The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Epidemiology
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Anatomy
Pathophysiology
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Etiology
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
Genetics
Prognostic Factors
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
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The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
medtigo
Alport Syndrome
Updated :
February 2, 2023
The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
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