Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by Kashtan, 1999).
Alport syndrome is a genetically heterogeneous ... Alport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (review by Kashtan, 1999). Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type IV collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance (104200) is rare (Kashtan, 1999). See also benign familial hematuria (BFH; 141200), a phenotypically similar, but milder disorder. Alport syndrome is also a feature of 2 contiguous gene deletion syndromes involving the COL4A5 gene: Alport syndrome and diffuse leiomyomatosis (308940) and Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis (AMME; 300194).
Alport (1927) reported a family in which affected individuals showed progressive renal disease with hematuria and deafness. Affected males died early of uremia, while females lived to old age. The report of Alport (1927) was the fourth concerning ... Alport (1927) reported a family in which affected individuals showed progressive renal disease with hematuria and deafness. Affected males died early of uremia, while females lived to old age. The report of Alport (1927) was the fourth concerning a single pedigree that was also studied by Dickinson (1875), Guthrie (1902), and Kendall and Hertz, 1912 (review by Cohen et al., 1961). The renal disease became evident as recurrent microscopic or gross hematuria as early as childhood, earlier in males than in females. Progression to renal failure was gradual and usually occurred in males by the fifth decade. The renal histology was nonspecific; both glomerular and interstitial abnormalities, including foam cells, were observed. Although initially reported as a dominant trait with possible partial sex-linkage, it later became apparent that this was an X-linked dominant condition (Cohen et al., 1961; O'Neill et al., 1978; Evans et al., 1980). Perkoff et al. (1951, 1958) reported a large Utah kindred with hereditary chronic interstitial nephritis associated with sensorineural deafness. The kindred was further studied by O'Neill et al. (1978), who observed X-linked inheritance. Men were more severely affected than women. Microscopic hematuria was found to be the most reliable urinary criterion of hereditary nephritis in both males and females. The hematuria was often accompanied by red cell casts, indicating that the renal lesion was a glomerulitis. There were striking urinary abnormalities in early childhood which progressed to renal failure in adulthood. Affected women had less obvious urinary findings and rarely developed uremia. O'Neill et al. (1978) reported another large kindred with X-linked hereditary nephritis without hearing difficulties. Iversen (1974) described the characteristic course of Alport syndrome in males: 'In connection with one of the infectious diseases of childhood or a common cold in early childhood or adolescence, he will suddenly begin to suffer from massive haematuria or headache or oedema of the face. The urine shows haematuria and/or proteinuria and often also cylindruria and leukocyturia. These urinary signs may in one and the same patient vary in degree during the following months, and in some patients they may almost disappear, but they may become more pronounced again during the next infectious disease or after physical strain. There may be more or less pronounced hypertension....Most boys with this disease die from uraemia during adolescence.' There may also be secondary involvement of a transplanted kidney. Zhou et al. (1992) reported a 27-year-old male who developed hematuria in childhood and terminal renal failure at the age of 25 years. He had no hearing loss or ocular lesions. Electron microscopy demonstrated splitting of the lamina densa of the glomerular basement membrane (GBM). The proband's mother had had persistent microscopic hematuria since the age of 40 years but no other manifestations. Smeets et al. (1992) reported a boy with severe Alport syndrome who developed end-stage renal disease (ESRD) by age 17, accompanied by deafness. Transplantation with the kidney of an unrelated donor was followed by rapidly progressive antiglomerular basement membrane nephritis, leading to loss of the transplant almost 7 months after grafting. His affected maternal grandfather died from renal failure at the age of 26 years. His mother and sister both displayed hematuria. Guo et al. (1995) reported a woman who presented at the age of 19 years with microscopic hematuria and nephrotic syndrome. The diagnosis of Alport syndrome was confirmed by the finding of typical glomerular basement membrane abnormalities on a renal biopsy taken at that age. There was progressive renal failure, and she began chronic hemodialysis at age 30. A cadaveric kidney transplantation was done 2 years later. Family history showed that her father had sensorineural hearing loss and died at age 36 of renal failure. An elder sister had microscopic hematuria, proteinuria with normal kidney function, and hearing loss. Molecular genetic studies identified 2 mutations in cis in the COL4A5 gene (303630.0012), and skewed X-inactivation studies showed favoring of the mutant allele. Turco et al. (1995) reported a man with late-onset Alport syndrome confirmed by genetic analysis (G54D; 303630.0013). Microhematuria was first discovered at age 22 years. He reached end-stage renal disease at age 40, and had a successful transplant at age 41. He also had bilateral sensorineural hearing loss and subcapsular posterior lens opacities. The proband had 2 daughters, aged 15 and 13 years. Since age 2, the older daughter had had mild irregular microhematuria with normal renal function; a renal biopsy at age 8 showed a thinning of the glomerular basement membrane. In the other daughter, Microhematuria was discovered at age 7. Ocular and auditory assessments were normal in both sisters. The proband's mother was known to have microhematuria. - Clinical Variability Hasstedt et al. (1986) tested for clinical and genetic heterogeneity among 23 Utah kindreds with Alport syndrome. End-stage renal disease had occurred in 72 (49%) of 148 known affected males and in 13 (8%) of 171 known affected females. No father-son affected pairs occurred in any of the kindreds, and there was no evidence for autosomal inheritance. Eighty-four percent of daughters of affected fathers were affected, and 49% of sons and 48% of daughters of affected mothers were affected. One of 3 clinical phenotypes occurred in each of the 23 kindreds: juvenile Alport syndrome with deafness, adult Alport syndrome with deafness, or adult Alport syndrome without deafness or other defects. There was some evidence for intrakindred phenotypic heterogeneity for onset of ESRD: the age of 31 years for ESRD was taken as the divide between the juvenile and adult forms. M'Rad et al. (1992) reviewed 31 families with Alport syndrome. Although there was clinical variability in ophthalmic signs and the age of development of end-stage renal disease, homogeneity tests failed to show evidence of genetic heterogeneity. All were consistent with X-linked inheritance, which was confirmed by linkage studies.
Suspicion that the mutation responsible for Alport syndrome might reside in the gene for the alpha-5 chain of collagen IV was raised by the demonstration that the COL4A5 gene maps to Xq22-q23, the same region known to contain ... Suspicion that the mutation responsible for Alport syndrome might reside in the gene for the alpha-5 chain of collagen IV was raised by the demonstration that the COL4A5 gene maps to Xq22-q23, the same region known to contain the locus for the X-linked form of Alport syndrome (Myers et al., 1990). Barker et al. (1990) identified 3 different structural anomalies in the COL4A5 gene (303630.0001-303630.0003) in affected members of 3 Utah kindreds with X-linked Alport syndrome. Zhou et al. (1992) demonstrated that juvenile-onset Alport syndrome without hearing loss or ocular lesions is also due to mutation in the COL4A5 gene (303630.0006). Renieri et al. (1996) used SSCP analysis of the entire coding sequence of the COL4A5 gene to search for mutations in 201 unrelated Italian patients with Alport syndrome. A causative mutation was found in only 45% of individuals. The authors noted that SSCP analysis can potentially detect 80% of mutations. They suggested that their failure to detect a higher percentage of mutations in these patients may indicate that disease-causing mutations occur not only in the exons but also in the promoter region, within introns, or in alternatively spliced exons. They commented that an alternative explanation could be the involvement of other genes within the Xq region. Knebelmann et al. (1996) screened 48 of the 51 exons of the COL4A5 gene by SSCP analysis and identified 64 mutations and 10 sequence variants among 131 unrelated Alport syndrome patients, which represents a mutation detection rate of approximately 50%. They reported that all different types of mutations were observed in juvenile-type Alport syndrome whereas only glycine substitutions and splicing mutations were observed in adult-type Alport syndrome. Barker et al. (1996) identified a novel mutation in the COL4A5 gene (L1649R; 303630.0014) in Alport syndrome patients. In contrast to most described COL4A5 mutations in Alport syndrome, each of which accounts for the disease in a single family, the L1649R mutation was found in over 7% of the 121 families studied. In males with the L1649R mutation, renal failure preceded hearing loss by approximately 10 years, and the cumulative frequency of hearing loss was 60% by age 60. Barker et al. (1996) noted that substantial variability occurs in the ages at appearance of end-stage renal disease and functional hearing loss among individuals with identical mutations, emphasizing the fallibility of generalizations about the phenotype associated with a specific mutation that is observed in only a small number of Alport syndrome patients.