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Alport Syndrome

A doctor speaks – what is Alport Syndrome?

Alport Syndrome is a rare inherited condition that can cause progressive kidney damage, hearing loss and eye abnormalities. The most common form is X-linked Alport Syndrome which affects approximately 85% of people with Alport Syndrome*. The other form affecting approximately 10-15% of people is called autosomal recessive Alport Syndrome*. People who are ‘carriers’ of the autosomal recessive form are sometimes referred to as having autosomal dominant Alport Syndrome. There is some change and debate about the naming of the term autosomal dominant as well as the term ‘carrier’.
 

Professor Neil Turner explains X-linked Alport Syndrome and autosomal recessive Alport Syndrome.

Professor Neil Turner explains X-linked Alport Syndrome and autosomal recessive Alport Syndrome.

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So the common type of Alport syndrome that everybody- well, let's say every medical student is supposed to know - [laugh] is, affects young men. Because it's X-linked. Men have one X chromosome and one Y chromosome. So if they inherit an X chromosome with the Alport mutation on it, that's their only copy. They don't have another matching chromosome with a normal copy on it. So it's very easy to understand why they should get severe Alport syndrome. So they would typically begin to get protein in their urine in their teens. Maybe start losing their hearing some time during their teens. And then increasingly lose their kidney function in their late teens and into their twenties. And the average age at which patients like that used to get kidney failure was in their mid to late twenties. Fortunately that's now later, with ACE inhibitors. Now you can get exactly the same kind of, of Alport syndrome from two other genes, which aren't on the X chromosome. So there are three genes that can cause Alport syndrome. They're called collagen 4 - alpha 3, 4, and 5.So 5 is the one that's on the X chromosome, and 3 and 4 aren't. But if you have two abnormal copies of either the 3 or the 4 gene, you'll get exactly the same thing as a, a boy with X-linked Alports. Now it's very rare to inherit two abnormal copies of, of one of the other genes. So the majority of people that we see who are affected at a young age, are boys. But boys and girls could be equally affected by the other type. And it's thought that it might cause up to fifteen percent of typical Alport syndrome.
 

Professor Neil Turner explains what autosomal dominant is and why there is some debate about its name.

Professor Neil Turner explains what autosomal dominant is and why there is some debate about its name.

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So autosomal dominant means that you have one copy of the abnormal gene, but you get disease. It's slightly controversial whether we should be calling it autosomal dominant, because many people with one abnormal copy, probably most people with one abnormal copy don't get severe kidney disease in their lifetime. But some do. And in some families that seems to be more common. And in those families it's sometimes been called autosomal dominant. Other people say, "Actually you should just call these people unlucky carriers." It means the same thing. So they have one abnormal copy, and they get kidney disease. Usually much later in life. And often without the hearing loss, or at least without the severe hearing loss that patients with typical Alport syndrome get.
 

Professor Frances Flinter explains why there is debate about the label of ‘carrier’.

Professor Frances Flinter explains why there is debate about the label of ‘carrier’.

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The terminology is controversial. And certainly, there's quite strong pressure from American colleagues and from some in Europe to label everybody who has a mutation in an Alport gene as having Alports, regardless of whether or not they've just got a bit of blood in their urine, or they've got full blown clinical features and kidney failure. And the reason they do that is that they want to make sure that carriers get the right sort of follow-up, that they also have their blood pressure and their urine tested once a year, with a low threshold for prescribing an ACE inhibitor if they get high blood pressure or protein in their urine. But I've found that for many parents whose children just have a little bit of blood in their urine, and perhaps a biopsy that shows thin basement membranes, with a single mutation in the Alport gene - if you refer to them as having Alports, they go away and they read up all about Alport syndrome and fear quite unnecessarily, in most cases, that their child is going to develop kidney failure, hearing problems and so on. And I've seen the use of that language cause a lot of distress in families, and it's taken quite a while to unpick all of that. So I would prefer at a genetic level to describe people who have a single mutation as being carriers of Alports. And then qualify that if they develop symptoms to describe them as manifesting carriers. And I would only refer to them as being affected with Alports for, if they are carriers of X-linked Alports and go on to develop renal impairment and hearing problems, and so on. And that's a problem that affects probably only five or ten percent of carriers, female carriers, of X-linked Alports. And particularly because we now know that early treatment of high blood pressure and proteinuria with ACE inhibitors can protect their kidney function, we really should in the future be able to prevent the vast majority of carriers from having significant problems.
Alport Syndrome can affect a large number of people in a family, although occasionally it is spontaneous in mutation which means that the person is the first to get it in their family. Below, Professor Neil Turner, Consultant Adult Nephrologist and Professor Frances Flinter, Consultant Geneticist explain the genetic causes of Alport Syndome and treatment outlook. To find out more about specific topics like treatment and diagnosis, click on the topic summaries on the left.
 

Professor Frances Flinter explains the genetic causes of Alport Syndrome.

Professor Frances Flinter explains the genetic causes of Alport Syndrome.

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So we think all people with Alport syndrome have the condition as a result of a mutation in one or two genes. The majority of cases of Alports are what we call X-linked. They're caused by an alteration in the gene on the X chromosome. And that therefore affects males much more significantly than females, because men only have one X chromosome whereas women have two X chromosomes. So women have two copies of the gene for X-linked Alports, and men only have one copy. And if they have a mutation in that one and only copy, then they will inevitably be affected by the condition. Whereas women who inherit a mutation in one of their two copies of that gene are usually much more mildly affected. A smaller proportion of patients with Alport syndrome have what we call autosomal recessive Alports, because they inherit a mutation in both copies of the gene that's on one of the autosomes. So a gene that we all have two copies of, men and women. So, for patients with autosomal recessive Alports, sex doesn't play a role in that, it's simply a question of a child having parents who are both carriers of recessive Alports and then being unlucky and inheriting the mutated gene from both parents. Now we know that carriers of recessive Alports, like carriers of X-linked Alports, have usually much more mild features. And they can be passed down for several generations through a family. And sometimes that's led people to suggest that we should call carriers of Alports, or refer to them as having dominantly inherited Alports. But I don't actually think dominantly inherited Alports exists, because people who are carriers of Alports don't have the full range of features that would be enough for us to refer them- to them, as having Alport syndrome. They don't usually have the hearing problems, they don't have the eye problems, and the majority of them will retain normal kidney function. So I don't use the term autosomal dominant Alports, I talk about people who are carriers of recessive or X-linked Alports as being manifesting carriers if they develop some symptoms.
 

Professor Neil Turner explains how Alport Syndrome affects the kidneys.

Professor Neil Turner explains how Alport Syndrome affects the kidneys.

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So patients with Alport syndrome, like most other kidney diseases, are completely unaware that there's anything happening in their kidneys until quite late on. Some of them notice - or their parents notice - blood in the urine, when they're babies. But really you wouldn't know anything was going on after that time, unless you did tests of urine or of kidney function. And for people with severe Alport syndrome, their kidney function gradually deteriorates. So that typically, people with severe Alports would be getting into serious kidney trouble in their late teens or twenties without treatment. Fortunately, that's getting a bit later now. In addition to that, there are people who carry the Alport gene. And carriers is maybe not the best term, because quite a few of those people in their lifetime do get kidney disease. Maybe up to a third of them, max. So, most of them are fine. Those people may also get abnormalities of their, in their urine and kidney function, as the years go by. But on the whole are less severely affected.
 

Professor Neil Turner says treatments continue to get better for people with Alport Syndrome.

Professor Neil Turner says treatments continue to get better for people with Alport Syndrome.

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There's never a disease you would wish to have, is there. So… The good thing, that there is a lot of good news about Alport syndrome. We're able to slow it down now, and we never thought we would be able to do that as soon as it's proving that we are. And the treatments for patients who do get kidney failure have improved no end in my lifetime, they're so much better than they were. So the great majority of people with Alports - even if they develop kidney failure - are leading really healthy, good lives. And that, that's a fantastic change. I, I think we , we did a quick look, and there are nearly five hundred people transplanted or on dialysis with Alports - all, great majority transplant in the UK now. And of course fifty years ago there were none. But it's an extraordinary change. We will continue to make huge changes in the future. Those treatments will continue to get better. And it looks as if we're going to increasingly be able to slow down the rate at which people get kidney failure. So hopefully more people will be out there, not needing dialysis and transplantation. So yes, you wouldn't wish it on anybody. But if you have it, the outlook is much better than it was. And we can really now offer things that, that make a difference. And that's a huge step forward.

*Savige J, Colville D, Rheault M, Gear S, Lennon R, Lagas S, Finlay M, Flinter F. Alport syndrome in women and girls. Clinical Journal of the American Society of Nephrology. 2016 Sep 7;11(9):1713-20.
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