The Experts below are selected from a list of 5223 Experts worldwide ranked by ideXlab platform
Judy Savige - One of the best experts on this subject based on the ideXlab platform.
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expert consensus guidelines for the genetic diagnosis of Alport Syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Oliver Gross, Frances Flinter, Jie Ding, Francesca Ariani, Francesca Mari, Mirella Bruttini, Alessandra Renieri, Constantinos Deltas, Daniel P GaleAbstract:Recent expert guidelines recommend genetic testing for the diagnosis of Alport Syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport Syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport Syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport Syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport Syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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Alport Syndrome in women and girls
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Judy Savige, Deb Colville, Michelle N Rheault, Susie Gear, Rachel Lennon, Sharon Lagas, Moira Finlay, Frances FlinterAbstract:Alport Syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport Syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%–30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport Syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport Syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport Syndrome should be tested at least annually for albuminuria and hypertension. The “Expert guidelines for the diagnosis and management of Alport Syndrome” recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport Syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic counseling, informed of their reproductive options, and monitored closely during pregnancy for the development of hypertension.
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ocular features in Alport Syndrome pathogenesis and clinical significance
Clinical Journal of The American Society of Nephrology, 2015Co-Authors: Judy Savige, Deb Colville, Shivanand Sheth, Anita Leys, Anjali Nicholson, Heather G MackAbstract:Alport Syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3 and COL4A4 (autosomal recessive) genes result in absence of the collagen IV α3α4α5 network from the basement membranes of the cornea, lens capsule, and retina and are associated with corneal opacities, anterior lenticonus, fleck retinopathy, and temporal retinal thinning. Typically, these features do not affect vision or, in the case of lenticonus, are correctable. In contrast, the rarer ophthalmic complications of posterior polymorphous corneal dystrophy, giant macular hole, and maculopathy all produce visual loss. Many of the ocular features of Alport Syndrome are common, easily recognizable, and thus, helpful diagnostically, and in identifying the likelihood of early-onset renal failure. Lenticonus and central fleck retinopathy strongly suggest the diagnosis of Alport Syndrome and are associated with renal failure before the age of 30 years, in males with X-linked disease. Sometimes, ophthalmic features suggest the mode of inheritance. A peripheral retinopathy in the mother of a male with hematuria suggests X-linked inheritance, and central retinopathy or lenticonus in a female means that recessive disease is likely. Ocular examination, retinal photography, and optical coherence tomography are widely available, safe, fast, inexpensive, and acceptable to patients. Ocular examination is particularly helpful in the diagnosis of Alport Syndrome when genetic testing is not readily available or the results are inconclusive. It also detects complications, such as macular hole, for which new treatments are emerging.
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Alport Syndrome its effects on the glomerular filtration barrier and implications for future treatment
The Journal of Physiology, 2014Co-Authors: Judy SavigeAbstract:The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have come to realise that permselectivity depends on size and not necessarily charge, that the molecular sieve depends on the podocyte contractile apparatus and is highly dynamic, and that protein uptake by proximal tubular epithelial cells stimulates signalling and the production of transcription factors and inflammatory mediators. Alport Syndrome is the second commonest monogenic cause of renal failure after autosomal dominant polycystic kidney disease. Eighty per cent of patients have X-linked disease caused by mutations in the COL4A5 gene. Most of these result in the replacement of the collagen IV α3α4α5 network with the α1α1α2 heterotrimer. Affected membranes also have ectopic laminin and increased matrix metalloproteinase levels, which makes them more susceptible to proteolysis. Mechanical stress, due to the less elastic membrane and hypertension, interferes with integrin-mediated podocyte–GBM adhesion. Proteinuria occurs when urinary levels exceed tubular reabsorption rates, and initiates tubulointerstitial fibrosis. The glomerular mesangial cells produce increased TGFβ and CTGF which also contribute to glomerulosclerosis. Currently there is no specific therapy for Alport Syndrome. However treatment with angiotensin converting enzyme (ACE) inhibitors delays renal failure progression by reducing intraglomerular hypertension, proteinuria, and fibrosis. Our greater understanding of the mechanisms underlying the GBM changes and their consequences in Alport Syndrome have provided us with further novel therapeutic targets.
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clinical and genetic features in autosomal recessive and x linked Alport Syndrome
Pediatric Nephrology, 2014Co-Authors: Yan Yan Wang, Deb Colville, Frances Flinter, Hayat Dagher, Helen Storey, Vanessa Sivakumar, Mardhiah Mohammad, Judy SavigeAbstract:Background This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport Syndrome.
Clifford E. Kashtan - One of the best experts on this subject based on the ideXlab platform.
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clinical trial recommendations for potential Alport Syndrome therapies
Kidney International, 2020Co-Authors: Andre B Weinstock, Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Rachel Lennon, Sharon Lagas, David L Feldman, Alessia Fornoni, Jeffrey H Miner, James F SimonAbstract:Abstract Alport Syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport Syndrome community as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry, academic researchers, clinicians, regulatory agencies, and—most critically—patients with Alport Syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.
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Renal transplantation in patients with Alport Syndrome: patient selection, outcomes, and donor evaluation
International Journal of Nephrology and Renovascular Disease, 2018Co-Authors: Clifford E. KashtanAbstract:Alport Syndrome is an inherited disorder of basement membrane collagen IV that frequently results in end-stage renal disease. Patients with Alport Syndrome who undergo renal transplantation have generally excellent outcomes. Posttransplant antiglomerular basement membrane nephritis is a rare complication of renal transplantation for Alport Syndrome. Because Alport Syndrome is a genetic disorder, potential related donors must be carefully evaluated in order to minimize harm.
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Alport Syndrome facts and opinions
F1000Research, 2017Co-Authors: Clifford E. KashtanAbstract:In this commentary, I review recent advances in Alport Syndrome genetics, diagnostics, and therapeutics. I also offer some opinions regarding strategies to optimize the early identification of affected individuals to promote early therapeutic intervention.
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advances and unmet needs in genetic basic and clinical science in Alport Syndrome report from the 2015 international workshop on Alport Syndrome
Nephrology Dialysis Transplantation, 2016Co-Authors: Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Frances Flinter, Jeffrey H Miner, Judith Savige, Constantinos Deltas, Roser Torra, Isavella Savva, Laura PerinAbstract:Alport Syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis.
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the 2014 international workshop on Alport Syndrome
Kidney International, 2014Co-Authors: Jeffrey H Miner, Oliver Gross, Clifford E. Kashtan, Sharon Lagas, Frances Flinter, Colin Baigent, Parminder K Judge, Judith Savige, Dave Blatt, Jie DingAbstract:Alport Syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport Syndrome, estimated to affect 1 in 5000–10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport Syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3–5, was organized by individuals and families living with Alport Syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities—patient families, physicians, geneticists, researchers, Pharma, and funding organizations—were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function.
Oliver Gross - One of the best experts on this subject based on the ideXlab platform.
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Novel COL4A5, COL4A4, and COL4A3 Mutations in Alport Syndrome
Human Mutation, 2020Co-Authors: Mato Nagel, Sylvia Nagorka, Oliver GrossAbstract:This study summarizes 47 novel mutations identified during routine molecular diagnostics for Alport Syndrome. We detected 34 in COL4A5, the gene responsible for X-linked Alport Syndrome, and 13 in COL4A3 and COL4A4, the genes responsible for autosomal recessive Alport Syndrome. A high detection rate of 90% was achieved among patients with typical clinical symptoms and a characteristic family history in both X-linked and autosomal recessive forms, and it can be assumed that most relevant mutations have been identified. In numerous positively tested patients, genetic variations which are unknown were detected. © 2005 Wiley-Liss, Inc.
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the importance of clinician patient and researcher collaborations in Alport Syndrome
Pediatric Nephrology, 2020Co-Authors: Michelle N Rheault, Oliver Gross, Frances Flinter, Judith Savige, Michael J Randles, Andre Weinstock, Melissa Stepney, Neil A Turner, Gina Parziale, Jeffrey H MinerAbstract:Alport Syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport Syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport Syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
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clinical trial recommendations for potential Alport Syndrome therapies
Kidney International, 2020Co-Authors: Andre B Weinstock, Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Rachel Lennon, Sharon Lagas, David L Feldman, Alessia Fornoni, Jeffrey H Miner, James F SimonAbstract:Abstract Alport Syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport Syndrome community as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry, academic researchers, clinicians, regulatory agencies, and—most critically—patients with Alport Syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.
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expert consensus guidelines for the genetic diagnosis of Alport Syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Oliver Gross, Frances Flinter, Jie Ding, Francesca Ariani, Francesca Mari, Mirella Bruttini, Alessandra Renieri, Constantinos Deltas, Daniel P GaleAbstract:Recent expert guidelines recommend genetic testing for the diagnosis of Alport Syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport Syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport Syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport Syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport Syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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advances and unmet needs in genetic basic and clinical science in Alport Syndrome report from the 2015 international workshop on Alport Syndrome
Nephrology Dialysis Transplantation, 2016Co-Authors: Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Frances Flinter, Jeffrey H Miner, Judith Savige, Constantinos Deltas, Roser Torra, Isavella Savva, Laura PerinAbstract:Alport Syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis.
Frances Flinter - One of the best experts on this subject based on the ideXlab platform.
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the importance of clinician patient and researcher collaborations in Alport Syndrome
Pediatric Nephrology, 2020Co-Authors: Michelle N Rheault, Oliver Gross, Frances Flinter, Judith Savige, Michael J Randles, Andre Weinstock, Melissa Stepney, Neil A Turner, Gina Parziale, Jeffrey H MinerAbstract:Alport Syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport Syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport Syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
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expert consensus guidelines for the genetic diagnosis of Alport Syndrome
Pediatric Nephrology, 2019Co-Authors: Judy Savige, Oliver Gross, Frances Flinter, Jie Ding, Francesca Ariani, Francesca Mari, Mirella Bruttini, Alessandra Renieri, Constantinos Deltas, Daniel P GaleAbstract:Recent expert guidelines recommend genetic testing for the diagnosis of Alport Syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport Syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport Syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport Syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport Syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability.
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Alport Syndrome in women and girls
Clinical Journal of The American Society of Nephrology, 2016Co-Authors: Judy Savige, Deb Colville, Michelle N Rheault, Susie Gear, Rachel Lennon, Sharon Lagas, Moira Finlay, Frances FlinterAbstract:Alport Syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal recessive (15%). Many renal physicians think of Alport Syndrome as primarily affecting men. However, twice as many women are affected by the X-linked diseases. Affected women are commonly undiagnosed, but 15%–30% develop renal failure by 60 years and often hearing loss by middle age. Half of their sons and daughters are also affected. Autosomal recessive Alport Syndrome is less common, but is often mistaken for X-linked disease. Recessive inheritance is suspected where women develop early-onset renal failure or lenticonus. Their family may be consanguineous. The prognosis for other family members is very different from X-linked disease. Other generations, including parents and offspring, are not affected, and on average only one in four of their siblings inherit the disease. All women with Alport Syndrome should have their diagnosis confirmed with genetic testing, even if their renal function is normal, because of their own risk of renal failure and the risk to their offspring. Their mutations indicate the mode of inheritance and the likelihood of disease transmission to their children, and the mutation type suggests the renal prognosis for both X-linked and recessive disease. Women with X-linked Alport Syndrome should be tested at least annually for albuminuria and hypertension. The “Expert guidelines for the diagnosis and management of Alport Syndrome” recommend treating those with albuminuria with renin-angiotensin-aldosterone system (RAAS) blockade (and adequate birth control because of the teratogenic risks of angiotensin converting enzyme inhibitors), believing that this will delay renal failure. Current recommendations are that women with autosomal recessive Alport Syndrome should be treated with RAAS blockade from the time of diagnosis. In addition, women should be offered genetic counseling, informed of their reproductive options, and monitored closely during pregnancy for the development of hypertension.
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advances and unmet needs in genetic basic and clinical science in Alport Syndrome report from the 2015 international workshop on Alport Syndrome
Nephrology Dialysis Transplantation, 2016Co-Authors: Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Frances Flinter, Jeffrey H Miner, Judith Savige, Constantinos Deltas, Roser Torra, Isavella Savva, Laura PerinAbstract:Alport Syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis.
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the 2014 international workshop on Alport Syndrome
Kidney International, 2014Co-Authors: Jeffrey H Miner, Oliver Gross, Clifford E. Kashtan, Sharon Lagas, Frances Flinter, Colin Baigent, Parminder K Judge, Judith Savige, Dave Blatt, Jie DingAbstract:Alport Syndrome, historically referred to as hereditary glomerulonephritis with sensorineural deafness and anterior lenticonus, is a genetic disease of collagen α3α4α5(IV) resulting in renal failure. The collagen α3α4α5(IV) heterotrimer forms a network that is a major component of the kidney glomerular basement membrane (GBM) and basement membranes in the cochlea and eye. Alport Syndrome, estimated to affect 1 in 5000–10,000 individuals, is caused by mutations in any one of the three genes that encode the α chain components of the collagen α3α4α5(IV) heterotrimer: COL4A3, COL4A4, and COL4A5. Although angiotensin-converting enzyme inhibition is effective in Alport Syndrome patients for slowing progression to end-stage renal disease, it is neither a cure nor an adequate long-term protector. The 2014 International Workshop on Alport Syndrome, held in Oxford, UK, from January 3–5, was organized by individuals and families living with Alport Syndrome, in concert with international experts in the clinical, genetic, and basic science aspects of the disease. Stakeholders from diverse communities—patient families, physicians, geneticists, researchers, Pharma, and funding organizations—were brought together so that they could meet and learn from each other and establish strategies and collaborations for the future, with the overall aim of discovering much needed new treatments to prolong kidney function.
Jeffrey H Miner - One of the best experts on this subject based on the ideXlab platform.
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the importance of clinician patient and researcher collaborations in Alport Syndrome
Pediatric Nephrology, 2020Co-Authors: Michelle N Rheault, Oliver Gross, Frances Flinter, Judith Savige, Michael J Randles, Andre Weinstock, Melissa Stepney, Neil A Turner, Gina Parziale, Jeffrey H MinerAbstract:Alport Syndrome is caused by mutations in the genes COL4A3, COL4A4 or COL4A5 and is characterised by progressive glomerular disease, sensorineural hearing loss and ocular defects. Occurring in less than 1:5000, Alport Syndrome is a rare genetic disorder but still accounts for > 1% of the prevalent population receiving renal replacement therapy. There is also increasing awareness about the risk of chronic kidney disease in individuals with heterozygous mutations in Alport Syndrome genes. The mainstay of current therapy is the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, yet potential new therapies are now entering clinical trials. The 2017 International Workshop on Alport Syndrome in Glasgow was a pre-conference workshop ahead of the 50th anniversary meeting of the European Society for Pediatric Nephrology. It focussed on updates in clinical practice, genetics and basic science and also incorporated patient perspectives. More than 80 international experts including clinicians, geneticists, researchers from academia and industry, and patient representatives took part in panel discussions and breakout groups. This report summarises the workshop proceedings and the relevant contemporary literature. It highlights the unique clinician, patient and researcher collaborations achieved by regular engagement between the groups.
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clinical trial recommendations for potential Alport Syndrome therapies
Kidney International, 2020Co-Authors: Andre B Weinstock, Oliver Gross, Clifford E. Kashtan, Michelle N Rheault, Rachel Lennon, Sharon Lagas, David L Feldman, Alessia Fornoni, Jeffrey H Miner, James F SimonAbstract:Abstract Alport Syndrome is experiencing a remarkable increase in preclinical investigations. To proactively address the needs of the Alport Syndrome community as well as offer clarity for future clinical research sponsors, the Alport Syndrome Foundation hosted a workshop to generate consensus recommendations for prospective trials for conventional drugs. Opinions of key stakeholders were carefully considered, including those of the biopharmaceutical industry, academic researchers, clinicians, regulatory agencies, and—most critically—patients with Alport Syndrome. Recommendations were established for preclinical researchers, the use and selection of biomarkers, standards of care, clinical trial designs, trial eligibility criteria and outcomes, pediatric trial considerations, and considerations for patient engagement, recruitment, and treatment. This paper outlines their recommendations.
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pathogenicity of a human laminin β2 mutation revealed in models of Alport Syndrome
Journal of The American Society of Nephrology, 2017Co-Authors: Steven D Funk, Raymond H Bayer, Andrew F Malone, Karen K Mckee, Peter D Yurchenco, Jeffrey H MinerAbstract:Pierson Syndrome is a congenital nephrotic Syndrome with eye and neurologic defects caused by mutations in laminin β 2 ( LAMB2 ), a major component of the glomerular basement membrane (GBM). Pathogenic missense mutations in human LAMB2 cluster in or near the laminin amino-terminal (LN) domain, a domain required for extracellular polymerization of laminin trimers and basement membrane scaffolding. Here, we investigated an LN domain missense mutation, LAMB2-S80R, which was discovered in a patient with Pierson Syndrome and unusually late onset of proteinuria. Biochemical data indicated that this mutation impairs laminin polymerization, which we hypothesized to be the cause of the patient’s nephrotic Syndrome. Testing this hypothesis in genetically altered mice showed that the corresponding amino acid change (LAMB2-S83R) alone is not pathogenic. However, expression of LAMB2-S83R significantly increased the rate of progression to kidney failure in a Col4a3 −/− mouse model of autosomal recessive Alport Syndrome and increased proteinuria in Col4a5 +/− females that exhibit a mild form of X-linked Alport Syndrome due to mosaic deposition of collagen α 3 α 4 α 5(IV) in the GBM. Collectively, these data show the pathogenicity of LAMB2-S80R and provide the first evidence of genetic modification of Alport phenotypes by variation in another GBM component. This finding could help explain the wide range of Alport Syndrome onset and severity observed in patients with Alport Syndrome, even for family members who share the same COL4 mutation. Our results also show the complexities of using model organisms to investigate genetic variants suspected of being pathogenic in humans.
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functional assessment of a novel col4a5 splice region variant and immunostaining of plucked hair follicles as an alternative method of diagnosis in x linked Alport Syndrome
Pediatric Nephrology, 2017Co-Authors: Andrew F Malone, Steven D Funk, Tarek Alhamad, Jeffrey H MinerAbstract:Background Many COL4A5 splice region variants have been described in patients with X-linked Alport Syndrome, but few have been confirmed by functional analysis to actually cause defective splicing. We sought to demonstrate that a novel COL4A5 splice region variant in a family with Alport Syndrome is pathogenic using functional studies. We also describe an alternative method of diagnosis.
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albumin contributes to kidney disease progression in Alport Syndrome
American Journal of Physiology-renal Physiology, 2016Co-Authors: George Jarad, Russell H Knutsen, Robert P Mecham, Jeffrey H MinerAbstract:Alport Syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen-α3α4α5(IV) changes the glomerular basement membr...
