Alport syndrome and its type IV collagen defect
Alport syndrome is an inherited type IV collagen fault that typically presents with haematuria (blood in the urine) in childhood or adolescence, with hearing loss and sometimes eye changes.
Remember
Haematuria from childhood, hearing loss and affected male relatives on the mother's side suggest Alport syndrome, an inherited type IV collagen fault that is usually X-linked (the gene lies on the X chromosome).
Memory aid
one collagen, three organs, so think kidney, ear and eye
The same type IV collagen is found in the kidney, the cochlea of the ear and the lens of the eye, so one faulty collagen can affect all three.
Type IV collagen is the main structural protein of basement membranes, which are thin supporting sheets under cells. In Alport syndrome, a gene for one of its chains is faulty.
In the kidney, this collagen gives strength to the glomerular basement membrane, the part of the blood filter that holds back blood cells and protein. When the collagen is abnormal, the membrane is weak and leaks red blood cells into the urine. That is haematuria, and over the years the scarring leads to kidney failure.
Haematuria in childhood or adolescence is the typical presentation. It is often microscopic (too little blood to see) and found on screening. Children and young adults commonly have repeated episodes of frank haematuria, meaning blood visible by eye. Protein in the urine (proteinuria) tends to appear later, and its rise is a marker of progression.
The same collagen is found in the cochlea, the organ of hearing in the inner ear, and in the lens of the eye. The disease therefore also causes sensorineural hearing loss, meaning loss of hearing because the inner ear or its nerve is damaged, and sometimes eye problems.
It is most often X-linked: the gene lies on the X chromosome. An affected man has one X chromosome and so no second normal copy of the gene, whereas a woman's second X chromosome partly compensates. In the X-linked form, male sex is a strong factor for a poorer prognosis, so kidney failure comes earlier.
Treatment is supportive. Starting an ACE inhibitor (a kidney-protective blood pressure medicine) early can slow progression, and transplantation is used for kidney failure.
Key facts
- Cause
- a mutation in COL4A3, COL4A4 or COL4A5 makes the type IV collagen abnormal.
- First sign
- haematuria in childhood or adolescence, often with recurrent visible episodes.
- Hearing
- sensorineural hearing loss typically affects higher frequencies, may be missed in early childhood and usually follows the haematuria.
- Eyes
- eye changes such as lens abnormalities occur, but they are less common than hearing loss and typically appear in the late teenage years.
- Inheritance
- usually X-linked, in about 85 percent of families, though autosomal recessive and, rarely, autosomal dominant forms exist (autosomal patterns affect women as often as men).
- Women
- in X-linked disease, those who carry one faulty copy are usually less severely affected than men, with disease that progresses more slowly.
- Treatment
- supportive, with an early ACE inhibitor to slow progression, and transplantation for kidney failure.
Exam traps
- Autoantibodies against type IV collagen are not the cause of Alport syndrome: that is anti-glomerular basement membrane disease, an acquired autoimmune attack on healthy collagen, sometimes with lung bleeding, whereas in Alport syndrome the collagen is itself faulty.
- In X-linked disease, female sex does not predict the poorer outcome, because women have a second, normal X chromosome and on average progress more slowly.
- A missense change (one that swaps a single building block) is the milder option, because large deletions and nonsense or frameshift changes, which cut the protein short, carry the highest risk of early kidney failure in males.
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