GENETICS OF CLASSIC ALPORT'S SYNDROME

doi:10.1016/S0140-6736(88)90753-2

The Lancet

Volume 332, Issue 8618, 29 October 1988, Pages 1005-1007

https://doi.org/10.1016/S0140-6736(88)90753-2 Get rights and content

Abstract

41 families with classic Alport's syndrome (hereditary nephritis with sensorineural deafness) were studied. All their pedigrees were compatible with X-linked inheritance. DNA probes were used to investigate genetic linkage in these families. Linkage to probe S21 (DXS17) was confirmed (LOD score = 4·72 at θ = 0·06), localising the gene for Alport's syndrome to the middle of Xq; thus the disorder is X-chromosomal in nature.

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Cited by (186)

Alport Syndrome: Achieving Early Diagnosis and Treatment
2021, American Journal of Kidney Diseases
Citation Excerpt :
The identification of COL4A5 as the locus for X-linked Alport syndrome was rapidly followed by the cloning and sequencing of COL4A3 and COL4A4 and the discovery of homozygous and compound heterozygous variants in these genes in patients with autosomal recessive Alport syndrome.6,7 Eventually heterozygous variants in these genes were found in families with autosomal dominant transmission of a nephropathy with characteristic ultrastructural features of Alport syndrome,24-27 firmly establishing the existence of an autosomal dominant form of Alport syndrome, a hypothesis that had been advanced by some groups28,29 but questioned by others.18 Although the precise proportion of Alport cases attributable to the autosomal dominant form has not been defined, it appears to account for a substantially greater fraction of affected individuals than previously understood.24,25
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.
Genotype and Outcome After Kidney Transplantation in Alport Syndrome
2018, Kidney International Reports
Alport syndrome (AS) is caused by mutations in α3/α4/α5 (IV) collagen genes, the severity of which determine the progression of AS. Posttransplantation outcome is good, although anti−glomerular basement membrane (anti-GBM) glomerulonephritis occurs in 3% to 5% of recipients, clustering in patients with a severe mutation. We assessed whether the severity of the underlying AS mutation affects graft and patients outcome after transplantation, including the occurrence of anti-GBM nephritis.
We included 73 AS patients with an identified mutation (COL4A5, 57 patients; COL4A3, 9 patients; COL4A4, 6 patients; heterozygous composite COL4A3 and A4, 1 patient) who underwent transplantation between 1971 and 2014 and who had received a total of 93 kidney grafts.
In all, 41 patients had a severe mutation (COL4A5, 30 patients; COL4A3, 6 patients; COL4A4, 5 patients), and 32 had a nonsevere mutation (COL4A5, 27 patients; COL4A3, 4 patients; COL4A4, 1 patient). Patient survival was similar in patients with severe and nonsevere mutations (89% vs. 84% at 5 years, 83% vs. 75% at 10, 15, and 20 years; P = 0.46). Graft survival was not affected by the severity of mutation (77% vs. 63% at 5 years, 60% vs. 55% at 10 years, 55% vs. 55% at 15 years, and 55% vs. 50% at 20 years; P = 0.65). Clinically significant anti-GBM glomerulonephritis occurred in 1 male patient with severe COL4A5 mutation 6 years after transplantation recurred in a subsequent graft, leading twice to graft loss.
Although severe mutations affect the severity of AS, they do not have an impact on patient and graft survival after transplantation. De novo anti-GBM nephritis after transplantation was less frequent than previously reported, occurring in only 1.4% of AS patients, and in 2% of males with COL4A5 mutation.
Natural History and Genotype–Phenotype Correlation in Female X-Linked Alport Syndrome
2017, Kidney International Reports
Citation Excerpt :
They revealed that the risk of developing ESRD before the age of 40 was 12%, while the median age for developing ESRD was not detected (>80 years). Flinter et al.6 reported that among 113 female XLAS patients, 15% developed chronic renal failure at an average age of 40. In our cohort, 52 of 336 female XLAS patients developed ESRD, with the youngest developing it at the age of 15 years.
X-linked Alport syndrome (XLAS) is a hereditary disease characterized by progressive nephritis, hearing loss, and ocular abnormalities. Affected male patients usually progress to end-stage renal disease in early or middle adulthood, and disease severity is strongly correlated with genotype. However, the clinical course in female patients has rarely been reported.
We conducted a retrospective analysis of females with genetically proven XLAS (n = 275) and their affected female family members (n = 61) from 179 Japanese families. Patients suspected to have Alport syndrome from pathologic findings or a family history who were referred from anywhere in Japan for genetic diagnosis between 2006–2015 were included in this study. Clinical and laboratory data were collected from medical records at the time of registration for genetic analysis.
Proteinuria was detected in 175 genetically proven patients (72.6%), and the median age for developing proteinuria was 7.0 years. Fifty-two of 336 patients developed end-stage renal disease with a median renal survival age of 65.0 years. No obvious genotype–phenotype correlation was observed. Additionally, targeted sequencing for podocyte-related genes in patients with severe phenotypes revealed no obvious variants considered to be modifier genes except for 1 patient with a COL4A3 gene variant.
This study revealed that phenotypes in female XLAS patients may be severe, but genotype does not help to predict the disease severity. Clinicians must therefore pay careful attention to the clinical course and appropriate treatment in females with XLAS.
Speech, language, and hearing function in twins with Alport syndrome: A seven-year retrospective case report
2017, Journal of Otology
Alport syndrome is an X-linked syndrome that results in nephritis, renal failure, sensorineural hearing loss, and eye deficits. As a result of sensorineural hearing loss, these individuals are likely to experience difficulties in the area of speech and language. While studies in the past have examined the speech and language characteristics of children with syndromic sensorineural hearing loss, to our knowledge there are no previous studies to have documented the speech and language characteristics of these children on a long-term basis. The current study addresses this limitation by reporting speech, language, hearing, and function of twin brothers with X-linked Alport syndrome across a seven-year period. Information was collected by examining the medical records of the participants as well as through a verbal interview with the participants' guardian. Results revealed that the participants' hearing abilities gradually deteriorated over the seven-year period which affected their speech and language development as well. The kidney function tests revealed significant presence of hematuria (blood in the urine) as well as proteinuria (protein in the urine) suggesting chronic kidney dysfunction. This longitudinal study demonstrates the functional relationship between the kidneys and the cochlea, although they appear to be independent of one another. As individuals with Alport syndrome exhibit systemic complications, interdisciplinary collaboration is essential among health care providers including audiologists, speech-language pathologists, nephrologists, and ophthalmologist to promote evidence-based practice.
Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice
2023, Genes
Next-Generation Sequencing (NGS) Analysis Illustrates the Phenotypic Variability of Collagen Type IV Nephropathies
2023, Genes

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Occasional SurveyGENETICS OF CLASSIC ALPORT'S SYNDROME

Abstract

Kidney Int

Am J Med

Am J Med

Am J Med

Kidney Int

Hereditary familial congenital haemorrhagic nephritis

Br Med J

"Idiopathic" or congenital hereditary and family haematuria

Lancet

Hereditary familial congenital haemorrhagic nephritis

Guy's Hosp Rep

Hereditary familial congenital haemorrhagic nephritis occurring in sixteen individuals in three generations

Guy's Hosp Rep

Hereditary nephropathy with hearing loss—"Alport's syndrome"

Acta Paediatr Scand

Genetic heterogeneity among kindreds with Alport's syndrome

Am J Hum Genet

Case 43511, case records of the Massachusetts General Hospital

N Engl J Med

Renal pathology in hereditary nephritis with nerve deafness

Arch Pathol

Characteristic ultrastructural lesion of the glomerular basement membrane in progressive hereditary nephritis (Alport's syndrome)

Lab Invest

Alport's syndrome: emphasizing electron microscopic studies of the glomerulus

Am J Pathol

Pathologic characteristics of hereditary nephritis

Arch Pathol

Alport's syndrome: experience at Hôpital Necker

Kidney Int

The glomerular basal lamina in hereditary nephritis

J Pathol

A heredo-familial syndrome characterised by renal disease, inner ear deafness and ocular changes

Harefuah

Congenital hereditary hematuria

N Engl J Med

Anterior lenticonus and Alport's syndrome

Acta Ophthalmol

Ocular manifestations of Alport's syndrome: a hereditary disorder of basement membranes?

Br J Ophthalmol

Concomitant progressive deafness, chronic nephritis and ocular lens disease

Arch Ophthalmol

Reversal of deafness after renal transplantation in Alport's syndrome

Laryngoscope

Occasional Survey
GENETICS OF CLASSIC ALPORT'S SYNDROME