Long-term effects of cyclosporine A in Alport's syndrome.
BACKGROUND: In 1991, our initial results of cyclosporine A (CsA) administration in eight patients with Alport's syndrome were published. A significant decrease in or disappearance of proteinuria and apparently good tolerance to CsA were observed in all patients. METHODS: CsA administration has been maintained in these eight patients with the aim of obtaining further information about the clinical course of the disease. The ages of these eight patients currently range from 15 to 27 years, and the mean duration of treatment is from 7 to 10 years (x = 8.4 years). RESULTS: Renal function has remained stable, with no evaluable changes in serum creatinine levels compared with pre-CsA treatment values. Proteinuria in all patients has either remained negative or are values far lower than pretreatment levels. A second renal biopsy was performed in all patients after five years of CsA administration. No aggravation of the lesion present at the first biopsy or lesions typical of cyclosporine intoxication was observed. CONCLUSIONS: After a mean duration of 8.4 years and with no deterioration in renal function, we found possible beneficial effects of the continued treatment of CsA in patients with Alport's syndrome who present evidence of progression to renal insufficiency. (+info)
Hereditary nephritis (with unusual renal histology): report of a first case from the West Indies.
A 21-year-old Grenadian girl undergoing investigation in Trinidad for anaemia was diagnosed as a case of hereditary nephritis. She had the clinical features of a nephropathy, nerve deafness and an ocular defect. Renal histology was exceptional in that in addition to the typical findings of a hereditary nephritis, cystic areas generally associated with medullary cystic disease were noted. Several members of the patient's maternal family were afflicted with either deafness visual distrubances or renal disease. (+info)
Autosomal recessive Alport syndrome: linkage analysis and clinical features in two families.
BACKGROUND: Genetic heterogeneity is a well-known feature of Alport syndrome (AS). Most families with AS show an X-linked dominant pattern of inheritance but about 15% of families show an autosomal inheritance of the disease. Autosomal recessive AS may account for 10% of the total number of cases and is caused by mutations in the COL4A3 and COL4A4 genes. The clinical spectrum of this rare disorder has not been well clarified. METHODS: We present two families with AS. Two affected members of these families have entered end-stage renal disease (ESRD) in their 30s, and the other three are older than 15 years and have normal serum creatinine. Four of the five patients have deafness but none have ocular abnormalities. Two have been transplanted and have not suffered from anti-GBM antibody nephritis. Men and women are equally affected. We have performed linkage analysis for chromosome 2 with the following markers: D2S279, COL4A3/4 DNTR, COL4A4 RFLP Hae III. RESULTS: We demonstrate that both families, one of them consanguineous, are linked to the COL4A3/4 locus. CONCLUSIONS: We can conclude that the only significant difference between the X-linked and the autosomal recessive forms of AS lies in the fact that in the latter females are as affected as males; thus the idea that autosomal recessive AS causes ESRD during childhood must be discarded. Other clinical features such as age of deafness or the presence of post-transplant anti-GBM antibody nephritis show no differences between the entities. Thus an accurate familial study is mandatory in patients with AS, as the identification of the different patterns of inheritance may cause a great difference in genetic counselling. Linkage analysis is the only effective molecular diagnosis that can be performed nowadays. (+info)
Identification of COL4A5 defects in Alport's syndrome by immunohistochemistry of skin.
BACKGROUND: The COL4A3-COL4A4-COL4A5 network in the glomerular basement membrane is affected in the inherited renal disorder Alport's syndrome (AS). Approximately 85% of the AS patients are expected to carry a mutation in the X-chromosomal COL4A5 gene and 15% in the autosomal COL4A3 and COL4A4 genes. The COL4A5 chain is also present in the epidermal basement membrane (EBM). It is predicted that approximately 70% of the COL4A5 mutations prevent incorporation of this chain in basement membranes. METHODS: We investigated whether or not COL4A5 defects could be detected by immunohistochemical analysis of the EBM. Punch skin biopsies were obtained from 22 patients out of 17 families and two biopsy specimens from healthy males were used as controls. RESULTS: In four cases with the COL4A5 frameshift or missense mutations, the COL4A5 chain was either lacking from the EBM (male) or showed a focally negative pattern (female). In three other patients with a COL4A5 missense mutation, a COL4A3 and a COL4A4 mutation, respectively, the COL4A5 staining was normal. A (focally) negative EBM-COL4A5 staining was found in three patients of six families with a diagnosis of AS and in one family of a group of four families with possible AS. CONCLUSIONS: The (focal) absence of COL4A5 in the EBM of skin biopsy specimens can be used for fast identification of COL4A5 defects. Combined with polymorphic COL4A5 markers, both postnatal and prenatal DNA diagnosis are possible in the family of the patient. (+info)
Absence of the alpha6(IV) chain of collagen type IV in Alport syndrome is related to a failure at the protein assembly level and does not result in diffuse leiomyomatosis.
X-linked Alport syndrome is a progressive nephropathy associated with mutations in the COL4A5 gene. The kidney usually lacks the alpha3-alpha6 chains of collagen type IV, although each is coded by a separate gene. The molecular basis for this loss remains unclear. In canine X-linked hereditary nephritis, a model for X-linked Alport syndrome, a COL4A5 mutation results in reduced mRNA levels for the alpha3, alpha4, and alpha5 chains in the kidney, implying a mechanism coordinating the production of these 3 chains. To examine whether production of alpha6 chain is under the same control, we studied smooth muscle cells from this animal model. We determined the canine COL4A5 and COL4A6 genes are separated by 435 bp, with two first exons for COL4A6 separated by 978 bp. These two regions are >/= 78% identical to the human sequences that have promoter activity. Despite this potential basis for coordinated transcription of the COL4A5 and COL4A6 genes, the alpha6 mRNA level remained normal in affected male dog smooth muscle while the alpha5 mRNA level was markedly reduced. However, both alpha5 and alpha6 chains were absent at the protein level. Our results suggest that production of the alpha6 chain is under a control mechanism separate from that coordinating the alpha3-alpha5 chains and that the lack of the alpha6 chain in Alport syndrome is related to a failure at the protein assembly level, raising the possibility that the alpha5 and alpha6 chains are present in the same network. The lack of the alpha6 chain does not obviously result in disease, in particular leiomyomatosis, as is seen in Alport patients with deletions involving the COL4A5 and COL4A6 genes. (+info)
Role for transforming growth factor-beta1 in alport renal disease progression.
BACKGROUND: Alport syndrome results from mutations in either the alpha3(IV), alpha4(IV), or alpha5(IV) collagen genes. The disease is characterized by a progressive glomerulonephritis usually associated with a high-frequency sensorineural hearing loss. A mouse model for an autosomal form of Alport syndrome [collagen alpha3(IV) knockout] was produced and characterized. In this study, the model was exploited to demonstrate a potential role for transforming growth factor-beta1 (TGF-beta1) in Alport renal disease pathogenesis. METHODS: Kidneys from normal and Alport mice, taken at different stages during the course of renal disease progression, were analyzed by Northern blot, in situ hybridization, and immunohistology for expression of TGF-beta1 and components of the extracellular matrix. Normal and Alport human kidney was examined for TGF-beta1 expression using RNase protection. RESULTS: The mRNAs encoding TGF-beta1 (in both mouse and human), entactin, fibronectin, and the collagen alpha1(IV) and alpha2(IV) chains were significantly induced in total kidney as a function of Alport renal disease progression. The induction of these specific mRNAs was observed in the glomerular podocytes of animals with advanced disease. Type IV collagen, laminin-1, and fibronectin were markedly elevated in the tubulointerstitium at 10 weeks, but not at 6 weeks, suggesting that elevated expression of specific mRNAs on Northern blots reflects events associated with tubulointerstitial fibrosis. CONCLUSIONS: The concomitant accumulation of mRNAs encoding TGF-beta1 and extracellular matrix components in the podocytes of diseased kidneys may reflect key events in Alport renal disease progression. These data suggest a role for TGF-beta1 in both glomerular and tubulointerstitial damage associated with Alport syndrome. (+info)
Genetic linkage of autosomal-dominant Alport syndrome with leukocyte inclusions and macrothrombocytopenia (Fechtner syndrome) to chromosome 22q11-13.
Fechtner syndrome is an autosomal-dominant variant of Alport syndrome, manifested by nephritis, sensorineural hearing loss, cataract formation, macrothrombocytopenia, and polymorphonuclear inclusion bodies. As opposed to autosomal-recessive and X-linked Alport syndromes, which have been genetically well studied, the genetic basis of Fechtner syndrome remains elusive. We have mapped the disease-causing gene to the long arm of chromosome 22 in an extended Israeli family with Fechtner syndrome plus impaired liver functions and hypercholesterolemia in some individuals. Six markers from chromosome 22q yielded a LOD score >3.00. A maximum two-point LOD score of 7.02 was obtained with the marker D22S283 at a recombination fraction of 0. Recombination analysis placed the disease-causing gene in a 5.5-Mb interval between the markers D22S284 and D22S1167. No collagen genes or genes comprising the basement membrane have been mapped to this region. (+info)
X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males.
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, non-sense 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. (+info)