Alport syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]

Synonyms and keywords: Hereditary nephritis, hemorrhagic familial nephritis

Overview

Alport syndrome is a genetic condition characterized by the progressive loss of kidney function and hearing. Alport syndrome can also affect the eyes. The presence of blood in the urine (hematuria) is almost always found in this condition.

Historical Perspective

Alport syndrome was first identified in a British family by Dr. Cecil A. Alport in 1927.

Pathophysiology

Genetics

Alport syndrome is caused by mutations in the COL4A3, COL4A4, and COL4A5 collagen biosynthesis genes. Mutations in any of these genes prevent the proper production or assembly of the type IV collagen network, which is an important structural component of the glomerular basement membranes in the kidney, inner ear, and eye.

This syndrome can have different inheritance patterns depending on the type of genetic mutation. In most people with Alport syndrome, the condition is inherited in an X-linked pattern, due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome.

Alport syndrome 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. Most often, the parents of a child with an autosomal recessive disorder are not affected but are only carriers of one copy of the altered genes.

In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, which explains why most affected males eventually develop chronic kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.

Associated Conditions

Some associated conditions that occur with Alport syndrome are chronic kidney failure, and proteinuria.

Microscopic Pathology

Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. When mutations prevent the formation of type IV collagen fibers, the basement membranes of the kidneys are not able to filter waste products from the blood and create urine normally, allowing blood and protein to enter into the urine.

The abnormalities of type IV collagen in the glomerular basement membrane cause gradual scarring of the kidneys, eventually leading to chronic renal failure in many people with the disease.

Diagnosis

Diagnostic criteria

Gregory et al, 1996, give the following 10 criteria for the diagnosis of Alport syndrome . 4 of the 10 criteria must be met for an accurate diagnosis:

• Family history of nephritis and of unexplained hematuria in a first degree relative of the index case or in a male relative linked through any numbers of females.
• Persistent hematuria without evidence of another possibly inherited nephropathy such as thin GBM disease, polycystic kidney disease or IgA nephropathy.
• Bilateral sensorineural hearing loss in the 2000 to 8000 Hz range. The hearing loss develops gradually, is not present in early infancy and commonly presents before the age of 30.
• A mutation in a COL4An gene (where n = 3, 4 or 5).
• Immunohistochemical evidence of complete or partial lack of the Alport epitope in glomerular, or epidermal basement membranes, or both.
• Widespread glomerular basement membrane ultrastructural abnormalities, in particular thickening, thinning and splitting.
• Ocular lesions including anterior lenticonus, posterior subcapsular cataract, posterior polymorphous dystrophy and retinal flecks.
• Gradual progression to ESRD in the index case of at least two family members.
• Macrothrombocytopenia or granulocytic inclusions.
• Diffuse leiomyomatosis of the esophagus or female genitalia, or both.

Symptoms

• Hematuria
• Peripheral edema, anasarca
• Decrease or loss of vision
• Difficulty hearing
• Flank pain
• Eye pain
• Lacrimation
• Photophobia

Physical examination

Vital signs

• Systemic hypertension

Eyes

Fundoscopy shows

• Cataracts
• Subcapsular posterior lens opacities
• Lenticonus
• Retinal flecks (dot-and-fleck retinopathy)
• Posterior polymorphous corneal dystrophy/corneal epithelial erosions

Ears

• Sensorineural deafness

Extremities

• Peripheral edema
• Anasarca
• Leimyomatosis

Laboratory findings

Urinalysis

• Microscopic hematuria
• Pyuria
• Red cell casts
• Cylindrical casts
• Proteinuria

Electrolytes and Metabolic disturbances

• Increased BUN
• Increased serum creatinine levels
• Hypoalbuminemia

Renal biopsy

• Irregularly thin and attenuated glomerular basement membrane
• Splitting of glomerular basement membrane
• Scarring of tubules and interstitium

Treatment

• As there is no known cure for the condition, treatments are symptomatic.
• Patients are advised on how to manage the complications of chronic kidney failure and the proteinuria that develops is often treated with ACE inhibitors, although they are not always used simply for the hypertension.
• Once kidney failure has developed, patients are given dialysis or can benefit from a kidney transplant, although this can cause problems.
• The body may reject the new kidney as it contains normal type IV collagen, which may be recognized as foreign by the immune system.
• Gene therapy as a possible treatment option has been discussed.

References

This article incorporates public domain text from The U.S. National Library of Medicine

External links

Laboratory for Molecular Diagnostics, Center for Nephrology and Metabolic Disorders, Dr Mato Nagel

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