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Alport syndrome

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Alport syndrome

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Alport syndrome

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Alport syndrome etiology typically involves an inherited defect.

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USMLE® Step 1 style questions USMLE

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A 15-year-old boy comes to the office because of malaise, anorexia, nausea, and decreased urination. His mother says that he is having problems hearing. Physical examination shows decreased hearing bilaterally with the Rinne test and bilateral edema in the lower extremities. Urinalysis shows microscopic hematuria and proteinuria. A peripheral blood smear reveals microcytic anemia. Which of the following is the most likely diagnosis? 

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Contributors:

Thomas Schmid

Collagens are a family of proteins that are collectively the most abundant protein in the body, and can be found throughout the various connective tissues.

Each member of the family is named with a Roman numeral, and if mutated or absent, can lead to problems in the tissues where that particular collagen is found.

Alport syndrome occurs as a result of mutations in Type IV collagen, which is particularly important in the glomerulus of the kidney, the eye, and the cochlea, and that’s why the symptoms of Alport syndrome are specific to those tissues.

Type IV collagen is a sheet-like structure found in all basement membranes and serves to support cells and form barrier.

The three basement membrane layers are the lamina lucida, lamina densa (where type IV collagen is), and lamina reticularis.

Now within the kidneys, there are glomeruli, which filter the blood and that together with a tubule forms a nephron.

These glomeruli happen to have a basement membranes, called the glomerular basement membrane, or GBM, and that GBM, along with the fenestrated, meaning has pores, capillary endothelium and the podocyte slit diaphragm, forms a selective filter, meaning that water and certain other plasma components can escape the capillary, forming the filtrate that will become urine, but red blood cells and most proteins stay in the glomerular capillary.

In Alport syndrome, kidney function is normal through early childhood, but over time, the missing or nonfunctional type IV collagen causes the GBM to become thin and overly porous.

This allows red blood cells to pass right through from the capillary to the urinary filtrate leading to microscopic hematuria, which is where red blood cells are seen in the urine under a microscope, and this might eventually lead to gross hematuria, where the red blood cells can be seen with the naked eye.

Over time, excessive amounts of protein start to get through the filter, resulting in proteinuria, or protein in the urine.

And finally this excessive protein loss and other factors cause the GBM to undergo sclerosis.

As there are less and less healthy glomeruli, somebody with Alport syndrome might develop renal insufficiency or even failure, which can lead to renovascular hypertension as well.

Together the hematuria, renal insufficiency, and hypertension contribute to the categorization of Alport syndrome as a glomerulonephritis.

Another cause of glomerulonephritis called Goodpasture syndrome is caused by autoantibodies against the basement membrane in the glomeruli and the alveoli.

So although abnormality in the basement membrane is from a different cause, the result is similar in these two syndromes.

Another part of the body affected in Alport syndrome is the ear, which can lead to hearing loss, and usually this isn’t present at birth, but starts in childhood or adolescence, and the precise mechanism is unclear.

One proposed mechanism involves the cochlea or inner ear structure which contains the Organ of Corti, which has really small, but highly specialized set of hair cells that are attached to a basement membrane.

Abnormal type IV collagen might prevent those hair cells from generating normal nerve signals in response to sound vibrations.

Because it’s an inner ear problem, this is a type of sensorineural hearing loss, as opposed to middle ear and outer ear problems, which would lead to conductive hearing loss.

Some patients with Alport syndrome also have eye findings, which are also not typically present at birth.

These include anterior lenticonus, where the center part of the lens starts to push into the anterior chamber because the anterior lens capsule lacks the integrity to maintain the shape of the lens.

Myopia, or nearsightedness, and lens opacities can result as well.

Other eye changes in Alport syndrome include having white or yellow flecks around the macula, which is the central part of the retina, as well as having problems with the cornea, like recurrent erosions.