NCUS NEWSLETTER
Newsletter for the National Collaborative Usher Study
Issue 2
Autumn 2005


Contents
1 Note from the Editor (Mary Guest)
1 Yasmin Hughes' introduction
2 Worldwide response
3 Testing vision
5 The eye in balance testing
6 DNA sequencing
8 Sense membership
8 Recruitment update


Note from the Editor

Hello, and welcome to the second issue of
our Newsletter for everyone involved in the
National Collaborative Usher Study. Since I
wrote in May, over 30 new families have agreed
to take part, which means the NCUS ‘family’
is growing fast and involves extended family
members living abroad who have taken the
trouble to send their blood samples. Each sample
which wings it way to us gives more information
for the molecular geneticists to work on and
is vital to the process of understanding the
condition in families. In this issue, Dr. Elene
Haralambous explains how DNA Sequencing
can be used to find the genetic cause of Usher
syndrome and why these samples are so
important.

With more DNA to work on, we are pleased
to welcome our new Research Assistant,
Yasmin Hughes who will be working with Dr.
Haralambous at the Institute of Child Health
until January 2007. Lynne Martindale, who
discovered quite recently that she had Usher
syndrome, has kindly sent us her impressions.
We have included comment from Jeanne
Ennals too which we hope fortifi es those of
you who are waiting for the clinical tests.
On the subject of waiting for appointments; if
you have not yet completed the vision hearing
and balance tests yet you will be hearing from
Melanie Gonsalves in the next few months; you
have not been forgotten. Your travel costs are
covered and if you need to stay overnight your
hotel will be booked and paid for by the NCUS.

Last time we focused on hearing and balance,
now, in this issue, Dr. Zubin Saihan describes
investigations into vision which many of you
have undergone and why these tests are
important.

On behalf of all of us here at Sense, at the
Institute of Child Health and at the Institute
of Ophthalmology we wish you a happy and
joyful festive time with your families and a
peaceful year in 2006.

Mary Guest, Editor
Project Manager
E-mail: mary.guest@sense.org.uk


Yasmin Hughes' introduction

Hi, my name is Yasmin Hughes.
I have recently joined the genetics
team at the Institute of Child
Health (ICH) in London. My role
as a Research Assistant is to work
with the Molecular Geneticist,
Dr. Elene Haralambous, in analysing blood samples
received from the family members. We search for
any genetic changes which may be responsible for
the presentation of the Usher symptoms in those
individuals. My interest in genetics began whilst
studying for my Masters of Biochemistry degree at
the University of Bath, where I graduated from this
summer. I find studying the genetics that result
in causing Usher syndrome fascinating. I look
forward to meeting families who have taken part
in the study in the near future.
Thank you and hope to see you soon. Yasmin


A worldwide response: FAMILY COORDINATOR, LIZ COOK

In the last newsletter I described how
participation in the study brings families
together, often for the first time, to talk about
how the condition affects them. It is helpful
for me to meet family members altogether,
to discuss the study and answer questions.
Meeting all of the family also enables me to
take a detailed family history and of course to
obtain a blood sample from everyone.

Sometimes, however, it is simply not possible
to get everyone together in the same place at
the same time, particularly when relatives live
abroad. This does not prevent those family
members from being involved in the study.
In the last six months, we have received blood
samples and information from relatives living
in Australia, New Zealand, the United States,
Canada, Brazil, Italy and some of the more
far flung corners of the United Kingdom. A
complete set of samples from each family
is extremely important to the work of the
geneticists, obtaining a blood sample from the
family member living abroad often completes
the picture.

Family members abroad who want to take part
are sent a letter with full details of the study,
together with a “blood pack” which includes
a blood bottle and all the appropriate return
packaging. If you wish to take part, you need
to have a blood sample taken by your doctor
and return it to us in London by the quickest
route, which is usually an international courier
service. The NCUS pays all expenses.

We have had a really positive response from
relatives living abroad and we aim to keep you
informed through this newsletter. Thank you
everyone for making this happen.

Letters from our families

Lynne Martindale

Lynne first heard about the NCUS in Blackpool,
at a meeting of the Retinal Awareness Group.
As with so many, Lynne, who was born in
1950, was not diagnosed with Usher Type II
until quite late in life.

‘It all started when I had a letter from Liz Cook
asking if I was interested in taking part. I said
‘yes’ and that is how I got involved.
We came up to Finsbury Park to see Liz to take
a blood sample from me, then Liz came to see
my mum to take a blood sample from her,
to help with the research. I can’t wait to hear
what the result will be!

Following this, I met Zubin Saihan at Moorfi elds
to go through the test. Zubin was very good
and explained everything about what was going
to happen throughout the whole procedure and
we had a break in between so that I was not
worn out. To see my eyes on the computer was
amazing and I was able to have a copy of the
photos for a keepsake.

Next, I went to see Nell Rangesh for the hearing
and balance tests. Nell explained the whole
procedure as we went along, which was good.
When I had the hearing and balance done, I
did fi nd that a little bit diffi cult, trying to focus
on the screen but I think I got there in the
end. I found one of the balance tests (caloric
test), with warm and cool water in the ear, a
bit uncomfortable and I was relieved after the
water had drained out but it was all worth it
in the end, especially for this research. I am so
pleased that I have done it. Well done to all of
you in getting involved with the research.
I could not have gone through with all these
tests without the help and support from my
husband, Dave’.

Comments from Jeanne Ennals

Thank you so much for kindly visiting my
mother and myself in Shenfield, in September,
in connection with the National Collaborative
Usher Study.

The information you imparted was extremely
helpful and interesting. We do hope that you
were also helped to understand my brother’s
situation a little more as a result of our
discussion and trust the blood samples will
assist the scientists to study the gene affecting
our family.

We are grateful for all you are doing in the Usher
Study and thank you again for the support you
are giving to our family. We are very appreciative,
and look forward to hearing again in due course.


Testing vision in Usher syndrome
DR ZUBIN SAIHAN

Many of you have already attended Moorfields
to have the vision tests done. So far, we
have recruited 199 people from 160 families
and over 170 people have already had eye
examinations.

Those of you who have had eye tests are aware
that the tests can take a few hours to perform.
We really appreciate your help and cooperation
in having these tests as they provide us with
much useful information about how the eyes
are affected in Usher syndrome.
Why are these tests done?

There are at least 8 genes that are known to
cause different types of Usher syndrome in humans. Changes in these genes affect the
eye and inner ear in different ways, giving
rise to the hearing loss (and sometimes
balance problems) and in all cases to Retinitis
Pigmentosa (RP).

The RP seen in Usher syndrome can vary a
great deal from person to person. By asking
questions and performing certain tests we
are able to fi nd out exactly what problems
people are having which gives us a better
understanding of how the retina is functioning.
Here is a description of four of the tests that we
have routinely performed in this study and also
what they tell us about the function of the eye.

Visual Acuity

This test, using a log MAR chart, tests how
far down a chart of letters someone can read.
The letters are large at the top and get smaller
as you read down the chart. This gives us an
objective test of the clarity of central vision.
It relies upon many factors including the
correct glasses/contact lens prescription, the
presence of cataracts and on the health of the
‘macula’ which is the central part of the retina
responsible for central vision.

Visual Field Tests

This allows us to test specifi c areas in each
eye. In RP, different parts of the retina can be
affected. This can result in loss of function and
ultimately in loss in the ability to see light in
those areas. The test is done by using lights of
3 different sizes, 64mm2, and 1mm2,
0.25 mm2. These are represented in the pictures
below as black, green and red lines respectively.
It is easier to see the largest size light and this
represents the largest area on all fi eld tests. The
smaller lights are always more diffi cult to see
and always represent a smaller area on the field
test. We have been seeing different patterns of field loss with people with Usher syndrome.
The pictures above represent different patterns
that we have seen in some of the Usher
population from the study.

Optical Coherence Tomography

Optical Coherence Tomography or OCT is a
non-invasive technology that creates a highresolution
colour image of the eye by shining
a light source into the eye and analyzing the
refl ected light rays to form an image. The
colours seen on the OCT scans are not the
actual colours of the retina but simply represent
a scale showing the amount of reflectivity of
different layers in the retina to light shone in
to the eye. We are using OCT to visualise the
central part of the retina.

In the pictures below you can see 3 OCT scans.
The scans represent a 6mm area of the retina
centred on the macula. The upper scan is of
a person who does not have RP. The lower
two scans are from two people with Usher
syndrome from our study.

Two changes we
see often on these
scans of the central
retina are retinal
thickening or thinning.

Thickening of the
retina in RP can be due
to the development
of cystic spaces within
the retina. This is
sometimes called
‘macula oedema’.
Sometimes these
changes can interfere
with central vision and
visual acuity. Tablets
can, for some, reduce
swelling and improve
central vision. 

Scanning Laser Ophthalmoscope

The Scanning Laser Ophthalmoscope (SLO) is
another non-invasive technology which allows
us to visualise the layer underneath the retina,
the Retinal Pigment Epithelium (RPE). The RPE
is important in maintaining a healthy retina.
In a healthy retina, there is turnover of
retinal cells (rods and cones) this process
produces a product called lipofuscin which
is dealt with by the RPE. The presence of
this substance is mainly responsible for the
white colour seen in these images which are
called ‘autofluorescence’. If the retina is not
functioning normally, it will not produce
this substance and thus will appear darker in
colour. Similarly, an excess of this product can
appear as areas of brightness.

We have observed different patterns of
autofluorescence in people with Usher in this
study. One pattern we have seen is a ring of brightness around
the macula. We
have done work
to show that
this ring most
likely represents
a watershed area
enclosing healthy
retina within, and
less healthy retina
outside.

The pictures above represent colour
photographs of the retina on the left compared
to the SLO images of the same eyes on the
right.

Once again, thanks for all your help. I have
enjoyed meeting all the Usher families so far
and we look forward to reporting back some of
our findings from the study in 2006.


The Eye in Balance Testing
DR.NELL RANGESH

One question that comes up frequently as I fi x
the goggles and camera for balance testing is
about recording eye movements:

“If the balance organs are inside my ears, how
can recording my eye movements tell you
anything about my balance?”

One way to answer this question is to explain
briefly how our balance works. We have all
seen that a child learning to walk keeps falling
over until he learns to balance while standing
upright. The human balance system is quite
complex and dependant on vision, information from the muscles and joints and balance
(vestibular) information from the inner ears,
which continuously send signals to the brain
about our head position and movement. We
take simple actions such as walking, bending,
turning or looking up for granted and become
aware of our balance only when there is a
change in the information that the brain is
used to receiving, e.g. when there is damage
to the inner ear.

Information that is received for balance is
integrated in specialised centres in the brain. The
higher brain centres then decide whether the information received warrants any further action
to maintain the balance. For example, if we make
a rapid head movement, the inner ear sends
signals to the brain, which in turn sends signals
to the eye muscles to fix the eye and keep our
vision steady. Similarly, we can sit on a moving
train and read a book or watch the scenery
outside without the words on the page moving
in time with the movement of the train, because
the balance organs stabilise our eye movements.

The eye and ears
are therefore
closely interlinked
and function as
a unit to give us
stability. We use
this response
when performing
balance tests.
When we rotate
the person in the
balance chair,
the movement is
detected by the
balance centres
in the inner ear.

These then send the message to the brain
which responds by producing corresponding
eye movements. When this is performed in
darkness, the eye is unable to fix on an object
and keeps moving in response to the inner ear
signals. This eye movement is called nystagmus
and can be recorded using electrodes or
captured by infra red camera. By examining the
eye movements, we can then draw conclusions
about the health and level of function of the
balance organs.

Earlier studies on Usher syndrome have shown
that balance may be a major factor in clinically
differentiating Usher subtypes. In the earlier
example of a child learning to walk, it is clear
that motor milestones get affected if the
balance system is not intact. This is exactly
what happens in Usher type 1 where there
is a significant delay in walking sometimes
well beyond 18 months. In Usher type 2 there
are no balance problems, while the balance
involvement in Usher type 3 is very variable.
Our fi ndings at the moment mirror previous
studies, but it is too early to draw significant
conclusions before we have sufficient numbers.


How data from ‘DNA sequencing’ can be used to
determine the genetic cause of Usher syndrome
DR ELENE HARALAMBOUS.

Dear NCUS participants,
A huge thanks to everyone who has enrolled in
the NCUS study. Some of you have requested
some further information on the genetic side of
the project. So in response, I’ve put together a brief description of part of what we do which I
hope you find helpful.

What is a gene?

We are made up of billions of cells. Every cell
contains a set of genes (30,000 genes in all). 

Genes are ‘instructions’ which tell our bodies
how to develop and work normally. They
determine everything from hair and eye colour,
sex, height, tendency to obesity, our personality
and millions of other characteristics that make
each of us unique.

How are genes inherited?

Each gene is found in duplicate, one is inherited
from the mother and one from the father.
How does a gene carry out its job?

Each gene codes for one protein. The protein
then carries out the instruction e.g. make the
eyes blue; make strong/weak fingernails etc.

Why is gene investigation important in
Usher syndrome?

Hearing and vision are delicate and complex
systems and many 100s of genes are needed
to make a normal ear and eye and to ensure
normal hearing and vision. Changes (also called
mutations) in the structure of some of these
genes may cause Usher syndrome.

What is DNA?

DNA is the building block of genes. DNA stands
for deoxyribonucleic acid. Four types of DNA
exist which differ slightly in their molecular
structure. These are called adenine (A), thymine
(T), cytosine (C) and guanine (G). The structure
of any gene is determined by the sequence of
the four DNA molecules.

The ‘sequence’ of DNA means the order in
which these 4 chemicals are arranged
e.g. ACGTAAAC
or ACGAAAAC
or ACGCAAAC

The order is vitally important for any gene and
DNA ‘sequencing’ involves working out the
order of these 4 chemicals.

Changes in the order of the 4 chemicals can
be quite common. Sometimes a change in
sequence may represent a harmless variation
(something that makes one person slightly
different from someone else), or, sometimes
the change in sequence may completely disrupt
the function of the gene.

What are the aims of DNA sequencing in
Usher syndrome?

1. To determine if any DNA sequence changes
exist in the genes being investigated.

2. To determine if the changes are involved in
causing Usher syndrome.

What type of data do we get from
DNA sequencing?

Figure 1 shows the type of data we get from
using a DNA sequencer, where each of the 4
different bases/chemicals is distinguished by
colour: red, black, green and blue.

The scientist then has to determine if there is
a change in the DNA sequence (with respect
to the normal sequence) and, if a change is
present, whether it might be responsible for
Usher syndrome.


Sense membership

Become a member of Sense and get more
involved in the work we do.

The Sense Membership scheme is thriving, with
new members joining every week and we would
like even more people to enjoy the benefits of
membership. As a member you will be kept
informed on services, news and events through
our magazine Talking Sense. Our members’
only section on the Sense website will soon be
going live and this will give you exclusive access
to a whole range of information and materials
about Sense and deafblindness, news, contact
with other members, the opportunity to produce
your own personal homepage and much more.

You will also be able to tell us what you think by taking part in regular consultations on issues
such as our campaigning work and how we
can improve our services to deafblind people.
Members also have the right to vote at annual
meetings. So why not join us and get more
involved.

Annual membership costs £12.50. For more
details you can return the enclosed form, access
our website: www.sense.org.uk/involved/join/or
contact me directly on
Tel: 020 756 13309 Text: 020 7272 9648
Email: libby.hawkins@sense.org.uk.

I look forward to welcoming you as a new
member very soon.

Libby Hawkins Sense Membership Co-ordinator


Recruitment update

Recruitment to the study continues to go well,
with 161 families now recruited since mid
November.

We hope to complete recruitment to the study
early on in the New Year to allow time for all
the clinical tests and genetic analysis to be
completed before the study ends in 2007.

At this point in the study, we would
particularly like to recruit more families with
Type 1 Usher (where the affected members
of the family are profoundly deaf). If you are
in contact with such a family, please ask them
to contact me or refer to the Sense website. I
am always happy to visit any interested families
at home, with an interpreter if required, to
discuss the study and answer questions.

Liz Cook
Family Coordinator
National Collaborative Usher Study
liz.cook@sense.org.uk


Editor’s note
We plan to send out the next issue of our NCUS Newsletter
If you have any news, letters or questions, please send them
March 1st 2006. mary.guest@sense.org.uk, Sense, 11-13
London N4 3SR, Tel: 020 7272 7774 Text: 020 7272 9648


The National Collaborative Usher Study
is funded by grants from the Big Lottery
Fund, the British Retinitis Pigmentosa
Society and Defeating Deafness.