Genetics and deafblindness

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Genetics and deafblindness

• Where have we been and
• where are we going
• Bill Kimberling and Claes Moller

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Genetics and deafblindness

• How we are working together
• as clinician-geneticist
• Bill Kimberling and Claes Moller

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Do I have a patient with a problem ?
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Does this child have a syndrome?
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Maybe there is a problem?
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Teenage!!I would like to be as all other
young people !!!Late diagnosisDenial
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Why is it important to know the cause?

• To get a correct diagnose
• To learn from other experiences
• To determine the prognosis of the disorder
• Progression of hearing loss.
• Usefulness of aids and/or implants.
• Progression of vision loss.
• Other associated symptoms.-dysfunctions
• Correct rehabilitations
• Treatments are expected to be specific to the
  cause
• One can avoid or justify other expensive tests.
• Patients and family often want and need a reason
  for the problem.

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Children with hearing loss

• 50 of children (7years) with HL have visual
  impairment
• (normal hearing- 20)
• Mandatory visual examinations

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Syndromal hearing losses, some problems

• 50 of children with HL have additional problems
• 30 of all hearing losses are syndromatic
• 80-100 different syndromes
• Many rare syndromes
• Many different organs
• Often starts as non-syndromic HL
• Difficult to diagnose

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Deafblindness(I am neither deaf nor blind !)

• Congenital deafblindness
• Congenital deafness with vision loss
• Congenital blindness with progressive hearing
  loss
• Aquired blindness with hearing loss
• Combined hearing-vision loss
• Different perspectives
• 1 1 3

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Causes of Deafness Where do I start ?What is
known in the literature?
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How do I diagnose possible deafblindness ?

• Pedigree
• Dysmorphology
• Neurology, Otolaryngology,
• Audiology
• Vision
• Balance Function
• Radiology
• Kidney
• Heart
• Tests for Viral Infections
• Genetics

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Most deafblind syndromes have retinal
degeneration
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Questions for a clincian

• Does this child have deafblindness?
• Does this child have Usher syndrome ?
• How is the prognosis?
• How will we perform habilitation-treatment?
• How large is the variation of symptoms?
• How many types?
• How common is Usher?
• How do I communicate my results?

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Charles Usher If you cant look
back and you cant look forward, You better
look up!!
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Usher syndrome what did we know 1985 ?

• Most people profoundly deaf with RP
• Are there different ways to inherit US ?
• Do 25 have additional psychiatric problems?
• Is there 1, 2, 3, 4 or 5 different types?
• Is there 1 gene causing it , or even 2 or 3 ?
• I am deafblind so I have Usher
• What is deafblindness?
• Oh you mean Hellen Keller

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Usher syndromeWhat is it?

• Defined as hearing loss with retinitis pigmentosa
  in the absence of other significant symptoms.
• It is inherited as an autosomal recessive.
• There are three clinical types.
• There are at least nine genes involved

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Clinical Types

• Type 1
• Profound hearing loss (deaf).
• Early onset RP.
• Balance problems.
• Type 2
• Moderate to sever hearing loss (hard of hearing)
• RP evident in their teens
• No balance problems
• Type 3
• Progressive hearing loss.
• Looks like type 2 as children.
• Looks like type 1 as older adults.

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Comparison of hearing loss between Usher type I,
II and III
II
III
III
I
__ Usher type II _?_ Usher type III
(USH3) _?_ Usher type I
__ Usher type II _?_ Usher type III
(USH3) _?_ Usher type I
Type III can wrongly be diagnosed as type I
Type III can wrongly be diagnosed as type II
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Hearing

• Correct audiometry
• Serial audiograms
• Assess communication skills
• Improve communication by oral and signing

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Most children with Usher type I start as
nonsyndromal deafness with CI (1). Early
diagnosis maybe 2 CI ( rich countries)
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CI and Usher

• Life long commitment
• Rapid technical advances
• Early implantation in both type I and III
• Different implants for different hearing losses ?
• Short implants hearing aid
• CI other treatments (Growth hormone, gene
  therapy)

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If I go blind, and if CI dont work
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I am sorry, you have RP, you will be blind !!!!!!

• What is RP ?????
• Doctor , when will I be blind ???
• How will I get around ?
• Can I keep my work?
• Will I be able to see anything ?
• I am sorry, It varies, how would I know, there is
  nothing that can be done!!!
• Actually, we know quite a lot, by now, and we can
  help.

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Teenage
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20-40 years
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40 50 years
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Some people above50 years
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Most people will have central vision
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What do we know about vision in the long run
Visual acuity
Usher typ II
Usher typ I -
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What about Cataracts?
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Usher type II Cataracts
Usher type I
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Why is my child clumsy? why do I fall so often?

• How would I know
• Maybe the child is retarded as well
• Maybe it is the bad vision
• Maybe it will improve by age
• Maybe, maybe
• Actually, we know quite a lot, by now

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Input
output
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Balance - Type I
?
?
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Balance - type II
?
Sammanställande system
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Balance - type III
?
(?)
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Hello, is there anybody out there or am I the
only one ???

• Prevalence studies- how many ?
• Few
• Selected areas
• Geographical variation?
• How many of you do know the number of people with
  US in your country
• Is it a guesstimation ??

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without diagnose
without diagnose
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How Frequent Is Usher Syndrome?

• Earlier studies (mostly type I) 4 per 100,000.
• New studies type I 10 of congenitally deaf
  children
• Some data indicate that Usher type II is almost
  two times as frequent as type I.
• The overall frequency of Usher is guesstimated at
  gt10 per 100,000.

gt 250.000 worldwide
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So this is a genetic disease ??

• One patient
• Several family members
• Numerous relatives
• Uneducated professionals
• Even the Doctors !!

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Chromosomes
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Chromosomes
p
q
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94
34
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18
6
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Genetic subtypes of the __________________________
_________________________ Genetic subtype
Locus Gene
Protein __________________________________________
_________ USH 1B 11q13.5
MYO7A myosin VIIA USH 1C
11p15 USH1C harmonin USH 1D
10q21-22 CDH23
cadherin USH 1E 21q21
USH 1F 10q21-22 PCDH15
protocadherin 15 USH 1G
17q24-25 USH1G SANS USH 2A
1q32-42 USH2A
usherin USH 2B 3p23-24 USH 2C
5q14.3-q21.3 USH2C VLGR1
USH 3 3q21-q25 USH3
clarin 1
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Usherin mutations and protein domain structure
C319Y
N346H
C419F
Q566X
H308FS
Q684Q
MR1280IX
W409X
C847X
R1504FS
P560FS
R626X
E767FS
T967FS
R1295X
C1447FS
L260X
520
1050
1090
1500
300
1
COOH
LN
LE
LE
LE
LE
LE
LE
LE
LE
LE
LE
F3
F3
F3
NH2
F3
laminin-like EGF (LE)
FNIII
domain VI
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So, Professor Kimberling,Has the genetic
research in US helpt us?
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Usher syndrome

• Current Status and Future Possibilities

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Prerequisites for effective clinical trials

• Laboratory studies on potential therapies.
• Good animal models.
• Epidemiologic studies.
• Rapid, accurate and inexpensive methods of Usher
  diagnosis.
• An effective strategy for finding suitable and
  willing test subjects.
• Methods for measuring the expected clinical
  effects.

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Strategies for treatment of Usher syndrome

• Safety and geographic orientation
• Life style changes
• Smoking cessation
• Sunglasses
• Diet
• Vitamin supplementation and antioxidants
• Prosthetics
• Cochlear Implants
• Retinal Implants
• CNTF and other growth factors
• Gene therapy

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Life style and diet research

• Epidemiologic studies can identify factors in
  every day life that impact on the progression of
  symptoms.
• An example is a large study for macular
  dystrophy.
• But large numbers of RP patients need to be
  followed over a considerable period of time to
  get the same valuable information for Usher.
• Interactive and International databases are
  needed and more communication between research
  groups.

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Some examples of potentially important factors
that can be studied epidemiologically

• Light exposure
• Smoking
• Certain foods
• Pregnancy
• Medications
• Exercise
• Etc.

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Does vitamin supplementation slow the progression
of RP?

• Harvard medical school.
• First study reported Vitamin A slowed the
  progression of RP.
• Later study showed a greater effect when in
  combination with diet (fish important).
• BUT, it remains controversial.

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The vitamin A story.Why is it controversial?

• ERG was used to measure the effect.
• Measurement was barely recordable.
• Differences between groups were small.
• Groups could not be partitioned according to
  diagnosis (all RP patients lumped together).
• Vitamin A dosage on the edge of toxicity.
• No corroboration by an independent research
  group.
• Convincing animal model experiments are lacking.

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Do antioxidants slow progression of RP?

• The RP retina has high concentrations of oxygen.
• Animal models are suggestive.
• Shown helpful in macular degeneration.
• No studies for human RP or Usher syndrome, yet.
• Vitamin E, Vitamin C, alpha-lipoic acid,

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Prosthetic devices

• Cochlear implant
• Retinal implant

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Therapies for Usher syndrome CNTF

• CNTF Ciliary neurotropic factor
• Neuroprotective
• Novel delivery
• Encapsulated cells genetically programmed to make
  CNTF
• Inserted within the vitreous
• Phase I clinical trial completed.
• Sieving et al., (2006) PNAS Ciliary neurotrophic
  factor (CNTF) for human retinal degeneration
  phase I trial of CNTF delivered by encapsulated
  cell intraocular implants.
• Safety demonstrated
• Some indication that vision improved.
• Phase II clinical trials underway.

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How does CNTF delivery work?
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Gene therapyPrinciples

• Genes are information.
• When a gene is knocked out, the information is
  cell needs is missing.
• To correct the problem, the functional gene must
  be delivered to the cells that need to use that
  information

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Gene therapyConsiderations

• Delivery
• Most commonly uses tame viruses
• Gene size is important
• Regulation of expression
• Cell needs to make the right amount of protein
  under probably changing conditions
• Not all cells need to express the gene
• Immune responses
• Safety

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Gene therapy and the future

• Lancelot, the Briard Dog
• Lebers congenital amaurosis, a severe juvenile
  RP.
• Gene (RPE65) inserted via a viral vector in one
  eye.
• Acland, et al., (2005) Mol. Ther. Long-term
  restoration of rod and cone vision by single dose
  rAAV-mediated gene transfer to the retina in a
  canine model of childhood blindness.
• Gene therapy programs are now underway for Usher
  1b, 2a, and 3a in animal models

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Gene therapy is probably going to be the gold
standard of future treatment
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Tissue engineering

• A new field.
• Aim to grow a replacement tissue or organ.
• Uses stem cells.
• Requires sophisticated knowledge about how tissue
  growth is regulated.
• Offers an alternative/complement to prosthetics
  (implants)

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Take home points about Usher treatment

• There is already a lot that can be done.
• There are many different approaches being
  considered.
• The future is bright as evidenced by the
  increasing number of ongoing and planned clinical
  trials.
• We need to get ready for future gene specific
  trials.

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Usher Questions

• Where are we?
• Where are we going?
• Why do we want to get there?
• How are we going to get there?

Screening D/HOH school children
Epidemiology
Population Genetics
Gene Discovery
Molecular Mechanisms
Gene Therapy
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Statement 1The key to early
treatment/habilitation is early diagnosis !
True or false ??Statement 2Shall we screen
for Usher syndrome ?My child is deaf, and now
you say it will go blind!!! Statement 3 Is it
unethical to screen if you dont have any
treatment ?
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Neonatal hearing screening
Early identification and intervention is
important in deafness The diagnose of US is
today made when we discover the RP
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Mean diagnosis age depending on when you were
born

• Usher type I Usher type II
• 1910s ? 42 y
• 1920s 27y 40 y
• 1930s 28y 35y
• 1940s 24y 29y
• 1950s 18y 23y
• 1960s 12y 23y
• 1970s 9y 19y
• 1980s 9y 14y
• 1990s 4y 14y
• 2000s 2y 10y

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Late diagnosis give big confusions

• Why is my child deaf ?
• Why is my child clumsy ?
• Why has my child problems at night ?
• Why dont I like gymnastics and sports ?
• Why cant I have a drivers licence?
• Why cant I hear , I have good hearing ?
• Why cant I go on working in the factory?
• I dont dare to raise a family
• What is Usher?
• Deafblind-me ????

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Despair

• I went to the doctor and he told me that I would
  go
• deaf and blind. He does not know why, not when,
  but
• it might be in the near future. Then the doctor
  abruptly
• left the room.
• No, not my hearing, not my vision!!!!
• It is not fair! How could God do this to me?
• Why wasnt I told until I was grown up?
• Somebody help me !!!!

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Are there any advantages in genetic screening
for Usher syndrome?
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Improving the diagnostics for Usher syndrome

• If clinical trials are to be done on Usher types
  we must be able to
• Diagnose the genetic type rapidly and accurately.
• Screen at a reasonable cost.
• Be able to diagnose early in the development of
  the retinal dystrophy.
• Acquire the large number of potential subjects
  needed for such studies.

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High risk groups for retinitis pigmentosa

• Children in special education classes for the
  deaf and hard of hearing (D/HOH) student.
• 10-15 of all D/HOH children are reported to have
  Usher syndrome
• Children receiving cochlear implants
• Frequency of Usher type I is gt8
• Children who failed newborn hearing screening
  testing.

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Overall Usher screening strategy

• Purpose to detect children prior to the onset of
  overt symptoms.
• Subject population.
• Deaf and hard of hearing children
• Newborn hearing screening infants
• Kits taken home by children
• Questionnaire
• Oragene Saliva collection kit
• Informed consent forms
• FAQ sheet
• Parents supervise collection of sample and fill
  out forms
• Saliva and paperwork mailed back to the Usher
  center for testing

Funds for development and pilot studies provided
through the generous support of the Hear See Hope
Foundation in Seattle and the Foundation Fighting
Blindness
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Children are guilty of unpardonable rudeness when
they spit in the face of a companion neither are
they excusable who spit from windows or on walls
or furniture. St. John Baptist de La Salle, The
Rules of Christian Manners and Civility (c. 1695)
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Screening for Usher syndrome

• Initial test using the USHplex system developed
  at U of Iowa and Boys Town.
• Tiered testing to keep costs low (25 to 75 per
  person)
• Most common mutations screened first
• All positive results are verified by sequencing
• Follow up by ophthalmologic, balance, and hearing
  exams.
• Confirm by retesting DNA of child and, where
  possible, family
• Tell the family the results and offer genetic
  counseling.

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Usher syndrome found in two pediatric populations
through screening

• Study 1
• High School - Oregon
• 78 genotyped for Usher genes
• Nine positive
• 2 Usher 1B
• 3 Usher 1D
• 3 Usher 2A
• 11.5

• Study 2
• Cochlear Implant
• 55 children lt5 years
• Seven positive
• 2 Usher 1B
• 1 Usher 1C
• 3 Usher 1D
• 1 Usher 2A
• 8.2

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What is the true frequency of Usher syndrome?

• Since the sensitivity is only 50, the true
  frequency can be estimated as
• 8.2/0.50 16.4 of implanted children
• 10.5 / 0.50 21.0 of the deaf/HOH school
  population
• Implies that the population frequency is
• 1 of 5000 births
• More than 4 times higher than older surveys.
• Can the results be biased?
• Yes. Parents with suspicions may have been more
  likely to include their children in the study
• The solution
• Complete ascertainment
• Corroboration with more studies

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Conclusions about screening for Usher in the USA
population

• 15 to 20 of all D/HOH children have one or
  another type of Usher syndrome.
• USH2A appears to be a major Usher gene and is
  found primarily in the HOH population so
  screening needs to go beyond the schools for the
  deaf.
• DNA screening is both cost effective and detects
  a significant fraction of presymptomatic Usher
  cases at a reasonable cost.

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Genetic Databases

• An interactive database to be used by
• Researcher
• Primary clinicians
• ENT
• Audiology
• Ophthalmology
• Genetics
• Genotyping laboratories
• Patients and their families
• Internet based
• Routine questionnaires
• Entry of clinical information
• Visual and audiologic testing (?)
• Strict privacy rules and tiered access
• Periodic data mining
• Open to all qualified researchers

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Final thoughts

• Our understanding of Usher syndrome brings us to
  a new and exciting age where serious thought is
  being given to treatments the slow, prevent, and
  even cure that group of disorders.
• This is evidenced by the fact that at least two
  clinical trials relevant to Usher syndrome are
  currently underway.
• The need now is to develop an infrastructure that
  will facilitate future trails.
• Significant progress can be expected within the
  next 20 years

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Contributors

• BTNRH
• William Kimberling
• Dana Orten
• Carol Carney
• Maren Jensen
• Aki Oshima
• Connie Miles
• Oregon
• Richard Weleber
• Karmen Trzupek
• Jay Gense

• U of Iowa
• Richard Smith
• Carla Nishimura
• Edwin Stone
• Louisa Affliagato
• Mary Randolph
• All of the interested and involved teachers and
  counselors in the Oregon school system

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Contributors to the Usher Syndrome Project

• Boys Town Nat Res Hosp.Omaha,- Bill Kimberling
• Örebro University Hospital, Sweden- Claes Moller
• University Hospital, Nijmegan, Holland- Cor
  Cremers, Ronald Pennings
• University of Heidelberg, Heidelberg Germany-
  Klaus Rohrschneider
• Fundacion Jimenez Diaz, Madrid, Spain- Carmen
  Ayuso
• University of Ferrara, Ferrara, Italy- Alasandro
  Martini
• Universidad Javeriana, Bogota, Colombia- Marta
  Tamayo
• University of Cape Town Medical Center, Cape
  Town, S. Africa- Jackie Greenburg
• Univ Copenhagen Denmark - Lisbeth Tranenbjerg
• University of Iowa Medical Center, Iowa City,
  Iowa- Richard Smith
• Univ. Mich School of Medicine, Ann Arbor MI -
  J.R Heckenlively
• Scheie Eye Institute, Philadephia, PA- Samuel
  Jacobson
• University of Pittsburgh- Michael Gorin
• University of Minnestota- Sandra Davenport

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Can research be done better in Usher
syndrome?

• Yes and always ask the questions
• Is new knowledge always good?
• Will research do any good?
• Today , tomorrow ?
• Who decides which research should be done?
• How do researchers communicate the research?
• How do professionals keep themselves updated?
• How do professionals use the new knowledge?
• Will research create more resources to USH?

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Thanks for lettin us bend yur ears, podner
Wild Bill
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How many things the men of future ages shall
know, which are unknown to us. although the
nature of things does not give up its secret at
once. We think ourselves admitted to the
sanctum, but we find that we are only in the
outermost chamber. Carl von Linné 1707-1778