Vilka forskar på dövblindhet 2011? Medicin Sociologi Teknik Psykologi Pedagogik

Klinisk genetisk forskning-dövblindhet Min tanke för denna dag är: Inte bara ”korvstoppning” ”Pölse” Mycket diskussion Se möjligheter till sampel Se patienter/brukare som forskningspartners Genom att studera det ovanliga finner vi det vanliga

Klinisk genetisk forskning-dövblindhet Usher syndrom Alström syndrom Gen-etik Hörsel-syn Diagnostik Diskussion Genetik Progress av symptom Forskning och Livsstil Habilitering klinik Diet Teamforskning-Expertteam Genterapi Kognition Psykosocial CI

Usher syndrome Definition Hörselnedsättning/dövhet, näthinnesjukdom och ibland balansproblem autosomal recessiv. Tre kliniska typer. Minst elva olika gener Det genetiskt mest kartlagda syndromet Dr. Charles H. Usher

Clinical Types Type 1: Type 2: Type 3: Profound hearing loss (deaf). Early onset RP. Balance problems. Type 2: Moderate to severe 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.

without diagnose without diagnose

Mean diagnosis age depending on when you were born ( Mean diagnosis age depending on when you were born (..Prevalence of Usher in Sweden…Sadeghi, Möller et al 2004) Usher type I Usher type II 1910´s 42 y 1920´s 27y 1930´s 28y 35y 1940´s 24y 29y 1950´s 18y 23y 1960´s 12y 23y 1970´s 9y 19y 1980´s 9y 14y 1990´s 4y 14 y 2000´s 1-4 y 12 y 2010´s 1-3 y 10 y

How Frequent Is Usher Syndrome? New studies type I 10% of deaf children Some data indicate that Usher type II is almost two times as frequent as type I Geographical variations The overall frequency of Usher is guesstimated at >10 per 100,000. 250.000 worldwide

Diskussion 250.000 worldwide Hur kan man beforska prevalens i Norge Skall man identifiera Usher så tidigt som möjligt? Om ja, hur? 250.000 worldwide

Genotyp och fenotyp Våra gener konstruerar vår kropp och driver den….

Comparison of hearing loss between Usher type I, II and III _●_ Usher type III (USH3) _▲_ Usher type I _■_ Usher type II _●_ Usher type III (USH3) _▲_ Usher type I

Ushers Syndrom

Visual acuity life-long perspectives Usher typ II Usher typ I -

Teenage

20-40 years

40 – 50 years

(survival) analysis- visual field –The likelyhood of having <5 deg => 25% ≈ 38 årsålder risk ≈ 55 årsålder => 75% risk Usher typ I Usher typ II   (p<0.05)

Input output

Balance - Type I  

Ny forskning hörsel-syn Databas Sverige 370 personer USH I,II,III Analys av långtidsresultat hörsel, syn, genetik USA 60 pat visar möjligen skillnad beroende på genetisk typ Viktiga resultat vid behandling Kan bara behandla celler som fungerar

1991 Usher syndrome have at least one gene causing it One of the first hearing impairments to be cloned Consortium USA-Sweden-Italy-France -UK Needle in the haystack One DNA sample 2-3 months , today 5 minutes Apples and pears in different baskets type I or II or even III ?

_____________________________________________________ Genetic subtype Locus Gene Protein ________________________________________________ USH 1B 11q13.5 MYO7A myosin VIIA USH 1C 11p15 USH 1C harmonin USH 1D 10q21-22 CDH23 cadherin USH 1E 21q21 USH 1F 10q21-22 PCDH15 protocadherin 15 USH 2A 1q32-42 USH 2A usherin USH 2B 3p23-24 USH 2C 5q14.3-q21 g-protein USH 3 3q21-q25 USH3 clarin

Här finns generna för Usher syndrom Frolenkov et al.

Drag image to reposition. Double click to magnify further.          

Usher syndrome interactome as proposed by Uwe Wolfrum The function of the interactome is unclear. Structural in the cochlea? Tip and ankle links Cargo transport in the retina?

Usher interactome Complex machinery. Like a construction crane? Cargo transport?

Genetic diagnose of Usher 2011 Screening for Usher using DNA-chip Screening at a reasonable cost Screening not perfect Confirmation at a genetic lab Diagnose rapid and accurate Essential in the future if treatment

Can Usher syndrome be treated? 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 Aminoglycoside look alikes. Stem Cell Therapy Gene therapy

Prosthetic devices Cochlear implant Retinal implant A good possibility for restoring vision is the retinal implant. Several centers across the world are working on developing a device that is similar to the cochlear implant. It records images outside the eye and then transmits that information into a small chip sitting on the retina. That chip then stimulates the nerves on top of the retina which is interpreted by the brain as vision. Retinal implant research is at an early stage, although some clinical trials are currently underway but the resolution of vision is still poor. For example, facial recognition is not yet possible. One way of understanding the development of the retinal implant is to compare it with the cochlear implant. Over the years, the cochlear implant gradually improved as more channels were added. In the same way we can expect the retinal implant to improve with time as more and more pixels are added to the system, thus providing greater visual resolution. As a strategy of restoring vision, the retinal implant offers a great deal of hope.

dövblinda och hörselskadade barn med CI och/eller hörapparat Forskning Kommunikativ utveckling Utveckling av läs- och skrivförmåga Utveckling hos specifika populationer av barn Döva dövblinda och hörselskadade barn med CI och/eller hörapparat Språklig utveckling Hörsel/syn Kognitiv utveckling Intervention Neurofysiologisk utveckling

CI and Usher type 1 Most people with USH I will have CI 10% of all deaf children USH 1( Iowa, Sweden) Most USH1 undetected at time of implantation Habilitation not like non-syndromal deafness Second language sign language later tactile? Results if early implantation excellent Bilateral implantation Some persons USH 1 implanted at 10-15 y Sound recognition

CI and Usher Lif long commitment Rapid technical advances Early implantation in type I and III Different implants for different HL Short implants in type III Electro-acoustic hearing in type III

33 barn med icke-syndromal dövhet och CI. 8-15 årBarn med Usher Phonological skills and working memory in children with CI and Usher type I Henricson, Lyxell, Möller, Lidestam 33 barn med icke-syndromal dövhet och CI. 8-15 årBarn med Usher 6 barn med USH1 med CI, 8-15 år 43 barn med hörselnedsättning och hörapparat 136 normalhörande Preliminary results likvärdiga resultat avseende visuellt arbetsminne (WM). Normalhörande bättre på auditivt arbetsminne och lexikal ( Wass m fl) Barn med Usher bättre I vissa av dessa tester än andra barn med dövhet och CI , lägger sig nästan som barn med hörapparat

Forskning genetik-klinik-kognition-hörförståelse Kan orsaken till dövhet ( flimmerhårsskada) ha betydelse I framtiden olika CI, nya op-tekniker??

CI and Usher type 3 In childhood moderate -HL Oral communication Rapid progression- aquired deafness Visual progression variable Many have not learned sign language Hearing memory intact Sounds strange when implanted Finland-Sweden- USA Excellent results

Elektroakustisk stimulering (EAS) Frequency [kHz] 0,125 0,25 0,5 1 2 4 8 -10 audiogram Bas toner ej skadade Höga toner skadade 10 20 30 Hearing loss [dB] 40 50 60 70 80 90 100 110 Cochlea (utsträckt) Hörapparat + Cochlea Implant ( von Ilberg et al 1999)

Diskussion Vem vill vara den siste mohikanen? Vem skall Döva utan CI kommunicera med? Kommer teckenspråk att användas av Döva med tilläggshandikapp? Kommer någon med blindhet att tacka nej till visuellt implantat? Vilken forskning vill du se?

If I go blind and if CI don´t work ?

Finns det behandlingar vid plötslig hörselnedsättning?

STRESSFAKTOR – Exv. buller Mekanisk skada Metabol skada Oxidativ stress Blodflöde  Neurotrofiner Ca-bindande proteiner  ROM  [Ca2+] i Antioxidanter Skador på lipider, proteiner och DNA Allvarlig men reparabel skada Celldöd Apoptos/nekros

Förbehandling med antioxidanter skyddar mot bullerskada Vitamin C & E 4 kHz 20 kHz Tid Tröskelförändring (dB) Förbehandling med antioxidanter skyddar mot bullerskada Vitamin C & E Ulfendahl et al 2006 Behandlade djur Behandling: 24 tim före trauma + 4 veckor efter (dvs. kombination av prevention och intervention)

Ett dygn efter skadan kan det vara för sent! 4 kHz 20 kHz Tid Tröskelförändring (dB) Behandling: 24 tim efter trauma och under 4 veckor Behandlade djur Ett dygn efter skadan kan det vara för sent!

The Hearing Pill (Acetylcystein)

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. + This is an important question because of the studies that have been reported by researchers at Harvard. The use of vitamin A makes some biologic sense since there are high levels of vitamin A in the retina and it appears to be diminished in retinitis pigmentosa. A later study by the same group indicated that two helpings of fish (like salmon) will increase the effect of the vitamin A. But, the problem is that the results of the study are not generally accepted by those in the medical profession and many physicians will refuse to put a person on megadoses of vitamin A.

Prevention may be as simple as wearing sunglasses Animal studies suggest that light (uv and blue) accelerates the loss of rods and is especially damaging to Usher retinas Unproven in humans Depending upon the frequencies, filtering glasses may be appropriate even indoors.

Hur fungerar läkemedelstillförsel? The key to the CNTF treatment is the method of delivery. First cells are genetically modified so that the make and secrete large quantities of the CNTF molecule. Since human cells normally make CNTF, the modification needed is to up the amount being made. These cells are then encapsulated into a tube that looks somewhat like a sausage. The tube is surgically placed within eye as you see here. The cells receive nutrients from the fluid in the eye and release there CNTF which diffuses over to the retina where it, we hope, works its magic and helps the cells to survive. The delivery system is what is neat. Even if the CNTF trial is a failure, other growth factors or even drugs that must be delivered directly to the eye are very real possible targets for treatment. As I mentioned, the clinical trial is now in phase II and patients with retinitis pigmentosa and macular degeneration are being followed.

Reparation av muterad gen Vissa läkemedel kan “reparera” en skadad gen USH 1C har en ”nonsensmutation som kan lagas PTC124 Cellodling Retina Möss

Genterapi Målcell Protein X bildat från den infekterade cellen DNA för Virusvektor med genen för Protein X Protein X bildat från den infekterade cellen Cellkärna Målcell

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

Gene therapy Problems Delivery Regulation of expression 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

Gene therapy and the future Lancelot, the Briard Dog Leber’s congenital amaurosis, a severe juvenile RP. Gene (RPE65) inserted via a viral vector in one eye. Gene therapy humans with LCA-RP Cardiff-London 2009 Gene therapy programs are now underway for Usher 1b, 2a, and 3a (animal research)

Are there problems with late diagnosis? Preliminary results 100 persons with Usher type 2 Compared to 5000 from the Swedish population Questions concerning general health, anxiety depression

Headache

unhealthy

Diskussion Vilka kommer att stå först i tur om behandling kommer - barn-vuxna? Skall dessa nya forskningsfynd förmedlas till brukare eller är det att väcka falska förhoppningar eller depression? Om ja, hur ?

Anna 6 months Myocardiopathy 7 kg Always crying in the morning Infections Pediatrician - within normal limits

Anna 2 years Black spots in the neck Delayed walking age Delayed oral communication Difficult to find toys Nystagmus Visually impaired Mentally retarded ? No diagnosis

Anna 4 years Often sick , otitis media, urinary infections etc. Numerous visits to Dr. (300/3years) Low vision clinic Mentally retarded? Delayed language Hearing loss ??

Anna 5 years Ear, normal morphology Moderate sensorineural hearing loss ( inner ear) Habilitation , hearing aids etc. Deafblind Why, what ? No diagnose Crisis in the family

Anna 6 år

Anna 12 years Blind and deafblind Started Braille-difficult Progressive hearing loss Oral communikation - difficult No sign language Diabetes, kidney, liver…….. Numerous visits to the Drs. but… No diagnose

Anna 12 years Anna 21years

Alström syndrome 0 år 10 år 20 år 30 år 40 år Symtom Ögon Öron Balans Hjärta Blodfetter Diabetes Njurar Lever Tänder Övervikt Bukspottkörtel

Genetics ALMS1 gene 2p13 Large gene 4 frameshift and 2 nonsense mutations Encodes an unknown protein Two mouse models, original, ”fat aussie”

Prevalence 2006 350 kända fall 2010 650 kända fall Perinatal dödlighet, för tidig död Bättre metabol kontroll, transplantation Längre livslängd Om man letar man finner man England 50, Holland 30, USA 300, Sverige 10

En normal mus

Alström Sweden 2010 8 affected + 3 dead, 5-42 years Problems with yaws Ambitious, unrealistic “ stubborn Eating problems Longitudinal study Hugo 5 years CI female 42 years Cognitive research Theory of mind

Diskussion Hur gör vi för att upptäcka och diagnosticera mycket ovanliga diagnoser? Kan forskning vara lösningen? Vart sänder ni dessa fall i Norge? Vem tar ansvar? Vem betalar? Hur går det till?

Gen-Etik och konsekvenser för rehabilitering En patient Flera familjemedlemmar Många släktingar ” pårörende” Outbildade professionella

Diskussion Vem tar initativ till genetisk diagnostik? Vem meddelar resultat? Vilkas skall ta del av resultat? Bonusdiskussion Är det etiskt att ställa genetisk diagnos om man inte kan behandla?

Forskning och klinik Genotyp-fenotyp Arv-miljö Cohort-långtidsstudier Jämförande studier Medel till forskning ICF

Nationellt expertteam för diagnosticering av personer med dövblindhet Specialpedagog vuxna Psykolog vuxna Specialpedagog barn Psykolog barn Synpedagog Dövpsykiatriker Genetiker Öron-Audiologläkare Ögonläkare Koordinator

Det nationella expertteamet…. Ge en medicinsk och funktionell diagnos Alla åldrar många barn De svåraste fallen Syndrom Ofta syn-hörsel + andra organ Genetik allt viktigare Anmälan till teamet alltid i sampel med familjen Insamlande av alla data Undersökningar, perspektiv på långsiktighet och livsperspektiv Medicinsk och funktionell diagnos och därmed prognos Information till familj, landsting, kommun, mm Databas, forskning utveckling Statligt finansierad

Diskussion Vem skall forska? Vem skall betala? Skall expertteam-kompetancecenter forska? Vilken forskning saknar du? Hur många forskar på dövblindhet i Norge?

Despair Somebody help me !!!! 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 wasn´t I told until I was grown up? Somebody help me !!!!

although the nature of things does not give up its secret at once. 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