Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin-chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product.
- MeSH
- autoantigeny genetika MeSH
- chronická renální insuficience * komplikace MeSH
- dědičná nefritida * farmakoterapie genetika MeSH
- diabetes mellitus 2. typu * komplikace MeSH
- dítě MeSH
- glifloziny * MeSH
- hematurie MeSH
- kolagen typu IV genetika MeSH
- lidé MeSH
- mladý dospělý MeSH
- mutace MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mladý dospělý MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Genetic testing for pathogenic COL4A3-5 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 COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 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.
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.
- MeSH
- alfa-galaktosidasa terapeutické užití MeSH
- antagonisté antidiuretického hormonu farmakologie terapeutické užití MeSH
- antihypertenziva terapeutické užití MeSH
- dědičná nefritida diagnóza genetika terapie MeSH
- dieta s nízkým obsahem soli MeSH
- diferenciální diagnóza MeSH
- dítě MeSH
- dospělí MeSH
- everolimus farmakologie terapeutické užití MeSH
- Fabryho nemoc genetika klasifikace terapie MeSH
- hypertenze etiologie farmakoterapie MeSH
- imunosupresiva terapeutické užití MeSH
- inhibitory ACE MeSH
- lidé MeSH
- mnohočetné abnormality epidemiologie etiologie MeSH
- oktreotid aplikace a dávkování farmakologie MeSH
- polycystické ledviny autozomálně dominantní epidemiologie genetika komplikace terapie MeSH
- prevalence MeSH
- statiny farmakologie terapeutické užití MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
There are 3 major forms of autosomal dominant tubulointerstitial kidney disease (ADTKD): ADTKD due to UMOD mutations, MUC1 mutations, and mutations in the REN gene encoding renin. Lack of knowledge about these conditions contributes to frequent nondiagnosis, but with even limited knowledge, nephrologists can easily obtain a diagnosis and improve patient care. There are 3 cardinal features of these disorders: (1) the conditions are inherited in an autosomal dominant manner and should be considered whenever both a parent and child suffer from kidney disease; the presence of even more affected family members provides further support. (2) These conditions are associated with a bland urinary sediment, ruling out glomerular disorders. (3) There is a variable rate of decline in kidney function. The mean age of ESRD is approximately 45, but the range is from 17 to >75. ADTKD-UMOD is often but not always associated with gout in the teenage years. ADKTKD-REN is associated with signs of hyporeninemia: mild hypotension, mild hyperkalemia, anemia in childhood, and hyperuricemia and gout in the teenage years. The only clinical manifestation of ADTKD-MUC1 is slowly progressive CKD. Diagnosis should be made by genetic testing, and kidney biopsy should be avoided.
- MeSH
- dědičná nefritida komplikace diagnóza farmakoterapie genetika MeSH
- hepatocytární jaderný faktor 1-beta genetika MeSH
- lidé MeSH
- mucin 1 genetika MeSH
- mutace MeSH
- renin genetika MeSH
- uromodulin genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The most frequent cause of familial glomerular hematuria is thin basement membrane nephropathy (TBMN) caused by germline COL4A3 or COL4A4 gene mutations. Less frequent but important cause with respect to morbidity is Alport syndrome caused by germline COL4A5 gene mutations. The features of Alport syndrome include hematuria, proteinuria and all males with X-linked disease and all individuals with recessive disease will develop end stage renal disease, usually at early youth. In X-linked Alport syndrome, a clear genotype-phenotype correlation is typically observed in men. Deleterious COL4A5 mutations are associated with a more severe renal phenotype and more frequent high-frequency sensorineural hearing loss and ocular abnormalities. Less severe COL4A5 mutations result in a milder phenotype, with less frequent and later onset extrarenal anomalies. The phenotype in females is highly variable, mostly due to inactivation of one of the X chromosomes. Isolated cases may be caused by de novo COL4A5 mutations or by gonosomal mosaicism. Untreated autosomal recessive Alport syndrome, caused by COL4A3 and COL4A4 mutations, is typically associated with ESRD at the age of 23-25 years and extrarenal symptoms in both men and women. The TBMN phenotype is associated with heterozygous carriers of COL4A3, COL4A4 mutations. Molecular genetic testing is the gold standard for diagnosing these diseases. Although genotype-phenotype correlations exist, the phenotype is influenced by modifying factors, which remain mainly undefined. No therapy is available that targets the cause of Alport syndrome; angiotensin-converting enzyme inhibitor therapy delays renal failure and improves lifespan.
- MeSH
- biopsie MeSH
- dědičná nefritida * diagnóza genetika patologie terapie MeSH
- dospělí MeSH
- genetická predispozice k nemoci MeSH
- genetické asociační studie MeSH
- genetické nemoci vázané na chromozom X * diagnóza genetika patologie terapie MeSH
- glomerulární bazální membrána patologie MeSH
- hematurie * diagnóza genetika patologie terapie MeSH
- hemizygot MeSH
- kolagen typu IV genetika MeSH
- lidé MeSH
- prevalence MeSH
- proteinurie moč MeSH
- riziko MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Pacienti s dědičnými onemocněními ledvin tvoří 10–15 % pacientů s renálním selháním. Genetické faktory přispívají i k vývojovým anomáliím ledvin, které se pak v rodinách mohou vyskytovat opakovaně. Nejčastějším dědičným onemocněním ledvin je autosomálně dominantní polycystická choroba ledvin. V současné době je možné objem polycystických ledvin sledovat relativně přesně magnetickou rezonancí, což i koreluje s prognózou onemocnění. Jsou zmíněny i současné terapeutické možnosti. Dále jsou popsána další dědičná cystická onemocnění ledvin. V další části je diskutováno genetické pozadí Alportova syndromu, nefrotického syndromu a v neposlední řadě současný stav genetiky u nádorů ledvin.
The patients with hereditary renal diseases form about 10-15% of patients with renal failure. Genetic factors contribute to developmental kidney anomalies, which can affect multiple members of the respective families. The most common hereditary disease is autosomal dominant polycystic kidney disease (ADPKD). Nowadays, the renal volume can be evaluated by magnetic resonance. Higher volume correlates with faster glomerular filtration rate decline. The therapeutic possibilities for ADPKD are mentioned in the article. Other hereditary cystic renal disease are also described. Genetic background of Alport syndrome, nephrotic syndrome and renal tumours is discussed in details.
- MeSH
- cystická onemocnění ledvin diagnóza genetika terapie MeSH
- dědičná nefritida diagnóza genetika terapie MeSH
- dítě MeSH
- dospělí MeSH
- genetické nemoci vrozené * diagnóza genetika terapie MeSH
- lidé MeSH
- nádory ledvin diagnóza epidemiologie genetika MeSH
- nefrotický syndrom diagnóza genetika MeSH
- nefróza diagnóza genetika MeSH
- nemoci ledvin * diagnóza genetika terapie MeSH
- polycystické ledviny autozomálně recesivní diagnóza genetika MeSH
- předškolní dítě MeSH
- prognóza MeSH
- tuberózní skleróza diagnóza genetika terapie MeSH
- von Hippelova-Lindauova nemoc diagnóza genetika MeSH
- Wilmsův nádor diagnóza genetika terapie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- MeSH
- dědičná nefritida genetika komplikace MeSH
- lidé MeSH
- nemoci oční čočky terapie vrozené MeSH
- oční čočka chirurgie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- kazuistiky MeSH
Alport syndrome (AS) is a genetically heterogeneous hereditary renal disease. X-Linked AS (XLAS) is responsible for 80% to 85% of familial cases and is caused by mutations in the COL4A5 collagen gene. To date, indirect molecular diagnosis for XLAS is not well defined, and mutation screening of the COL4A5 gene is time consuming and complicated because of its large size and high allelic heterogeneity. Our aim is to facilitate XLAS genetic testing. METHODS: For linkage analysis, we tested the applicability of 4 microsatellite markers defining a 1.2-megabase region flanking the COL4A5 gene. For mutation screening of the COL4A5 gene, we describe a new strategy based on direct sequencing of hair root COL4A5 messenger RNA (mRNA). RESULTS: Three microsatellite markers proved accurate (DXS1120, DXS6802, and DXS1210) and 1 was discarded (DXS6797) because it was difficult to interpret. The mutation screening method provides results in 4 days, and when applied to 29 patients suspected of having XLAS, it identified mutations in 76% (22 of 29 patients). This study correlates COL4A5 mutations with effects at the mRNA level and suggests that mutations affecting mRNA splicing of the COL4A5 gene (41%; 9 of 22 patients) are more common than previously described. Many splicing mutations did not alter the canonical 5' and 3' splice sites. CONCLUSIONS: A more reliable linkage analysis and a simple, fast, and efficient mutation screening are now available for the genetic testing of patients with XLAS.
- MeSH
- dědičná nefritida diagnóza genetika MeSH
- genetická vazba genetika MeSH
- genetické testování metody MeSH
- kolagen typu IV genetika MeSH
- komplementární DNA genetika MeSH
- lidé MeSH
- mikrosatelitní repetice genetika MeSH
- RNA genetika MeSH
- sekvenční analýza DNA metody MeSH
- vlasový folikul fyziologie MeSH
- Check Tag
- lidé MeSH
- MeSH
- Bartterův syndrom diagnóza epidemiologie genetika MeSH
- dědičná nefritida diagnóza epidemiologie genetika MeSH
- Fabryho nemoc diagnóza genetika MeSH
- genetické nemoci vrozené diagnóza klasifikace prevence a kontrola MeSH
- lidé MeSH
- nemoci ledvin genetika MeSH
- plošný screening MeSH
- polycystická choroba ledvin diagnóza epidemiologie genetika MeSH
- Check Tag
- lidé MeSH
