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Alport Syndrome

The Experts below are selected from a list of 5223 Experts worldwide ranked by ideXlab platform

Judy Savige – 1st expert on this subject based on the ideXlab platform

  • expert consensus guidelines for the genetic diagnosis of Alport Syndrome
    Pediatric Nephrology, 2019
    Co-Authors: Judy Savige, Oliver Gross, Frances Flinter, Jie Ding, Francesca Ariani, Francesca Mari, Mirella Bruttini, Alessandra Renieri, Constantinos Deltas, Daniel P Gale

    Abstract:

    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.

  • Alport Syndrome in women and girls
    Clinical Journal of The American Society of Nephrology, 2016
    Co-Authors: Judy Savige, Deb Colville, Michelle N Rheault, Susie Gear, Rachel Lennon, Sharon Lagas, Moira Finlay, Frances Flinter

    Abstract:

    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.

  • ocular features in Alport Syndrome pathogenesis and clinical significance
    Clinical Journal of The American Society of Nephrology, 2015
    Co-Authors: Judy Savige, Deb Colville, Shivanand Sheth, Anita Leys, Anjali Nicholson, Heather G Mack

    Abstract:

    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.

Clifford E. Kashtan – 2nd expert on this subject based on the ideXlab platform

  • clinical trial recommendations for potential Alport Syndrome therapies
    Kidney International, 2020
    Co-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 Simon

    Abstract:

    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.

  • Renal transplantation in patients with Alport Syndrome: patient selection, outcomes, and donor evaluation
    International Journal of Nephrology and Renovascular Disease, 2018
    Co-Authors: Clifford E. Kashtan

    Abstract:

    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.

  • Alport Syndrome facts and opinions
    F1000Research, 2017
    Co-Authors: Clifford E. Kashtan

    Abstract:

    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.

Oliver Gross – 3rd expert on this subject based on the ideXlab platform

  • Novel COL4A5, COL4A4, and COL4A3 Mutations in Alport Syndrome
    Human Mutation, 2020
    Co-Authors: Mato Nagel, Sylvia Nagorka, Oliver Gross

    Abstract:

    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.

  • the importance of clinician patient and researcher collaborations in Alport Syndrome
    Pediatric Nephrology, 2020
    Co-Authors: Michelle N Rheault, Oliver Gross, Frances Flinter, Judith Savige, Michael J Randles, Andre Weinstock, Melissa Stepney, Neil A Turner, Gina Parziale, Jeffrey H Miner

    Abstract:

    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.

  • clinical trial recommendations for potential Alport Syndrome therapies
    Kidney International, 2020
    Co-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 Simon

    Abstract:

    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.