USH2018 Margaret Kenna Summary: Diagnostic and genetics of Usher Syndrome

USH2018 Margaret Kenna Summary: Diagnostic and genetics of Usher Syndrome


(Irmgard Reichstein) Okay, we
lost a little bit of time, but now we will start to summarize the
scientific conference from yesterday. And I will find only
very few words for that. We have the organizers
involved in that summary. So we will hear three summaries from Dr.
Margaret Kenna, she will start, and
also from Gwen Geleoc, both are from the Children’s
Hospital Harvard Medical School, and also from Prof. Uwe Wolfrum who
is from the University of Mainz, and I guess all of you
know him very well. I will make this very
short not to lose time, but I will mention you
will have the possibility to ask one or two questions afterwards,
due to time we cannot allow more. Please be so kind and prepare
really clear questions which are of general interest. If you have questions more or less
related to your personal situation, we kindly ask you to use the
lunch time, the breakfast and all the breaks we
will have during the day. Thank you very much, and here
is the first scientific talk. (applause) (Margaret Kenna) Is this on?
Can you hear me? Thank you. My name is Margaret Kenna, I am a pediatric ear, nose
and throat doctor in Boston. And I get to do this, and I’m
really privileged to be here, because we diagnose babies
with hearing loss at birth. And so because of that I’ve
learned a lot about the causes of hearing loss in young children,
and this is certainly one of them. But before I get going I want to
thank the planning committee. Gwen and I are the US version, but really it’s the people here
in Germany that did all the work as everybody has said, and
we really appreciate it. I also want to thank the interpreters. When we did this in Boston,
we were still looking for interpreters an hour before the conference started,
and I know how much work this is, all different types of interpretation
and translation and access. I know this is a lot of work, and
I’ve been watching interpreters and reading written text, and
it’s, they are really good! So anyway, thank you
very much for that. (applause) And finally, and of course
without the patients and the families there would be
no reason for us to be here. I’ve been to many of the
other family conferences. We are going to need a bigger room the
next time we do that, so it’s all good. So I’m going to just summarize very
briefly some of the information that was presented in the first
day about the diagnostic part of Usher syndrome. And obviously as many of the
previous speakers just said, without the diagnosis you
wouldn’t all know each other. And when we come to clinical
trials or treatments, you won’t know that you are eligible. So there is a whole bunch
of reasons to do this. Many of the speakers on the first
day, including Dr. Kimberling who was part of the team that
discovered the very first Usher gene, Myosin 7A – and I’m assuming
he is in here someplace – and then many of the other people
that are listed here talked about different aspects in the
genetics of Usher syndrome. Many other people
talked about treatments or the way the different
genes work together. So the truth is, this is really from
everybody in the last two days. So, Bill Kimberling,
as I just mentioned, really came up years
ago with seven steps to treatment for an inherited disease. And when he did this, we weren’t
very far down this pathway. And it was really starting with finding and the genes that cause
a particular disease. We are very far down that
path now with Usher syndrome. There are other genes
that we don’t know about, and the way the genes work we
are not completely sure about, but I think one of the
things that is really key and that Rebecca just alluded to is:
get your genotype done if you can. Figure out what the gene is. Make sure you actually have, if
that’s the case, Usher syndrome. There are a lot of other things that cause
hearing loss and vision impairment, and so having a correct diagnosis, what
ever the diagnosis is, really matters. Everybody knows there are at least
three types of Usher syndrome, but as Rebecca alluded to,
some of the presentations are rather atypical for what we know
from this little box up here. So it’s entirely possible
to have Usher syndrome type I and look like you have type II
or have type II and have type I, or have Usher syndrome III
and look like type I. So there is a lot to be learned
based on the genotype. And there also is a wide variation
in the way patients present. So this is the reason we get testing. These are the known genes, but almost certainly there
are other genes that are also an underlying reason
to have Usher syndrome or genes that interact
with these genes. And depending on how you
play with the genes or what you do to the genes really
may result in the clinical changes that we are all talking
about and hoping for. So here is the other reason
we need genetic testing. These are two of my patients. The one on the left, GJB2,
that is Connexin 26, this child presented as deaf. The patient on the right,
MYO7A, USH1B presented as deaf – same hearing test. And looking at a baby, when they
present they look exactly the same. For us to figure out
what to do with them, we have to do genetic testing. This is a patient with MYO7A USH1B. This patient has a profound hearing loss
this is a patient with USH1B, MYO7A, this patient does not have
a profound hearing loss, at least not at the beginning. And so both of these patients
have mutations in the same gene, but they didn’t have
the same mutations, and their clinical
presentation wasn’t the same. And actually the second patient here,
this patient walked on time, her balance is pretty good, she
wore hearing aids for years, and then her hearing loss progressed,
and now she has cochlear implants. So same gene, different mutations,
very important to figure this out. Bill Kimberling talked a lot about
the history of genetic testing, and there are probably people in
this room without research testing. And if they only have one gene
and they are not entirely sure, all these other things
now that are available, common mutation testing came
next, followed by single genes, followed by deafness panels, where
we have 120 or 30 or 60 genes, vision panels that are similar. What we probably need
is a combined vision and hearing loss panel, so
we are not missing anybody. And then now we are talking a
lot about testing whole exomes, that is the protein part of the DNA,
and then whole DNA testing. So things are progressing
really rapidly, but each step has the good news
and the other news. And it’s the other news that
we have to be careful about. So why knowing? Why does this matter? And when you call the insurance
company in the United States, they say exactly what
our first speaker said: why do you have to do this,
how is it going to change, why should we pay for it? Well, to get a diagnosis helps a lot. And then once there are
interventions that will also help. We also want to know how the genes
interact, how they affect both hearing and vision and balance and things that
we are not really looking at very hard, but we should be. And some genes only affect the
hearing or the vision, not both. Or some mutations in the same gene. And if you change this gene over
here, it’s like those little toys you push this box and the other boxes
move, like what happens over here. So anything that we do to
intervene we have to make sure it doesn’t make things worse. Other genes we don’t know about, Almost certainly there are
genes we don’t know about. And so for example USH2A, which is a really big gene and one of
the common causes of Usher syndrome. There are a lot of different
versions of USH2A. Which ones do you treat?
Which ones do you worry about? How do they look clinically? So, and finally, do you
actually have USH? And I know that sounds kind of silly, but there are people who
do have vision impairment and hearing loss, but they don’t have
the clinical diagnosis of Usher. And that would guide them
down a different pathway. And this really gets to talking about
what we consider Usher syndrome. It’s a particular type
of vision impairment, a particular type of hearing loss,
and there may be other things. So what else can we learn
from other people about when they study cilia, which are
the little cells, the little hairs – they are not really hairs –
but maybe there are other genes that have to do with
cilia, microtubules. We actually heard from two other
really excellent speakers in the last two days – Matt Tyska from
Nashville who talked about the gut. Well, how does that affect
the ears or the vision? But the system in the gut that he
is looking at is very reminiscent of what’s going on with Usher syndrome. So maybe there is something
that we can learn from that. And then Fred Schwaller from Berlin
talked about the skin. And once again, lots of similarities. So there are other organ systems
that we can learn from, and maybe they are even
involved in Usher syndrome. So the other thing is
better genetic testing. Anne-Françoise Roux talked about
finding the second mutation or even the third mutation and
how that affects the diagnosis and then the interventions. Are the mutations in places in
the DNA that we haven’t looked? Like in the introns, which is part
of how the DNA gets transcribed, or in the splicing which turns
out different types of genes, so different versions of the gene. Is it really dominant
or is it recessive? So are there to possible causes for the
hearing loss or the vision impairment? That happens. I know that sounds rare, but it’s not
that rare once you begin to look. And then, of course, most important
and as everybody before me mentioned, we need registries, we need to
be able to find the patients and families so that we
can do better networking, – although we are doing a
pretty good job of that – and then better treatment as
things come down the road. How will knowing the genes really help? Well, where are the genes expressed they don’t all start
out at the beginning. What type in mutation is present? What kind of intervention
is it going to be making the genes bigger, better,
smaller, different, replacing them, are there going to be medications? Yesterday there was a
very eloquent speaker on using something called Baclofen, which is something we use
for tight muscles. And maybe it will help
with vision and hearing. So I think we don’t know, but
without knowing the genes, and when the genes express
themselves we won’t know what to do. And then when to treat? So say you assume you know the gene, and we know that when the genes
are expressed at different times. So when do you do something about it? When do you do something
about the hearing loss? When do you do something
about the vision impairment? And if it turns out
there are GI symptoms, when to do something about that? And we can test
prenatally now for genes. I have patients or parents coming
to me, and their baby is not born yet, and they know the baby is going to have
something that affects their hearing or their vision. And they want to know what
that’s going to turn out like. And is there something they can
do before the baby is born? So these are tricky questions,
they are ethically tricky questions, and yet they are very
exciting questions. And it’s sort of what all of these
people, the families and the patients and the science folks together,
are going to figure out. So anyway, thank you very much. (applause) (Irmgard Reichstein) Thank
you very much, Dr. Kenna. We just decided to
bundle the questions. So please write your
questions, note them down, and at the end of the three talks you
will have time to ask questions, and we know then how much time
we have for that to be on time.

Leave a Reply

Your email address will not be published. Required fields are marked *