: Mutations in complement factor H (CFH), factor I (CFI), factor B (CFB), thrombomodulin (THBD), C3 and membrane cofactor protein (MCP), and autoantibodies against factor H (αFH) with or without a homozygous deletion in CFH-related protein 1 and 3 (∆CFHR1/3) predispose development of atypical hemolytic uremic syndrome (aHUS).

Methods: Different mutations in genes encoding complement proteins in 45 pediatric aHUS patients were retrospectively linked with clinical features, treatment, and outcome.

Results: In 47% of the study participants, potentially pathogenic genetic anomalies were found (5xCFH, 4xMCP, and 4xC3, 3xCFI, 2xCFB, 6xαFH, of which five had ∆CFHR1/3); four patients carried combined genetic defects or a mutation, together with αFH. In the majority (87%), disease onset was preceeded by a triggering event; in 25% of cases diarrhea was the presenting symptom. More than 50% had normal serum C3 levels at presentation. Relapses were seen in half of the patients, and there was renal graft failure in all except one case following transplant.

Conclusions: Performing adequate DNA analysis is essential for treatment and positive outcome in children with aHUS. The impact of intensive initial therapy and renal replacement therapy, as well as the high risk of recurrence of aHUS in renal transplant, warrants further understanding of the pathogenesis, which will lead to better treatment options.
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http://dx.doi.org/10.1007/s00467-012-2131-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382652PMC
August 2012

Genetic disorders in complement (regulating) genes in patients with atypical haemolytic uraemic syndrome (aHUS).

Nephrol Dial Transplant 2010 Jul 26;25(7):2195-202. Epub 2010 Jan 26.

Department of Paediatric Nephrology, Radboud University Nijmegen Medical Centre (RUNMC), P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Background: Atypical HUS (aHUS) is thought to be caused by predisposing mutations in genes encoding complement (regulating) proteins, such as Factor H (CFH), Factor I (IF), membrane co-factor protein (MCP) and Factor B (FB), or by auto-antibodies against CFH (alphaFH) in combination with a homozygous polymorphic deletion of the genes encoding Complement Factor H-related 1 and 3 (DeltaCFHR1/3). The clinical impact of this knowledge is high, as it might be a prognostic factor for the outcome of renal transplantations and kidney donations.

Methods: Mutational screening, by means of PCR and DNA sequencing, is performed in the above-mentioned genes in a group of 72 aHUS patients. Also, the presence of alphaFH and DeltaCFHR1/3 was tested in patients and controls.

Results: In 23 patients, a genetic aberration in at least one gene or the presence of alphaFH was found. A heterozygous mutation was observed in CFH in nine patients, in IF in seven patients and in MCP in three patients. No mutations were observed in FB. Seven patients presented alphaFH, of whom five also carried DeltaCFHR1/3. Three patients carried a combined mutation (two patients: IF and MCP; one patient: IF, alphaFH and DeltaCFHR1/3). A significant difference between patients and controls was detected for the presence of all three associated polymorphisms in CFH.

Conclusions: Genetic abnormalities or the presence of alphaFH were detected in 31.9% of the aHUS patients. Furthermore, bigenic mutations were present, indicating that routine DNA mutation analysis of all complement factors associated with aHUS is important.
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http://dx.doi.org/10.1093/ndt/gfq010DOI Listing
July 2010

Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.

Nephrol Dial Transplant 2008 Oct 28;23(10):3146-51. Epub 2008 Apr 28.

Department of Paediatric Nephrology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Background: Focal segmental glomerulosclerosis (FSGS) is a major cause of steroid-resistant nephrotic syndrome in childhood with a central role for the podocytes in the pathogenesis. Mutated proteins expressed in podocytes cause proteinuria. The role of combined gene defects in the development of FSGS is less clear.

Methods: We analysed seven podocyte genes known to cause proteinuria and FSGS in a group of 19 non-familial childhood-onset steroid-resistant FSGS patients. These genes include NPHS1, NPHS2, ACTN4, CD2AP, WT-1, TRPC6 and PLCE1. We also screened for the mitochondrial A3243G DNA transition associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and occasionally FSGS.

Results: No mutations were found in the ACTN4 and TRPC6 genes, and no mitochondrial A3243G DNA transition was found in our group of patients. Two patients showed mutations in the CD2AP gene, one combined with an NPHS2 mutation. A tri-allelic hit was found in a patient carrying compound heterozygous NPHS2 mutations and a heterozygous NPHS1 mutation. In another patient a de novo WT-1 mutation was found combined with a heterozygous NPHS1 mutation, and finally two patients showed three heterozygous PLCE1 mutations.

Conclusions: In our rather small group of 19 steroid-resistant FSGS patients, we found 11 mutations in podocyte genes in 6 patients. In four of them the found mutations could explain the pathology. Our data suggest that combined gene defects in podocyte genes may play a role in the development of FSGS.
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http://dx.doi.org/10.1093/ndt/gfn208DOI Listing
October 2008
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