Alport syndrome: facts and opinions.
Ontology highlight
ABSTRACT:
SUBMITTER: Kashtan C
PROVIDER: S-EPMC5247785 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
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. ...[more]
Similar Datasets
Project description:Congenial information is often judged to be more valid than uncongenial (but otherwise equivalent) information. The present research explores a related possibility concerning the process by which people label a claim as fundamentally factual (open to proof or disproof) or opinion (a matter of personal preference not amenable to falsification). Rather than merely being more skeptical of uncongenial claims, uncongenial claims may be metacognitively categorized as more opinion than factual, while congenial claims may be more likely to be categorized as factual. The two studies reported here attempt to trace a preliminary outline of how claims are categorized as fact, opinion, or some mix of the two in the context of mundane claims, contentious political issues, and conspiracy theories. The findings suggest that claims are more likely to be labeled factual (and, to a lesser extent, are less likely to be labeled opinion) to the extent that one subjectively agrees with the content of the claim. Conspiracy theories appear to occupy a middle-ground between fact and opinion. This metacognitive approach may help shed light on popular debate about conspiracy theories, as well as seemingly intractable political disagreements more generally, which may reflect fundamental differences in the perceived epistemic foundations of claims rather than simple disagreement over the facts of the matter. Given limitations of the stimuli and participant samples, however, it remains to be seen how generalizable these findings are.
| S-EPMC8044776 | biostudies-literature
Project description:Digenic Alport syndrome refers to the inheritance of pathogenic variants in COL4A5 plus COL4A3 or COL4A4 or in COL4A3 plus COL4A4 Where digenic Alport syndrome includes a pathogenic COL4A5 variant, the consequences depend on the sex of the affected individual, COL4A5 variant "severity," and the nature of the COL4A3 or COL4A4 change. A man with a pathogenic COL4A5 variant has all his collagen IV α3α4α5-heterotrimers affected, and an additional COL4A3 or COL4A4 variant may not worsen disease. A woman with a pathogenic COL4A5 variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further COL4A3 or COL4A4 variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic COL4A3 and COL4A4 variants, 75% of the heterotrimers are affected. The COL4A3 and COL4A4 genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (in cis) or recessive when they affect different chromosomes (in trans). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if COL4A3 and COL4A4 variants are known to be inherited on the same or different chromosomes.
| S-EPMC9718039 | biostudies-literature
Project description:Nepotistic practices are detrimental for academia. An analysis of shared last names among academics was recently proposed to measure the diffusion of nepotism, the results of which have had a huge resonance. This method was thus proposed to orient the decisions of policy makers concerning cuts and funding. Because of the social relevance of this issue, the validity of this method must be assessed. Thus, we compared results from an analysis of Italian and United Kingdom academic last names, and of Italian last and given names. The results strongly suggest that the analysis of shared last names is not a measure of nepotism, as it is largely affected by social capital, professional networking and demographic effects, whose contribution is difficult to assess. Thus, the analysis of shared last names is not useful for guiding research policy.
| S-EPMC3427342 | biostudies-literature
Project description:Alport syndrome affects up to 60,000 people in the United States. The proposed reclassification of thin basement membrane nephropathy and some cases of focal segmental glomerulosclerosis as Alport syndrome could substantially increase the affected population. The reclassification scheme categorizes Alport syndrome as 3 distinct diseases of type IV collagen ?3/4/5 based on a genetic evaluation: X-linked, autosomal, and digenic. This approach has the advantage of identifying patients at risk for progressive loss of kidney function. Furthermore, the shared molecular cause of Alport syndrome and thin basement membrane nephropathy arises from mutations in the COL4A3, COL4A4, and COL4A5 genes, which contribute to downstream pathophysiologic consequences, including chronic kidney inflammation. Recent evidence indicates that chronic inflammation and its regulation through anti-inflammatory nuclear factor erythroid 2-related factor 2 (Nrf2) and proinflammatory nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B) transcription factors plays a central role in renal tubular and glomerular cell responses to injury. Crosstalk between the Nrf2 and NF-?B pathways is important in the regulation of inflammation in patients with chronic kidney disease; moreover, there is evidence that an insufficient Nrf2 response to inflammation contributes to disease progression. Given the association between type IV collagen abnormalities and chronic inflammation, there is renewed interest in targeted anti-inflammatory therapies in Alport syndrome and other forms of progressive chronic kidney disease.
| S-EPMC7568086 | biostudies-literature
Project description: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.
| S-EPMC4182137 | biostudies-literature
Project description:BackgroundThere have been isolated case reports of arterial disease in males with Alport syndrome (AS), a systemic disorder of Type IV collagen. In this paper, we describe five new cases of AS associated with significant aortic disease including dissection and aneurysm.MethodsWe present brief clinical descriptions of five males with AS and aortic disease. We performed immunohistochemical analysis of the expression of the α5 chain of Type IV collagen in skin basement membranes from a previously reported family with AS and associated aortic disease and in the aortic media of male mice with X-linked Alport syndrome (XLAS) due to a nonsense mutation in the COL4A5 gene.ResultsThree of the five patients exhibited aneurysm and dissection of the thoracic aorta, occurring at 25-32 years of age, while one had aortic dilatation and another had aortic insufficiency. All five men required renal replacement therapy by age 20. Immunohistochemistry of skin biopsy specimens in previously reported male siblings with aortic disease confirmed that they had XLAS. We further found that the α5 chain of Type IV collagen is abnormally absent from aortic media of transgenic mice with XLAS.ConclusionsEarly onset aortic disease may be an unusual feature of AS. Screening of men with AS for aortic abnormalities may be clinically indicated in some families.
| S-EPMC2980995 | biostudies-literature
Project description: Not available
| S-EPMC3355248 | biostudies-literature
Project description:Background and objectivesAlport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.Design, setting, participants, & measurementsWe randomly assigned patients with Alport syndrome, ages 12-70 years and eGFR 30-90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight.ResultsPatients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P=0.02) ml/min per 1.73 m2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, -1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure.ConclusionsIn adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.Clinical trial registry name and registration numberA Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185.
| S-EPMC9718021 | biostudies-literature
Project description:Purpose of reviewIn Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold - an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with Angiotensin-Converting enzyme (ACE) inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function.Recent findingsMultiple approaches emerged recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on (1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, (2) development of DNA editing tools for gene therapy, (3) RNA splicing interference, and (4) control of mRNA translation.SummaryThere is a growing confidence that these approaches will ultimately provide cure for Alport patients. The development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.
| S-EPMC9159491 | biostudies-literature