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Clinical Journal of the American... Apr 2015Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Mutations in the COL4A5 (X-linked), or COL4A3... (Review)
Review
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.
Topics: Animals; Autoantigens; Collagen Type IV; Diagnostic Techniques, Ophthalmological; Eye Diseases; Female; Genetic Predisposition to Disease; Humans; Male; Mutation; Nephritis, Hereditary; Phenotype; Predictive Value of Tests; Prognosis; Risk Factors
PubMed: 25649157
DOI: 10.2215/CJN.10581014 -
Clinical Journal of the American... Sep 2016Alport syndrome is an inherited disease characterized by progressive renal failure, hearing loss, and ocular abnormalities. Inheritance is X-linked (85%) or autosomal...
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.
Topics: Albuminuria; Female; Genetic Testing; Genotype; Humans; Hypertension; Kidney Failure, Chronic; Mutation; Nephritis, Hereditary; Pedigree; Phenotype
PubMed: 27287265
DOI: 10.2215/CJN.00580116 -
Clinical Medicine (London, England) May 2023Inherited diseases are a frequent cause of end-stage kidney disease and often seen in the kidney clinic. Clinical genomic testing is increasingly available in the UK and...
Inherited diseases are a frequent cause of end-stage kidney disease and often seen in the kidney clinic. Clinical genomic testing is increasingly available in the UK and eligible patients in England can be referred through the NHS Genomic Medicine Service. Testing is useful for diagnosis, prognostication and management of conditions such as autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, autosomal dominant tubulointerstitial kidney disease (ADTKD) and focal segmental glomerulosclerosis (FSGS). As more patients undergo genomic testing and newer technologies such as whole genome sequencing are applied, we are developing a greater appreciation of the full phenotypic spectrum of inherited kidney diseases and the challenges associated with the interpretation of clinically significant variants.
Topics: Humans; Kidney Failure, Chronic; Nephritis, Hereditary; Polycystic Kidney, Autosomal Dominant; Genomics; Kidney; Mutation
PubMed: 37236798
DOI: 10.7861/clinmed.2023-RM2 -
Pediatric Nephrology (Berlin, Germany) May 2024Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies... (Review)
Review
Renal ciliopathies are a common cause of kidney failure in children and adults, and this study reviewed their ocular associations. Genes affected in renal ciliopathies were identified from the Genomics England Panels. Ocular associations were identified from Medline and OMIM, and the genes additionally examined for expression in the human retina ( https://www.proteinatlas.org/humanproteome/tissue ) and for an ocular phenotype in mouse models ( http://www.informatics.jax.org/ ). Eighty-two of the 86 pediatric-onset renal ciliopathies (95%) have an ocular phenotype, including inherited retinal degeneration, oculomotor disorders, and coloboma. Diseases associated with pathogenic variants in ANK6, MAPKBP1, NEK8, and TCTN1 have no reported ocular manifestations, as well as low retinal expression and no ocular features in mouse models. Ocular abnormalities are not associated with the most common adult-onset "cystic" kidney diseases, namely, autosomal dominant (AD) polycystic kidney disease and the AD tubulointerstitial kidney diseases (ADTKD). However, other kidney syndromes with cysts have ocular features including papillorenal syndrome (optic disc dysplasia), Hereditary Angiopathy Nephropathy, Aneurysms and muscle Cramps (HANAC) (tortuous retinal vessels), tuberous sclerosis (retinal hamartomas), von Hippel-Lindau syndrome (retinal hemangiomas), and Alport syndrome (lenticonus, fleck retinopathy). Ocular abnormalities are associated with many pediatric-onset renal ciliopathies but are uncommon in adult-onset cystic kidney disease. However the demonstration of ocular manifestations may be helpful diagnostically and the features may require monitoring or treatment.
Topics: Adult; Child; Animals; Mice; Humans; Kidney; Retinal Diseases; Nephritis, Hereditary; Retina; Kidney Diseases, Cystic; Ciliopathies
PubMed: 37644229
DOI: 10.1007/s00467-023-06096-5 -
Genes Nov 2022Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant...
Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked (NM_000495.5) gene or recessive variants in the / (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the -p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.
Topics: Adolescent; Humans; Child, Preschool; Adult; Nephritis, Hereditary; Greece; Collagen Type IV; Hematuria; Renal Insufficiency
PubMed: 36553470
DOI: 10.3390/genes13122203 -
Journal of the American Society of... Feb 2018
Topics: Humans; Nephritis, Hereditary; Oleanolic Acid
PubMed: 29371422
DOI: 10.1681/ASN.2017121322 -
European Journal of Medical Research Jul 2021Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the...
BACKGROUND
Alport syndrome and C3 glomerulonephritis (C3GN) are rare kidney diseases, frequently responsible for familial haematuria, proteinuria, and renal impairment. With the rapid development of molecular genetic testing, Alport syndrome causes have been restricted mostly to variants in the COL4A5 or COL4A3/COL4A4 genes. Moreover, a broad range of genetic contributors in the complement and complement-regulating proteins are definitely implicated in the pathogenesis of C3GN.
METHODS
We sought a family with persistent microscopic haematuria associated with renal failure. Clinicopathologic and follow-up data were obtained, and molecular genetic testing was used to screen for pathogenic variants.
RESULTS
We describe a three-generation family with Alport syndrome showing a dominant maternal inheritance. Notably, renal biopsy showed the concurrent histological evidence of C3GN in the proband harbouring an uncommon heterozygous variation in CFHR5, c.508G > A. The alteration leads to replacement of a highly conserved residue at position 170 of the β-strand subunit of CFHR5 (p.Val170Met). In silico analysis showed that the variation was predicted to deregulate complement activation by altering the structural properties and enhancing C3b binding capacity to compete with Complement Factor H (CFH), which was in line with experimental data previously published.
CONCLUSIONS
The comorbidity findings between Alport syndrome and C3GN indicate an underlying overlap and require further study.
Topics: Adult; Child, Preschool; Complement C3; Complement System Proteins; DNA; DNA Mutational Analysis; Female; Follow-Up Studies; Glomerulonephritis; Humans; Kidney Glomerulus; Male; Microscopy, Electron; Mutation; Nephritis, Hereditary; Pedigree; Retrospective Studies; Time Factors
PubMed: 34238373
DOI: 10.1186/s40001-021-00543-5 -
Journal of Medical Genetics Apr 1997Alport's syndrome (AS) is a progressive glomerulonephritis which is associated with high tone sensorineural deafness and characteristic eye signs. It accounts for 0.6%... (Review)
Review
Alport's syndrome (AS) is a progressive glomerulonephritis which is associated with high tone sensorineural deafness and characteristic eye signs. It accounts for 0.6% of all patients who start renal replacement therapy in Europe, and is most commonly inherited as an X linked disorder with a gene frequency of 1 in 5000. During the last six years several type IV collagen genes have been implicated in the aetiology of AS, and mutation detection studies are enabling genotype/phenotype correlations to be made, as well as facilitating carrier detection and prenatal diagnosis.
Topics: Collagen; Female; Genetic Therapy; Genotype; Humans; Kidney; Male; Nephritis, Hereditary; Phenotype; X Chromosome
PubMed: 9138159
DOI: 10.1136/jmg.34.4.326 -
Kidney International Aug 2023X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5...
X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.
Topics: Humans; Nephritis, Hereditary; Collagen Type IV; Mutation; Exons; RNA Splicing
PubMed: 37230224
DOI: 10.1016/j.kint.2023.05.006 -
The Journal of Physiology Sep 2014The glomerular filtration barrier comprises a fenestrated capillary endothelium, glomerular basement membrane and podocyte slit diaphragm. Over the past decade we have... (Review)
Review
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.
Topics: Animals; Glomerular Filtration Barrier; Humans; Kidney; Nephritis, Hereditary
PubMed: 25107927
DOI: 10.1113/jphysiol.2014.274449