Alport syndrome Dotaz Zobrazit nápovědu
Práce podává přehled imunohistologických a molekulárně genetických metod pro diagnostiku Alportova syndromu (AS) a uvádí praktické zkušenosti na souborech vlastních pozorování. Imunofluorescenční vyšetření za použití protilátek proti alfa řetězcům kolagenu IV bylo provedeno na kryostatových řezech z 29 punkčních biopsií ledvin a z 9 kožních excizí pro podporu diferenciální diagnózy AS zejména proti glomerulopatii tenkých membrán. V dalších 14 případech byly sledovány změny alfa řetězců u jiných chorob ledvin. Molekulárně genetické vyšetření AS nepřímou DNA diagnostikou bylo provedeno u 35 rodin se suspektní diagnózou AŠ a u 27 pacientů z pravděpodobnou mutací byl proveden mutační skreening COL4A5 genu přímou metodou SSCP. Mutace byla prokázána u 10 případů. Vzhledem ke genotypické i fenotypické variabilitě Alportova syndromu stoupá diagnostická výtěžnost teprve při kombinaci všech dosažitelných metod.
An overview of immunohistological and molecular genetic methods for diagnosis of Alport syn(AS) is given with practical experience from groups of authors' observations. Immunofluorescent investigation using antibodies against alfa chains of collagen IV was performed on cryostat sections from 29 punction nephrobiopsies and 9 skin excisions taken for support of differential diagnosis of AS particularly against the thin membranes glomerulopathy. Alfa chains deviations in other renal diseases were followed in another 14 cases. Molecular genetical investigation of AS by an indirect DNA diagnostics was performed in 35 families with presumed AS and in 27 patients with probable mutation a mutation screening of C0L4AS gene by a direct method SSCP was made. The mutation was proved in 10 cases. Because of genotypical and phenotypical variability of AS the diagnostic gain only increases when all the accessible methods are combined.
Autoři popisují kazuistiku 13leté dívky s renálním onemocněním, která se dostavila na ambulanci Dětské oční kliniky, FN Brno se subjektivní stížností oboustranného poklesu vizu. Oftalmoskopicky na fundu patrný fyziologický foveolární reflex, v makule velmi diskrétní změny na úrovni RPE, ostatní nález do periferie bez patologie. OCT obraz ukázal bilaterální atrofii makuly a změny na úrovni fotoreceptorů. Autoři podrobně popisují vzácnou oční manifestaci makulární atrofie u Alportova syndromu. Upozorňují na souvislost této retinální afekce s AS a zdůrazňují důležitost správné diagnostiky přínosné zejména u heterozygotních žen, u kterých je variabilita X vázaného onemocnění velká a přítomnost této retinální či jiné anomálie může podpořit podezření na toto celkové onemocnění a napomoci k celkové diagnostice systémového onemocnění. Autoři se dále věnují obecně možné oční manifestaci u pacientů s Alportovým syndromem a srovnávají nález s dostupnou světovou literaturou.
The authors mention a case report of a 13 year old girl with renal disease, who visited the outpatient Department of Pediatric Ophthalmology, University Hospital Brno with subjective complaints on decreased vision of both eyes. Ophthalmologic examination showed physiological foveolar reflex on fundus and very discrete changes of the retinal pigment epithelium in macula, the fundus periphery was without pathology. OCT images showed bilateral atrophy of central macula and changes at the level of the photoreceptors. The authors describe a rare ocular manifestation of macular atrophy with suspect Alport syndrome, which strengthened the suspicion of this disease. The authors also mention other possible ocular manifestations of Alport syndrome and compare the findings with the up to date international references.
- Klíčová slova
- makulární atrofie, lentikonus,
- MeSH
- dědičná nefritida * diagnóza komplikace patofyziologie MeSH
- geny vázané na chromozom X MeSH
- heterozygot MeSH
- lidé MeSH
- makulární degenerace * diagnóza genetika komplikace MeSH
- mladiství MeSH
- nemoci retiny diagnóza genetika komplikace MeSH
- optická koherentní tomografie MeSH
- retina * abnormality patologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
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.
Contributions to nephrology ; Vol. 117
204 s. : obr., tab., grafy ; 25 cm
- Klíčová slova
- makulární atrofie, lentikonus,
- MeSH
- dědičná nefritida * diagnóza komplikace patofyziologie MeSH
- geny vázané na chromozom X MeSH
- heterozygot MeSH
- lidé MeSH
- makulární degenerace * diagnóza genetika komplikace MeSH
- mladiství MeSH
- nemoci retiny diagnóza genetika komplikace MeSH
- optická koherentní tomografie MeSH
- retina * abnormality patologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
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.
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
- bazální membrána MeSH
- chromozom X MeSH
- dědičná nefritida etiologie genetika MeSH
- glomerulus MeSH
- percepční nedoslýchavost MeSH
- Publikační typ
- přehledy MeSH
