Genetic deficiency of a type of collagen in the cochlea and kidney resulting in hearing loss and hematuria with end-stage renal disease.
The mutation of the collagen type IV α-5 subunit on the X chromosome is responsible for abnormal synthesis of collagen IV.
Alport syndrome is a X-linked hereditary nephritis caused by mutations in type IV collagen, leading to a split lamina densa of the glomerular basement membrane: It also affects the eye and inner ear as well.
Hereditary form of glomerular injury typically X-linked.
Around for 10% of cases I thought to be spontaneous.
A genetic disorder affecting around 1 in 5,000-10,000 children.
It is characterized by glomerulonephritis, end-stage kidney disease, and hearing loss.
It can also affect the eyes, but does not usually affect sight, except when changes to the lens occur in later life.
Blood in urine is universal finding.
Proteinuria occurs as kidney disease progresses.
It is caused by an inherited defect in type IV collagen.
Type IV collagen is needed for the normal function of the ears, eyes, and kidneys.
Usually causes significant disease from young adult or late childhood life.
Patients with milder mutations or carriers develop disease later, or show only some of the features of classic disease.
Blood in urine is a usual from early infancy, identifiable on urine dipsticks.
In young children, gross hematuria may occur.
As the disease progresses proteinuria occurs and that is an indication for treatment with ACE inhibitors.
Hearing in Alport syndrome patients is normal at birth, but loss develops progressively, usually at the stage when kidney function is normal.
Hearing loss occurs when kidney function is normal, but proteinuria is present.
In some patients, hearing loss is only noted after kidney function has been lost.
Initially hearing changes are related to reduced ability to hear high-frequency sounds, and high-tone hearing loss.
Later it affects lower frequencies too.
In Alport syndrome hearing loss is not complete and good communication is possible with the use of hearing aids.
Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome.
Eye abnormalities are often seen in AS include: lenticonus, keratoconus, cataracts as well as retinal flecks in the macula and mid-periphery.
It is caused by mutations in COL4A3, COL4A4, and COL4A5.
These are the three of six human genes involved in basement membrane,type IV, collagen biosynthesis.
Mutations in these genes prevent the proper production/ assembly of the specialized type IV collagen ‘345’ network, an important structural component of basement membranes in the kidney, inner ear, and eye.
Type IV collagen is also found in other locations, including the alveoli of the lungs.
Type IV collagen 112 type is found in is the major isoform in most human basement membranes.
Mutations prevent the formation of 345 type IV collagen network in the glomerulus, as the 112 network, which is formed in fetal development persists into adult life.
Inheritance patterns depend on which specific mutation is present.
In most people with Alport syndrome the condition is inherited in an X-linked pattern: 85% have mutations in the COL4A5 gene.
In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome.
Most affected males eventually develop kidney failure.
In females, a mutation in one copy of the COL4A5 gene usually results in blood in the urine.
Most affected females do not develop kidney failure.
It can also be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated.
The parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene.
Autosomal dominant transmission of disease associated with mutations in COL4A3 and COL4A4 does occur.
The diagnosis can usually be made on a combination of clinical findings, family history and biopsy criteria.
Biopsy of kidneys or skin electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane (GBM), developing into areas of thinning and thickening, and finally into a complex appearance with apparent splitting, often described as a basketweave appearance.
Immunohistochemistry or immunofluorescence studies to identify the COL3-4-5 proteins in GBM can be helpful.
A family history of end-stage renal disease with hearing impairment is suggestive of Alport syndrome.
X-linked inheritance is the most common pattern, but genetic atypical presentations may be more common than currently thought.
ACE inhibitors can slow the deterioration of kidney function in Alport syndrome, delaying the need for dialysis or transplantation.
Proteinuria is a recommended indication for commencing treatment.
With end-stage renal disease patients require dialysis or kidney transplant.
With kidney transplantation some patients develop antibodies to type IV collagen resulting in progressive graft failure as a result of Goodpasture syndrome.
Hearing aids are often required in teenage or young adult years.
Males have more serious disease.
Type IV collagen is a major component in glomerular basement membrane.
Because type IV collagen is found in other tissues this genetic defect may be associated with nerve deafness, cataracts and lens dislocation.
Patients present between ages 5-20 years.
Initially the process is asymptomatic, while later stages are characterized by glomerulonephritis, glomerular destruction, hematuria and end-stage renal disease.
ANCA and antiglomerular basement membrane negative and C3 normal.
Urinalysis reveals gross hematuria and proteinuria.
Renal biopsy microscopy reveal glomerular and mesangial proliferation.
Alport’s syndrome-interstitial cells with accumulation of lipids, foam cells, may be present.
Under electron microscopy splitting of the lamina densa of the glomerular basement membrane may be seen.
No specific therapy exists, but dialysis utilized when end stage renal disease is present and renal transplantation is an option.