scholarly journals Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria

2021 ◽  
Author(s):  
Judy Savige ◽  
Helen Storey ◽  
Elizabeth Watson ◽  
Jens Michael Hertz ◽  
Constantinos Deltas ◽  
...  
Keyword(s):  
Renal Failure ◽  
Alport Syndrome ◽  
Pathogenic Variants ◽  
Persistent Proteinuria ◽  
Mutational Hotspots ◽  
Splicing Variants ◽  
History Of ◽  
Standards And Guidelines ◽  
Reference Databases ◽  
End Stage

AbstractThe 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

2018 ◽  
Author(s):  
Laurence Heidet ◽  
Bertrand Knebelmann ◽  
Marie Claire Gubler
Keyword(s):  
Renal Failure ◽  
Hearing Loss ◽  
Alport Syndrome ◽  
Significant Risk ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Aortic Disease ◽  
Converting Enzyme Inhibitors ◽  
Ocular Abnormalities ◽  
End Stage Renal Failure ◽  
End Stage

This chapter describes the clinical features of Alport syndrome. The characteristic features of this familial condition are haematuria with progressive nephropathy and sensorineural hearing loss. Most cases are X-linked so this is typically seen in boys and young men, but female heterozygous (‘carriers’) of X-linked Alport syndrome are also at significant risk of renal disease in their lifetime. The average age of end-stage renal failure is in the third or fourth decade. Those with autosomal recessive disease (approximately 15%) show a similar phenotype. Hearing loss characteristically develops during teenage years or as a young adult, usually as proteinuria becomes prominent and renal function begins to be lost. Angiotensin-converting enzyme inhibitors may modify this classic description. Ocular abnormalities are less consistent and tend to occur later, often after end-stage renal failure. Retinal changes do not affect sight. Lenticonus can be treated by lens replacement. Other ocular abnormalities occur rarely. Aortic disease has been reported in occasional families.

scholarly journals History of Medicine: The Emergence of Intestinal Dialysis.

2020 ◽  
pp. 1-8
Keyword(s):  
Renal Failure ◽  
Peritoneal Dialysis ◽  
Chronic Renal Failure ◽  
Experimental Studies ◽  
Artificial Kidney ◽  
Lowering Effect ◽  
Acacia Gum ◽  
The Usa ◽  
History Of ◽  
End Stage

Abstract In 1923, Georg Ganter at the University of Würzburg performed the first peritoneal dialysis for patients with chronic kidney disease. During the period from 1924 to 1938, intermittent peritoneal dialysis was used in the USA and Germany as a short-term replacement for the renal functions. In 1946, Fine and colleagues described the use of peritoneal irrigation in a patient with severe anuria, who survived after four days of continuous peritoneal lavage. In 1943, a Dutch physician named Willem Kolff developed the first dialyzer which was called “Artificial kidney” with aim of cleaning the blood of patients with acute renal failure. Kolff moved to the USA and improved the early design of the dialyzer and was manufactured in the early 1950s. During the 1980s and 1990s, experimental studies on animals suggested that dietary fibers including acacia gum have a urea lowering effect (Yatzidis et al., 1980; Rampton et al., 1984; Tetens et al., 1996). In 1996, in 1996, Bliss et al. reported that the use of acacia gum supplementation in adult patients with asymptomatic early chronic renal failure on low protein diet was associated with urea lowering effect. The use of Intestinal dialysis in symptomatic chronic renal failure patients was first described by Aamir Jalal Al-Mosawi in 2002. The achievement of six-year dialysis freedom with the use of intestinal dialysis in patients with end-stage renal failure was described by Aamir Jalal Al-Mosawi in 2009. Late during the 2000s, “Only medical talks” web site included Aamir Jalal Al-Mosawi in the list of famous physicians of all time for describing intestinal dialysis [9]. During the previous two decades there have been a plethora of publications describing the concepts, principles and use of intestinal dialysis including journal articles, conference papers and books. Some of these publications have been translated to eight languages confirming that intestinal dialysis has become an established medical therapeutic technology. The aim of this paper is to review the milestones associated with intestinal dialysis which was considered by many experts as a Nobel Prize winning technology.

Alport syndrome

2015 ◽  
Author(s):  
Laurence Heidet ◽  
Bertrand Knebelmann ◽  
Marie Claire Gubler
Keyword(s):  
Renal Failure ◽  
Hearing Aids ◽  
Alport Syndrome ◽  
Enzyme Inhibitors ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
End Stage Renal Failure ◽  
Animal Data ◽  
Average Survival ◽  
End Stage

Management of Alport syndrome has in the past been expectant and supportive. Modern hearing aids have substantially improved the function of affected individuals. However, animal data and more recently observational data from Alport registries strongly suggest a protective effect of angiotensin-converting enzyme inhibitors. There is a suggestion that early commencement of treatment may slow progression substantially. These should now be recommended for all with proteinuria, and possibly even before then for those known to harbour mutations certain to cause end-stage renal failure. A very small minority develop the difficult post-transplant complication of Alport anti-glomerular basement membrane disease. This can rarely be treated successfully and leaves some patients on long-term dialysis. However, overall, patients with Alport syndrome have better than average survival and other outcomes than other patients with end-stage renal failure. Most are successfully transplanted. The question of risk to heterozygous carriers from donating kidneys to their affected relatives arises frequently. The risks may be felt acceptable in some circumstances. Additional therapies are under investigation.

scholarly journals Genetic variants and clinical phenotypes in Korean patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Author(s):  
Young Jae Lee ◽  
Joo-hyun Jung ◽  
Bo Gyeong Kim ◽  
Mi-Jung Kim ◽  
Eun Hyue Moon ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Genetic Screening ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Diagnostic Screening ◽  
Pathogenic Variants ◽  
Recurrent Epistaxis ◽  
Common Clinical Presentation ◽  
History Of ◽  
Standards And Guidelines

Objectives. Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by recurrent epistaxis, telangiectasias, and visceral arteriovenous malformations (AVMs). Activin A receptor-like type 1 (ACVRL1/ALK1) and Endoglin (ENG) are the principal genes whose mutations cause HHT. A multicenter study to investigate the correlation between genetic variations and clinical outcomes in Korean HHT patients has been lacking.Methods. Seventy-two members from 40 families suspected of HHT based on symptoms were genetically screened for pathogenic variants in ACVRL1 and ENG. Patients with genetically diagnosed HHT were also evaluated.Results. In the HHT genetic screening, 42 patients from 24 of the 40 families had genetic variants that met the pathogenic criteria (pathogenic very strong, pathogenic strong, pathogenic moderate, or pathogenic supporting) based on ACMG Standards and Guidelines in either ENG or ACVRL1; 26 from 12 families (50%) in ENG, and 16 from 12 families (50%) in ACVRL1. The diagnostic screening of 42 genetically positive HHT patients based on the Curaçao criteria revealed that 24 patients (57%) were in the definite group, 17 patients (41%) were in the probable group, and 1 patient (2%) was in the unlikely group. Epistaxis was the most common clinical presentation (38/42, 90%), followed by visceral AVMs (24/42, 57%), and telangiectasia (21/42, 50%). Five patients (12%) did not have a family history of HHT clinical symptoms.Conclusion. Among patients having ACVRL1 or ENG genetic variants, only about half of them could be clinically diagnosed as definite HHT, suggesting that genetic screening is important to confirm the diagnosis.

scholarly journals Characterization of two polymorphic sites in the human kinin B1 receptor gene: altered frequency of an allele in patients with a history of end-stage renal failure.

1998 ◽  
Vol 9 (4) ◽  
pp. 598-604 ◽  
Author(s):  
D R Bachvarov ◽  
M Landry ◽  
I Pelletier ◽  
M Chevrette ◽  
C Betard ◽  
...  
Keyword(s):  
Renal Failure ◽  
Genomic Structure ◽  
Prognostic Significance ◽  
Control Sample ◽  
Control Group ◽  
Exon 2 ◽  
End Stage Renal Failure ◽  
B1 Receptor ◽  
History Of ◽  
End Stage

On the basis of the genomic structure of the human B1 receptor (B1R) for kinins, the presence of possible allelic polymorphisms of this gene was investigated using restriction fragment-length polymorphism and single-strand conformation polymorphism. The frequencies of the found alleles were determined in healthy volunteers and in patients with a history of end-stage renal failure, because there is evidence for a nephroprotective action of the kallikrein-kinin system. An A1098-->G polymorphism has been identified in exon 3 in a minority of volunteer blood donors, and is located 35 nucleotides downstream from the stop codon and 14 nucleotides upstream from the polyadenylation signal. The frequency of the G allele is 4.4% in the control sample and not significantly altered in patients with a history of end-stage renal failure. A second and more frequent polymorphism (18.1% of the alleles in the control group, prevalence of 33.3%) consists of a single base substitution (G-699-->C) in the putative promoter region. This polymorphism is significantly less frequent in the population of renal failure patients (prevalence of 20.6%) and determines an increased activity of the promoter function in constructions involving a reporter gene. The altered prevalence of this allele was also found in some etiologic subgroups of uremic patients. This study confirms the mapping of the B1R gene to 14q32. Other investigators have mapped the bradykinin B2 receptor (B2R) gene to a close site on human chromosome 14. A previously described B2R polymorphism (exon 2, C181-->T) had an allele frequency of 9.7% in the control sample and appears to be clinically neutral. The polymorphism of the B1R promoter may be a marker of prognostic significance for the preservation of renal function in diseased individuals.

scholarly journals X-linked Alport Syndrome

2000 ◽  
Vol 11 (4) ◽  
pp. 649-657 ◽  
Author(s):  
JEAN PHILIPPE JAIS ◽  
BERTRAND KNEBELMANN ◽  
IANNIS GIATRAS ◽  
MARIO DE MARCHI ◽  
GIANFRANCO RIZZONI ◽  
...  
Keyword(s):  
Renal Failure ◽  
Hearing Loss ◽  
Alport Syndrome ◽  
Hereditary Disease ◽  
Missense Mutations ◽  
Site Mutation ◽  
Dominant Form ◽  
End Stage Renal Failure ◽  
Male Patients ◽  
End Stage

Abstract. Alport syndrome (AS) is a type IV collagen hereditary disease characterized by the association of progressive hematuric nephritis, hearing loss, and, frequently, ocular changes. Mutations in the COL4A5 collagen gene are responsible for the more common X-linked dominant form of the disease. Considerable allelic heterogeneity has been observed. A “European Community Alport Syndrome Concerted Action” has been established to delineate accurately the AS phenotype and to determine genotype-phenotype correlations in a large number of families. Data concerning 329 families, 250 of them with an X-linked transmission, were collected. Characteristics of the 401 male patients belonging to the 195 families with COL4A5 mutation are presented. All male patients were hematuric, and the rate of progression to end-stage renal failure and deafness was mutation-dependent. Large deletions, nonsense mutations, or small mutations changing the reading frame conferred to affected male patients a 90% probability of developing end-stage renal failure before 30 yr of age, whereas the same risk was of 50 and 70%, respectively, in patients with missense or splice site mutation. The risk of developing hearing loss before 30 yr of age was approximately 60% in patients with missense mutations, contrary to 90% for the other types of mutations. The natural history of X-linked AS and correlations with COL4A5 mutations have been established in a large cohort of male patients. These data could be used for further evaluation of therapeutic approaches.

Alport syndrome

2015 ◽  
Author(s):  
Laurence Heidet ◽  
Bertrand Knebelmann ◽  
Marie Claire Gubler
Keyword(s):  
Renal Failure ◽  
Alport Syndrome ◽  
Chromosome 2 ◽  
Renal Disorder ◽  
End Stage Renal Failure ◽  
Type Iv ◽  
Increased Risk ◽  
Fourth Decade ◽  
Membrane Type ◽  
End Stage

Alport syndrome is an inherited renal disorder characterized by early haematuria, progressing to proteinuria, sensorineural hearing loss, and progressive renal failure typically in the third or fourth decade but with wide variation. It is responsible for about 1% of end-stage renal failure. Over 80% of cases are X-linked and young men are most affected, but heterozygous carriers of the abnormal gene are also at significantly increased risk of end-stage renal failure in their lifetime. Those affected by the autosomal recessive variant are phenotypically very similar. It is caused by mutations in tissue-specific isoforms of basement membrane (type IV) collagen encoded by COL4A5 (X chromosome), COL4A3, and COL4A4 (chromosome 2).

scholarly journals Renal replacement

2020 ◽  
pp. S17-S20
Author(s):  
L Brannigan
Keyword(s):  
Renal Failure ◽  
Renal Replacement Therapy ◽  
Short History ◽  
End Stage Renal Failure ◽  
Solute Exchange ◽  
Threatening Condition ◽  
Life Threatening ◽  
History Of ◽  
Comprehensive Text ◽  
End Stage

There are few, if any, technological advancements in the field of medicine that have been able to transform a life-threatening condition, in this case, end-stage renal failure, from a certain and horrible death, just some 100 years ago, to a condition manageable within the confines of one’s home. This refresher course, by no means a comprehensive text on peritoneal or haemodialysis, aims to provide the reader (a pre-part one FCA candidate) with the following brief overview: * A short history of dialysis * The basic physiology of fluid and solute exchange employed in renal replacement therapy (RRT) * The physical principals of RRT * Modality

scholarly journals Family history of end-stage renal disease among incident dialysis patients.

1997 ◽  
Vol 8 (12) ◽  
pp. 1942-1945 ◽  
Author(s):  
B I Freedman ◽  
J M Soucie ◽  
W M McClellan
Keyword(s):  
Renal Failure ◽  
African American ◽  
Family History ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Dialysis Patients ◽  
History Of ◽  
Stage Renal Disease ◽  
End Stage ◽  
Second Degree

As part of a larger study of genetic risk factors for the occurrence of renal failure, the prevalence of a family history of end-stage renal disease (ESRD) in first- and second-degree relatives of all incident dialysis patients treated in Georgia, North Carolina, and South Carolina (ESRD Network 6) in 1994 was ascertained. Family histories were obtained from 4365 dialysis patients (83% of those eligible), and 856 (20%) reported having a family history of ESRD. Among race-sex groups, 14.1% of Caucasian men, 14.6% of Caucasian women, 22.9% of African-American men, and 23.9% of African-American women reported a first- or second-degree relative with ESRD (P = 0.001). The prevalence of relatives with ESRD varied by the reported etiology: 22.2% in diabetes mellitus; 18.9% in hypertension, 22.7% in glomerulonephritis; and 13.0% of other etiologies (P = 0.001). Patient characteristics independently associated with family history of ESRD included race, younger age, higher levels of education, and etiology of ESRD. In this report, it is concluded that a large proportion of incident ESRD cases have close relatives with ESRD in whom preventive actions might be directed. Genetic analyses in multiply affected families may identify the inherited factors contributing to progressive renal failure.

Guidelines for Genetic Testing and Management of Alport Syndrome

2021 ◽  
pp. CJN.04230321
Author(s):  
Judy Savige ◽  
Beata S. Lipska-Zietkiewicz ◽  
Elizabeth Watson ◽  
Jens Michael Hertz ◽  
Constantinos Deltas ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Genetic Testing ◽  
Family History ◽  
Kidney Function ◽  
Alport Syndrome ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Persistent Proteinuria ◽  
Function Impairment ◽  
History Of

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.

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