scholarly journals The Genetics, Current Research, and Future Treatment of Alport Syndrome

2017 ◽  
Vol 6 (1) ◽  
pp. 1-7
Author(s):  
Elise Alexandra Kikis ◽  
Emily Holland Williams
Keyword(s):  
Basement Membrane ◽  
End Stage Renal Disease ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
Autosomal Dominant ◽  
Basement Membranes ◽  
Type Iv ◽  
Stage Renal Disease ◽  
End Stage

Alport syndrome is a type IV collagen disease that affects the glomerular basement membrane of approximately one in every 5000 people. The disease was first described by A. Cecil Alport in 1927 as “a dominantly inherited hereditary nephritis.” The three genotypes of the disease are X-linked dominant, autosomal recessive, and autosomal dominant. The X-linked dominant genotype is the most common, accounting for 80% of all cases of Alport syndrome, affecting mainly men. The autosomal recessive and autosomal dominant types affect men and women equally. Alport syndrome is caused by mutations on the COL4A3, COL4A4, and COL4A5 genes, which code the ?3, ?4, and ?5 (IV) chains that make up type IV collagen molecules, an important component of basement membranes. Thus, Alport syndrome results in malformed basement membranes, with symptoms including renal impairment, hematuria, bilateral sensorineural hearing loss, and an abnormal structure of the glomerular basement membrane. Alport syndrome also often progresses to end-stage renal disease, especially in men with X-linked Alport syndrome. At this point, there is no cure for Alport syndrome. However, there are many successful treatments for its symptoms. Angiotensin-converting enzyme (ACE) inhibitors are often given to patients in the early stages of Alport syndrome. For patients with end-stage renal disease, dialysis or kidney transplants are considered the best course of action.

scholarly journals Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis.

1995 ◽  
Vol 5 (9) ◽  
pp. 1714-1717
Author(s):  
J Ding ◽  
J Stitzel ◽  
P Berry ◽  
E Hawkins ◽  
C E Kashtan
Keyword(s):  
Basement Membrane ◽  
Renal Disease ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
Premature Stop Codon ◽  
Sensorineural Deafness ◽  
Type Iv ◽  
Base Pair Deletion ◽  
Carboxy Terminal

Autosomal recessive Alport syndrome can arise from a mutation in either of the genes COL4A3 and COL4A4 on chromosome 2, which encode, respectively, the alpha 3 and alpha 4 chains of Type IV collagen. This report describes a mutation in COL4A3 in a girl who presented at age 5 with hematuria and proteinuria, lacking any family history of renal disease. Renal biopsy at age 8 showed immunoglobulin A nephropathy and Alport syndrome. Sensorineural deafness developed during adolescence, and the patient's renal disease progressed to terminal renal failure by age 20. She received a living related donor renal allograft at age 20 and developed antiglomerular basement membrane nephritis of the allograft 8 months after transplantation. Amplification and sequencing of exon 5 of COL4A3 (counting from the 3' end of the gene) revealed a 7-base-pair deletion, producing a shift of the reading frame and the creation of a premature stop codon. Each parent was heterozygous for the normal and mutant exon 5 sequences. This mutation in COL4A3 would result in the loss of 222 amino acids from the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The mutant chain would be unable to form trimers with other Type IV collagen alpha chains. In addition, the mutant chain would lack the Goodpasture epitope, which resides in the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The absence of this epitope may underly the subsequent development of anti-glomerular basement membrane nephritis in the allograft.

Alport Syndrome and Thin Glomerular Basement Membrane Nephropathy: A Practical Approach to Diagnosis

2009 ◽  
Vol 133 (2) ◽  
pp. 224-232 ◽  
Author(s):  
Mark Haas
Keyword(s):  
Electron Microscopy ◽  
Basement Membrane ◽  
Renal Biopsy ◽  
Glomerular Basement Membrane ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
The Past ◽  
Type Iv ◽  
Pathologic Features

Abstract Context.—Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogenous conditions characterized by structural abnormalities in the glomerular basement membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen α3 [α3(IV)] and α4 chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the α5 chain of type IV collagen [α5(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport syndrome. Objectives.—To review diagnostic pathologic features of each of the above conditions, emphasizing the need for immunohistology for α3(IV) and α5(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for α5(IV) on a skin biopsy in family members of patients with Alport syndrome also is reviewed. Data Sources.—Original and comprehensive review articles on the diagnosis of Alport syndrome and TBMN from the past 35 years, primarily the past 2 decades, and experience in our own renal pathology laboratory. Conclusions.—Although Alport syndrome variants and TBMN do not show characteristic light microscopic findings and can be difficult to differentiate from each other even by electron microscopy, using a combination of electron microscopy and immunohistology for α3(IV) and α5(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most cases.

scholarly journals Comparison of alpha5(IV) collagen chain expression in skin with disease severity in women with X-linked Alport syndrome.

1998 ◽  
Vol 9 (8) ◽  
pp. 1433-1440
Author(s):  
K Nakanishi ◽  
K Iijima ◽  
N Kuroda ◽  
Y Inoue ◽  
Y Sado ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Renal Disease ◽  
Disease Severity ◽  
End Stage Renal Disease ◽  
Alport Syndrome ◽  
Expression Ratio ◽  
Female Patients ◽  
Stage Renal Disease ◽  
End Stage ◽  
Epidermal Basement Membrane

X-Linked Alport syndrome is caused by mutations in the type IV collagen alpha5 chain gene. Male patients usually develop end-stage renal disease, whereas female patients have more variable phenotypes from asymptomatic hematuria to end-stage renal disease. The variable phenotypes in female patients may be attributable to different X-chromosome inactivation patterns. Therefore, the correlation between disease severity and the degree of alpha5 chain expression in the epidermal basement membrane of female patients with X-linked Alport syndrome was examined. To estimate the disease severity in X-linked Alport syndrome, the ratios of protein to creatinine in single voided urine samples were used. Expression of the alpha5 chain in the epidermal basement membrane was examined by an indirect immunofluorescence method using an anti-alpha5 chain monoclonal antibody. A total of 25 female patients with X-linked Alport syndrome from 17 families was examined. Multiple regression analysis using disease severity as the response variable, and age, family history of nephritis, female and male family history of end-stage renal disease, serum creatinine concentration, and alpha5(IV) expression ratio in the epidermal basement membrane as explanatory variables showed that only alpha5(IV) expression ratio was a significant factor, and that it showed a highly significant negative association with disease severity (adjusted r2=0.71, P=0.0001). These findings suggest that variable alpha5 chain expression, possibly caused by different X-inactivation patterns, is responsible for the variable disease severity in female patients with X-linked Alport syndrome, and that immunohistochemical examination of alpha5 chain expression in the epidermal basement membrane may be a simple and useful method for predicting patient outcome.

Approach to the Diagnosis of Thin Basement Membrane Nephropathy in Females With the Use of Antibodies to Type IV Collagen

2001 ◽  
Vol 125 (5) ◽  
pp. 631-636
Author(s):  
Ginette Lajoie
Keyword(s):  
Basement Membrane ◽  
Type Iv Collagen ◽  
Unknown Etiology ◽  
Supporting Evidence ◽  
Thin Basement Membrane Nephropathy ◽  
Female Patients ◽  
Type Iv ◽  
Stage Renal Disease ◽  
End Stage ◽  
Gbm Thickening

Abstract Context.—Thin basement membrane nephropathy is recognized by a diffusely thin glomerular basement membrane (GBM) ultrastructurally. In contrast to Alport syndrome (AS), there is no GBM thickening, lamellation, or granular inclusions. Morphologically, there is overlap between thin basement membrane nephropathy and AS in female patients in whom there might be only thin GBM and no pathognomonic findings of AS. Objective.—To determine if the use of antibodies to collagen IV is helpful in making the distinction between thin basement membrane nephropathy and AS in female patients with primarily thin GBMs. Design.—We examined renal biopsies from 9 adult female patients with thin GBMs for the presence of α1, α3, α4, and α5 chains of type IV collagen by immunofluorescence. Results.—In 2 patients with segmental GBM staining, no suggestion for AS was found on physical examination or in their family history. In the remaining 7 patients with normal GBM staining, 4 had family members with end-stage renal disease of unknown etiology, raising the suspicion of X-linked or autosomal-recessive AS. Three patients were presumed to have thin basement membrane nephropathy. Conclusion.—Segmental GBM staining for α3, α4, and α5 chains of type IV collagen raises the suspicion of AS in the presence of adequate controls and other supporting evidence. Normal GBM staining for α3, α4, and α5 chains of type IV collagen, however, does not exclude AS.

scholarly journals Identification of patients with autosomal dominant polycystic kidney disease at highest risk for end-stage renal disease.

1997 ◽  
Vol 8 (10) ◽  
pp. 1560-1567 ◽  
Author(s):  
A M Johnson ◽  
P A Gabow
Keyword(s):  
Kidney Disease ◽  
Risk Ratio ◽  
End Stage Renal Disease ◽  
Autosomal Dominant ◽  
Renal Survival ◽  
Polycystic Kidney ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stage Renal Disease ◽  
End Stage ◽  
Risk Ratios

To identify those potential factors that, early in the course of disease, mark a population of patients with autosomal dominant polycystic kidney disease (ADPKD) who have worse renal survival, survival analysis and risk ratio calculation for 1215 ADPKD patients were performed. Survival times were calculated as time to dialysis, transplantation, or death. Risk ratios were calculated using the Cox proportional hazards model. Three hundred eighty-eight patients entered end-stage renal disease and 205 patients died. ADPKD2 subjects had longer renal survival than ADPKD1 subjects (median survival, 68 versus 53 yr; P < 0.0005; risk ratio, 2.5). Women had significantly better renal survival than men (56 versus 52 yr; P < 0.0001; risk ratio, 1.6). Subjects who were diagnosed before age 30 and those who developed hypertension before age 35 had worse renal survival than those subjects who were diagnosed after age 30 or those who remained normotensive after age 35, respectively (age of diagnosis: 49 versus 59 yr; P < 0.0001; risk ratio, 3.2; hypertension: 51 versus 65 yr; P < 0.0001; risk ratio, 4.4). Similarly, those who had an episode of gross hematuria before age 30 had a worse renal outcome than those who did not (49 versus 59 yr; P < 0.0001; risk ratio, 2.6). We have also calculated risk ratios for a combined model. When therapeutic interventions become available for this disease, these populations with high risk ratios should be considered for such interventions.

Diagnosis of infected kidney cysts in patients with autosomal dominant polycystic kidney disease and end-stage renal disease

Urologiia ◽  
2021 ◽  
Vol 3_2021 ◽  
pp. 50-55
Author(s):  
A.E. Lubennikov Lubennikov ◽  
A.A. Shishimorov Shishimorov ◽  
R.N. Trushkin Trushkin ◽  
T.K. Isaev T ◽  
O.N. Kotenko Kotenko ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Polycystic Kidney Disease ◽  
End Stage Renal Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Kidney Cysts ◽  
Autosomal Dominant Polycystic Kidney ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals Prevalence of clinical, pathological and molecular features of glomerular basement membrane nephropathy caused by COL4A3 or COL4A4 mutations: a systematic review

2020 ◽  
Vol 13 (6) ◽  
pp. 1025-1036 ◽  
Author(s):  
Andreas Matthaiou ◽  
Tsielestina Poulli ◽  
Constantinos Deltas
Keyword(s):  
Basement Membrane ◽  
Alport Syndrome ◽  
Autosomal Dominant ◽  
Wide Spectrum ◽  
Age At Onset ◽  
Histological Finding ◽  
Basement Membranes ◽  
Thin Basement Membrane Nephropathy ◽  
Molecular Features ◽  
Thin Basement Membrane Disease

Abstract Background Patients heterozygous for COL4A3 or COL4A4 mutations show a wide spectrum of disease, extending from familial isolated microscopic haematuria, as a result of thin basement membranes (TBMs), to autosomal dominant Alport syndrome (ADAS) and end-stage renal disease (ESRD). Many patients are mentioned in the literature under the descriptive diagnosis of TBM nephropathy (TBMN), in which case it actually describes a histological finding that represents the carriers of autosomal recessive Alport syndrome (ARAS), a severe glomerulopathy, as most patients reach ESRD at a mean age of 25 years. Methods We performed a systematic literature review for patients with heterozygous COL4A3/A4 mutations with the aim of recording the spectrum and frequency of pathological features. We searched three databases (PubMed, Embase and Scopus) using the keywords ‘Autosomal Dominant Alport Syndrome’ OR ‘Thin Basement Membrane Disease’ OR ‘Thin Basement Membrane Nephropathy’. We identified 48 publications reporting on 777 patients from 258 families. Results In total, 29% of the patients developed chronic kidney disease (CKD) and 15.1% reached ESRD at a mean age of 52.8 years. Extrarenal features and typical Alport syndrome (AS) findings had a low prevalence in patients as follows: hearing loss, 16%; ocular lesions, 3%; basement membrane thickening, 18.4%; and podocyte foot process effacement, 6.9%. Data for 76 patients from 54 families emphasize extensive inter- and intrafamilial heterogeneity, with age at onset of ESRD ranging between 21 and 84 years (mean 52.8). Conclusions The analysis enabled a comparison of the clinical course of patients with typical ARAS or X-linked AS with those with heterozygous COL4A mutations diagnosed with TBMN or ADAS. Despite the consequence of a potential ascertainment bias, an important outcome is that TBM poses a global high risk of developing severe CKD, over a long follow-up, with a variable spectrum of other findings. The results are useful to practicing nephrologists for better evaluation of patients.

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