-
American Journal of Kidney Diseases :... Feb 2021Alport syndrome is a genetically and phenotypically heterogeneous disorder of glomerular, cochlear, and ocular basement membranes resulting from mutations in the... (Review)
Review
Alport syndrome is a genetically and phenotypically heterogeneous disorder of glomerular, cochlear, and ocular basement membranes resulting from mutations in the collagen IV genes COL4A3, COL4A4, and COL4A5. Alport syndrome can be transmitted as an X-linked, autosomal recessive, or autosomal dominant disorder. Individuals with Alport syndrome have a significant lifetime risk for kidney failure, as well as sensorineural deafness and ocular abnormalities. The availability of effective intervention for Alport syndrome-related kidney disease makes early diagnosis crucial, but this can be impeded by the genotypic and phenotypic complexity of the disorder. This review presents an approach to enhancing early diagnosis and achieving optimal outcomes.
Topics: Angiotensin-Converting Enzyme Inhibitors; Autoantigens; Biopsy; Collagen Type IV; Disease Progression; Early Diagnosis; Early Medical Intervention; Genetic Testing; Genotype; Glomerular Filtration Rate; Hematuria; Humans; Kidney; Kidney Failure, Chronic; Nephritis, Hereditary; Phenotype
PubMed: 32712016
DOI: 10.1053/j.ajkd.2020.03.026 -
Clinical Journal of the American... Jan 2022Genetic testing for pathogenic variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney...
Genetic testing for pathogenic variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic or is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that or heterozygotes do not act as kidney donors. Testing for variants in the genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.
Topics: Autoantigens; Collagen Type IV; Genetic Testing; Humans; Nephritis, Hereditary; Practice Guidelines as Topic
PubMed: 34930753
DOI: 10.2215/CJN.04230321 -
Clinical Journal of the American... Nov 2022Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the... (Review)
Review
Digenic Alport syndrome refers to the inheritance of pathogenic variants in plus or or in plus Where digenic Alport syndrome includes a pathogenic variant, the consequences depend on the sex of the affected individual, variant "severity," and the nature of the or change. A man with a pathogenic variant has all his collagen IV 345-heterotrimers affected, and an additional or variant may not worsen disease. A woman with a pathogenic variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further or variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic and variants, 75% of the heterotrimers are affected. The and genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome () or recessive when they affect different chromosomes (). 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 and variants are known to be inherited on the same or different chromosomes.
Topics: Humans; Male; Female; Nephritis, Hereditary; Pedigree; Autoantigens; Collagen Type IV; Proteinuria; Mutation
PubMed: 35675912
DOI: 10.2215/CJN.03120322 -
Pediatric Nephrology (Berlin, Germany) Jul 2019Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In... (Review)
Review
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.
Topics: Autoantigens; Collagen Type IV; Consensus; DNA Mutational Analysis; Genetic Testing; Genotype; High-Throughput Nucleotide Sequencing; Humans; Mutation; Nephritis, Hereditary; Phenotype; Practice Guidelines as Topic
PubMed: 29987460
DOI: 10.1007/s00467-018-3985-4 -
Pediatric Nephrology (Berlin, Germany) Mar 2021In 2013, we published a set of clinical practice recommendations for the treatment of Alport syndrome in this journal. We recommended delaying the initiation of... (Review)
Review
In 2013, we published a set of clinical practice recommendations for the treatment of Alport syndrome in this journal. We recommended delaying the initiation of angiotensin-converting enzyme inhibition until the onset of overt proteinuria or, in some cases, microalbuminuria. Developments that have occurred over the past 7 years have prompted us to revise these recommendations. We now recommend the initiation of treatment at the time of diagnosis in males with X-linked Alport syndrome and in males and females with autosomal recessive Alport syndrome. We further recommend starting treatment at the onset of microalbuminuria in females with X-linked Alport syndrome and in males and females with autosomal dominant Alport syndrome. This article presents the rationale for these revisions as well as recommendations for diagnostic tactics intended to ensure the early diagnosis of Alport syndrome.
Topics: Adolescent; Albuminuria; Child; Collagen Type IV; Humans; Nephritis, Hereditary; Proteinuria; Young Adult
PubMed: 33159213
DOI: 10.1007/s00467-020-04819-6 -
Kidney International May 2018Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous...
Mutations in the genes COL4A3, COL4A4, and COL4A5 affect the synthesis, assembly, deposition, or function of the collagen IV α345 molecule, the major collagenous constituent of the mature mammalian glomerular basement membrane. These mutations are associated with a spectrum of nephropathy, from microscopic hematuria to progressive renal disease leading to ESRD, and with extrarenal manifestations such as sensorineural deafness and ocular anomalies. The existing nomenclature for these conditions is confusing and can delay institution of appropriate nephroprotective therapy. Herein we propose a new classification of genetic disorders of the collagen IV α345 molecule with the goal of improving renal outcomes through regular monitoring and early treatment.
Topics: Autoantigens; Collagen Type IV; Consensus; DNA Mutational Analysis; Genetic Markers; Genetic Predisposition to Disease; Humans; Mutation; Nephritis, Hereditary; Phenotype; Predictive Value of Tests; Prognosis; Terminology as Topic
PubMed: 29551517
DOI: 10.1016/j.kint.2017.12.018 -
Trends in Pharmacological Sciences Nov 2019Alport syndrome (AS), a rare disease of basement membrane type IV collagen, impacts the kidneys, ears, and eyes. In severe cases, kidney failure occurs during... (Review)
Review
Alport syndrome (AS), a rare disease of basement membrane type IV collagen, impacts the kidneys, ears, and eyes. In severe cases, kidney failure occurs during adolescence or early adulthood, so most research has focused on remedies for kidney dysfunction. Planned and ongoing clinical studies using targets and therapeutic approaches discussed herein provide new hope for AS patients. The outcomes of these trials could suggest new treatments for more common forms of chronic kidney disease (CKD), demonstrating the importance of focusing on treatments for rare diseases.
Topics: Animals; Humans; Molecular Targeted Therapy; Nephritis, Hereditary; Randomized Controlled Trials as Topic; Renin-Angiotensin System
PubMed: 31455555
DOI: 10.1016/j.tips.2019.07.012 -
Kidney International. Supplement Mar 1997
-
Kidney International Nov 1996
-
Clinical and Experimental Nephrology Feb 2019Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three... (Review)
Review
Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.
Topics: Adult; Animals; Autoantigens; Collagen Type IV; Female; Genetic Association Studies; Genetic Predisposition to Disease; Heredity; Humans; Kidney; Male; Mutation; Nephritis, Hereditary; Phenotype; Prognosis; Risk Factors; Young Adult
PubMed: 30128941
DOI: 10.1007/s10157-018-1629-4