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The Spectrum of Albinism Ophthalmological, Ophthalmological, nystagmographic nystagmographic and and fMRI-Evaluation fMRI-Evaluation NOAH Department Departmentof ofOphthalmology Ophthalmology Barbara Barbara Käsmann Käsmann* * Paediatric Paediatric Ophthalmology Ophthalmology and and Paediatric Paediatric Low Low Vision Vision Head: Head: PD PD Dr. Dr. Barbara Barbara Käsmann Käsmann MD MD Department Department of of Ophthalmology Ophthalmology Chairman: Prof. Dr. Chairman: Prof. Dr. K.W. K.W. Ruprecht Ruprecht University University of of Saarland Saarland DD 66421 66421 Homburg Homburg (Saar) (Saar) *Ophthalmological *Ophthalmological Consultant Consultant for for NOAH NOAH Germany Germany National National Organisation Organisation for for Albinism Albinism and and Hypopigmentation Hypopigmentation Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan University Campus and Medical School, University of Saarland Germany Saarland: Saarland: Geographical Geographical center center of of Europe Europe Adjacent Adjacent to: to: -- France France -- Luxembourg Luxembourg -- Belgium Belgium Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and genetics genetics •• Oculocutaneous Oculocutaneous albinism albinism •• Ocular Ocular albinism albinism •• Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and genetics genetics ••Oculocutaneous Oculocutaneous albinism albinism ••Ocular Ocular albinism albinism ••Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and genetics genetics •• Oculocutaneous Oculocutaneous albinism albinism •• Ocular Ocular albinism albinism •• Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and genetics genetics ••Oculocutaneous Oculocutaneous albinism albinism ••Ocular Ocular albinism albinism ••Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Moleculargenetic Analysis As far as known up to now (May 2003) There are 11 genes whose alterations can be associated with albinism Type Type of of Albinism Albinism Chromosome Chromosome // Gene Gene Oculocutaneous Oculocutaneous Albinism Albinism •• OCA1 11 OCA1 11 // TYR TYR •• OCA2 15 OCA2 15 // PP •• OCA3 99 // TRP1 OCA3 (described (described only only in in Africans) Africans) TRP1 •• OCA4 55 // MATP OCA4 (Lit.: (Lit.: one one pt., pt., own own study: study: 44 patients) patients) MATP •• Syndromes Syndromes associated associated with with OCA OCA –– –– –– HPS HPS (1 (1 –– 4) 4) CHS CHS OCA OCA not not in in all all cases: cases: –– –– 3,5,10,22 3,5,10,22 11 // CHS CHS 15 15 // PP Prader Prader Willi Willi Syndrom Syndrom Angelman Angelman Syndrom Syndrom Okular Okular Albinism Albinism •• OA1 OA1 (Nettleship-Falls) (Nettleship-Falls) Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan XX (OA1) (OA1) Types of Albinism N N= = 286 286 Persons Persons with with Albinism Albinism Type of Albinism 9,93% n=28 3,19% n=9 25,53% n=72 OCA1 OCA2 OA Syndrome unclear 17,38% n=49 Unclear, Unclear, nn = = 28 28 43,97% n=124 ** Phaenotypically Phaenotypically not not conclusive conclusive ** Moleculargenetic Moleculargenetic analysis analysis Syndromes: not not yet yet finished finished -PWS -HPS Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Age Age Distribution Distribution in in our our Albinism Albinism Patients Patients Department Department of of Paediatric Paediatric Ophthalmology! Ophthalmology! Age Distribution N = 286 Patients with Albinism 70 Number of Patients 60 50 Number of Children due to Author being Medical Advisor to NOAH Germany NOAH NOAH 40 National National Organisation Organisation of of Albinism Albinism and and Hypopigmentation Hypopigmentation 30 20 10 0 5,00 15,00 25,00 35,00 45,00 55,00 65,00 75,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 Age (years) Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Significant Significant Differences Differences in in Phaenotype Phaenotype and and Ocular Ocular Findings Findings •• All All types types of of albinism albinism show show aa high high variability variability of: of: –– –– –– –– Iris Iris transillumination transillumination Hypopigmentation Hypopigmentation of of the the retinal retinal pigment pigment epithelium epithelium Foveal Foveal hypoplasia hypoplasia // dysplasia dysplasia Optic Optic nerve nerve head head morphology morphology •• Variability Variability depends depends on: on: –– –– Genotype Genotype Ethnical Ethnical background background Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Joel Joel Benton: Benton: Visit Visit and and Aquisitions Aquisitions at at the the Zoo Zoo (Life (Life of of Hon. Hon. Phineas Phineas T. T. Barnum, Barnum, Edgewood Edgewood Publishing Publishing Company, Company, Philadelphia Philadelphia 1891) 1891) "I "I went went through through scores scores of of booths, booths, where where curiosities curiosities and and monstrosities monstrosities of of all all kinds kinds were were exhibited, exhibited, and and was was able able to to make make some some purchases purchases and and engagements engagements for for the the American American Museum. Museum. Among Among these these was was the the Albino Albino family, family, consisting consisting of of aa man, man, his his wife, wife, and and son, son, who who were were by by far far the the most most interesting interesting and and attractive attractive specimens specimens of of their their class class II had had ever ever seen." seen." Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Lucassie Lucassie Family Family Milestones of Research •• Garrod Garrod AE: AE: Inborn Inborn errors errors of of metabolism, metabolism, Lecture Lecture II II Lancet Lancet 2, 2, 73-79, 73-79, 1908 1908 –– Albinism Albinism was was first first described described as as aa disorder disorder of of metabolism metabolism •• Trevor-Roper Trevor-Roper PD: PD: Marriage Marriage of of two two complete complete albinos albinos with with normally normally pigmented pigmented children children Br Br JJ Ophthalmol Ophthalmol 36, 36, 107-109, 107-109, 1952 1952 –– First First clues clues for for genetic genetic heterogeneity: heterogeneity: normally normally pigmented pigmented children children from from aa pair pair of of parents parents who who both both had had albinism albinism Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Main Main Types Types of of Albinism, Albinism, Chromosome Chromosome and and Gene Gene Subtypes Subtypes (11 (11 Genes, Genes, 17 17 Types) Types) OCA OCA 3: 3: OCA OCA33(up (upto tonow nowonly onlydescribed describedininAfrican Africanpersons) persons) (Red (rufous) Albinism) (Red (rufous) Albinism) OCA OCA 4: 4:Mutations Mutationsim imMATP-Gen, MATP-Gen,Chromosome Chromosome55 OCA OCA44(Lit.: (Lit.:Murray Murray2002: 2002:one oneTurkish Turkishperson personliving livinginin Germany; Germany;own ownstudy: study:44persons persons(3 (3Germans, Germans,11Belgium) Belgium) Mutations MutationsininTyrosinase-Gene, Tyrosinase-Gene,Chromosome Chromosome11 11 OCA2: OCA2: Mutations Mutationsininthe theTRP1-Gene, TRP1-Gene,Chromosome Chromosome99 Syndromes Syndromeswith with oculocutaneous oculocutaneousAlbinism Albinism HPS1 HPS1::Chromosome Chromosome10 10 HPS2 : Chromosome HPS2 : Chromosome 55 HPS3 HPS3::Chromosome Chromosome 33 HPS4 HPS4::Chromosome Chromosome22 22 (HPS1-Gene) (HPS1-Gene) (Adaptin, (Adaptin,AP3B1-Gene) AP3B1-Gene) (HPS3-Gene) (HPS3-Gene) (HPS4-Gene) (HPS4-Gene) CHS: CHS:Chromosome Chromosome11(CHS-Gene) (CHS-Gene) Ocular OcularAlbinism Albinism X-Chromosome X-Chromosome(OA1-Gene) (OA1-Gene) Hermansky-Pudlack-Syndrome Hermansky-Pudlack-Syndrome(HPS) (HPS) Typen HPS 1,2,3,4 Typen HPS 1,2,3,4 Chediak-Higashi-Syndrome Chediak-Higashi-Syndrome(CHS) (CHS) OA1: OA1:Type TypeNettleship-Falls Nettleship-Falls Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan May 2003 2003 of research: research: May quo of Status quo Status Mutations Mutationsininthe theP-Gene, P-Gene,Chromosome Chromosome15 15 OCA1A OCA1A OCA1B OCA1B OCA1B OCA1BTS TS(Temperature (Temperaturesensitive) sensitive) OCA1B MP (Minimal Pigment) OCA1B MP (Minimal Pigment) OCA1B OCA1BYA YA(Yellow (YellowMutant, Mutant,Yellow YellowAlbinism) Albinism) OCA2 OCA2 Prader-Willi-Syndrome Prader-Willi-Syndrome(PWS) (PWS) Angelman-Syndrome (AS) Angelman-Syndrome (AS) OCA1: OCA1: Hauptgruppen, Hauptgruppen, Gen Gen und und Chromosom Chromosom Untergruppen Untergruppen (11 (11 Gene, Gene, 17 17 Typen) Typen) Mutationen Mutationenim imP-Gen, P-Gen,Chromosome Chromosome15 15 OCA1A OCA1A OCA1B OCA1B OCA1B OCA1BTS TS(Temperatursensitiv) (Temperatursensitiv) OCA1B MP (Minimal-Pigment) OCA1B MP (Minimal-Pigment) OCA1B OCA1BYA YA(Gelbmutante, (Gelbmutante,Yellow YellowAlbinism) Albinism) OCA2 OCA2 Prader-Willi-Syndrome Prader-Willi-Syndrome(PWS) (PWS) Angelman-Syndrom (AS) Angelman-Syndrom (AS) OCA OCA 3: 3: OCA OCA33(bislang (bislangnur nurnur nurbei beiAfrikanern Afrikanernbeschrieben) beschrieben) (Roter (Roter(rufous) (rufous)Albinismus) Albinismus) OCA OCA 4: 4:Mutationen Mutationenim imMATP-Gen MATP-Gen OCA OCA44(bislang (bislangerst ersteinmal einmalbei beieinem einemTürken Türkenaus aus Deutschland Deutschlandbeschrieben) beschrieben) OCA1: OCA1: Mutationen Mutationenim imTyrosinase-Gen, Tyrosinase-Gen,Chromosom Chromosom11 11 OCA2: OCA2: Mutationen Mutationenim imTRP1-Gen, TRP1-Gen,Chromosom Chromosom99 Chromosom Chromosom55 Syndrome Syndromemit mit okulokutanem okulokutanemAlbinismus Albinismus HPS1 HPS1::Chromosom Chromosom10 10 HPS2 : Chromosom HPS2 : Chromosom 55 HPS3 HPS3::Chromosom Chromosom 33 HPS4 HPS4::Chromosom Chromosom22 22 (HPS1-Gen) (HPS1-Gen) (Adaptin, (Adaptin,AP3B1-Gen) AP3B1-Gen) (HPS3-Gen) (HPS3-Gen) (HPS4-Gen) (HPS4-Gen) CHS: CHS:Chromosom Chromosom11(CHS-Gen) (CHS-Gen) Okulärer OkulärerAlbinismus Albinismus X-Chromosom X-Chromosom(OA1-Gen) (OA1-Gen) Hermansky-Pudlack-Syndrome Hermansky-Pudlack-Syndrome(HPS) (HPS) Typen HPS 1,2,3,4 Typen HPS 1,2,3,4 Chediak-Higashi-Syndrom Chediak-Higashi-Syndrom(CHS) (CHS) OA1: OA1:Type TypeNettleship-Falls Nettleship-Falls Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Phaenotypic Phaenotypic examples, examples, three three main main albinism albinism types types Confirmed Confirmed by by molecular molecular genetic genetic analysis analysis OCA1 OCA1 OCA2 OCA2 OCA1, OCA1, OA OA Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan OA OA Distribution of the types of albinism N N == 309 309 Persons Persons Types 9,93% 3,19% 25,53% OCA1 OCA2 OA Syndrome unklar 17,38% unclear: unclear: nn = = 34 34 43,97% Syndromes: -PWS -HPS •• •• Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Phaenotype Phaenotype not not conclusive conclusive Moleculargenetical Moleculargenetical analysis analysis not not yet yet finished finished Age Age distribution distribution Paediatric Paediatric ophthalmologic ophthalmologic department! department! Age distribution N = 309 Persons 70 High number of patients due to the Head of the department being the medicval advisor to NOAH Germany Number of Patients 60 NOAH NOAH 50 40 National National Organisation Organisation for for Albinismus Albinismus and and Hypopigmentation Hypopigmentation 30 20 10 0 5,00 15,00 25,00 35,00 45,00 55,00 65,00 75,00 10,00 20,00 30,00 40,00 50,00 60,00 70,00 Age (years) Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan www.albinismus.info www.albinismus.info www.albinism.org www.albinism.org Phaenotype Phaenotype evident evident for for OCA OCA 1A 1A Chr. Chr. 11, 11, TYR-Gen TYR-Gen No No pigment pigment formation; formation; formerly formerly called: called: „tyrosinase-negative“ „tyrosinase-negative“ Arabian Arabian brother brother and and sister sister Characteristics Characteristics -- no no pigmentation pigmentation ever ever -- no no correlation correlation of of phaenotype phaenotype to to ethnic ethnic background background -- fast fast diagnosis diagnosis due due to to evident evident findings findings Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Phaenotype Phaenotype typical typical for for OCA OCA 22 Chr. Chr. 15, 15, P-Gen P-Gen Clear Clear pigment pigment formation; formation; formerly formerly called: called: „tyrosinase-positive“ „tyrosinase-positive“ Turkish Turkish boy boy –– phenotype phenotype different different from from family! family! Characteristics Characteristics -- different different degrees degrees of of pigment pigment formation formation -- obvious obvious correlation correlation of of phaenotype phaenotype to to ethnic ethnic background background -- often often delayed delayed diagnosis diagnosis due due to to near near to to normal normal phaenotype phaenotype Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Phaenotype Phaenotype of of OCA OCA 33 Rufous Rufous albinism, albinism, up up to to now now only only described described in in Africa Africa Characteristics Characteristics -- reddish reddish hair hair colour colour -- no no further further pigmentation pigmentation Father Father and and mother mother of of our our patient: patient: immigrants immigrants from from Ghana Ghana Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Problems Problems in in phaenotypical phaenotypical differentiation differentiation OCA OCA 1B, 1B, OCA2: OCA2: both both are are pigment pigment forming! forming! Therefore Therefore Tyrosinase-negative Tyrosinase-negative and and –positive –positive not not applicable! applicable! Characteristics Characteristics -- paenotypical paenotypical no no differentiation differentiation between between OCA1 OCA1 and and OCA2 OCA2 possible! possible! -- even even dark dark naevi naevi are are possible possible in in OCA1B OCA1B Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Problematic Problematic differentiation differentiation by by phaenotype phaenotype OCA OCA 1B, 1B, OCA2: OCA2: both both pigment pigment forming! forming! Look Look out out for for pigmentation pigmentation of of eye eye lashes! lashes! OCA1B: OCA1B: often often slightly slightly darker darker as as scalp scalp hair hair OCA2: OCA2: mostly mostly same same colour colour as as scalp scalp hair hair Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Phaenotype Phaenotype of of OA OA (Ocular (Ocular Albinism) Albinism) Two Two boys: boys: OCA1A, OCA1A, OA OA Charakteristika Charakteristika -- Eyes: Eyes: any any colour colour possible possible -- Cutaneous Cutaneous type: type: skin skin type type II –– IV IV possible possible -- Always: Always: typical typical family family history history -- Typical: Typical: Mother Mother shows shows signs signs of of carrier carrier status! status! Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Peculiarities Peculiarities in in Phaenotype Phaenotype Africans, Africans, Afro-Americans Afro-Americans OCA3, OCA3, African African girl girl as as shown shown In In former former slide slide Boy, Boy, aged aged 22 yrs. yrs. Father Father African African OCA1A OCA1A OCA2, OCA2, African African girl girl Characteristics Characteristics -- besides besides OCA3 OCA3 (rufous) (rufous) all all types types of of albinism albinism possible! possible! -OCA2: -OCA2: Africans Africans often often show show characteristic characteristic long long deletion deletion on on PP -- OCA3 OCA3 often often with with better better visual visual function function than than OCA1 OCA1 and and OCA2 OCA2 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Peculiarities Peculiarities in in Phaenotype Phaenotype „The „The Red Red Troops“ Troops“ Characteristics Characteristics -- Molecular Molecular genetics: genetics: OCA OCA 22 or or up up to to now now no no mutation mutation detectable detectable -- presumed presumed unknown unknown gene gene location? location? -- very very large large span span of of visual visual function function (if (if in in doubt: doubt: perform perform Albino-VEPC!) Albino-VEPC!) Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Peculiarities Peculiarities in in Phaenotype Phaenotype Be Be aware aware of of surprises surprises in in phaenotype phaenotype and and function! function! D.W. D.W. A.W. A.W. Both Both siblings: siblings: mol.-gen. mol.-gen. analysis: analysis: OCA2 OCA2 Visual Visual acuity acuity OD/OS OD/OS 20/20 20/20 No No strabism strabism Both Both sisters: sisters: Turkish Turkish family, family, gen. gen. analysis: analysis: OCA2 OCA2 Nystagmus Nystagmus Visus Visus um um 0,1 0,1 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Peculiarities Peculiarities in in Phaenotype Phaenotype OCA1B OCA1B and and OCA2 OCA2 often often show show gain gain of of pigmentation pigmentation during during childhood childhood African African girl girl had had been been as as pale pale as as newborn newborn brother brother Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Peculiarities Peculiarities in in Phaenotype Phaenotype Skin Skin Neurodermitis Neurodermitis slightly slightly more more frequent frequent than than in in average average population. population. Nape Nape naevus naevus (Unna*´s (Unna*´s mark) mark) frequent frequent in in all all forms forms of of OCA OCA *Unna, *Unna, Paul: Paul: German German dermatologist, dermatologist, 1850 1850 -- 1929 1929 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Hauptgruppen, Hauptgruppen, Gen Gen und und Chromosom Chromosom Untergruppen Untergruppen (11 (11 Gene, Gene, 17 17 Typen) Typen) OCA2: OCA2: Mutationen Mutationen im im P-Gen, P-Gen, Chromosome Chromosome 15 15 OCA2 OCA2 Prader-Willi-Syndrome Prader-Willi-Syndrome (PWS) (PWS) Angelman-Syndrom Angelman-Syndrom (AS) (AS) OCA OCA 3: 3: OCA OCA 33 (bislang (bislang nur nur nur nur bei bei Afrikanern Afrikanern beschrieben) beschrieben) (Roter (Roter (rufous) (rufous) Albinismus) Albinismus) Mutationen Mutationen im im TRP1-Gen, TRP1-Gen, Chromosom Chromosom 99 OCA OCA 4: 4: Mutationen Mutationen im im MATP-Gen MATP-Gen Chromosom Chromosom 55 OCA OCA 44 (bislang (bislang erst erst einmal einmal bei bei einem einem Türken Türken aus aus Deutschland Deutschland beschrieben) beschrieben) Syndrome Syndrome mit mit okulokutanem okulokutanem Albinismus Albinismus HPS1 HPS1 :: Chromosom Chromosom 10 10 HPS2 HPS2 :: Chromosom Chromosom 55 HPS3 HPS3 :: Chromosom Chromosom 33 HPS4 HPS4 :: Chromosom Chromosom 22 22 (HPS1-Gen) (HPS1-Gen) (Adaptin, (Adaptin, AP3B1-Gen) AP3B1-Gen) (HPS3-Gen) (HPS3-Gen) (HPS4-Gen) (HPS4-Gen) CHS: CHS: Chromosom Chromosom 11 (CHS-Gen) (CHS-Gen) Okulärer Okulärer Albinismus Albinismus OA1-Gen, OA1-Gen, X-Chromosom X-Chromosom Hermansky-Pudlack-Syndrome Hermansky-Pudlack-Syndrome (HPS) (HPS) Typen Typen HPS HPS 1,2,3,4 1,2,3,4 Chediak-Higashi-Syndrom Chediak-Higashi-Syndrom (CHS) (CHS) OA1: OA1: Type Type Nettleship-Falls Nettleship-Falls Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan 2003 May 2003 as of of May research as of research Status of Status Mutationen Mutationen im im Tyrosinase-Gen, Tyrosinase-Gen, Chromosom Chromosom 11 11 OCA1A OCA1A OCA1B OCA1B OCA1B OCA1B TS TS (Temperatursensitiv) (Temperatursensitiv) OCA1B MP OCA1B MP (Minimal-Pigment) (Minimal-Pigment) OCA1B YA (Gelbmutante, OCA1B YA (Gelbmutante, Yellow Yellow Albinism) Albinism) OCA1: OCA1: The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and Genetics Genetics ••Oculocutaneous Oculocutaneous albinism albinism ••Ocular Ocular albinism albinism ••Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Genetics / Heredity Single Single human human set set of of chronosomes chronosomes Associated Associated with with different different forms forms of of albinism: albinism: 99 chromosomes chromosomes 11 11 gene gene loci loci 11 33 55 99 10 10 11 11 15 15 22 22 XX Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan CHS-Gen CHS-Gen HPS-3-Gen HPS-3-Gen MATP-Gen MATP-Gen –– OCA4 OCA4 AP3B1-Gen AP3B1-Gen –– HPS2 HPS2 TRP1-Gen TRP1-Gen –– OCA3 OCA3 HPS1-Gen HPS1-Gen TYR-Gen TYR-Gen –– OCA2 OCA2 P-Gen P-Gen –– OCA2 OCA2 HPS4-Gen HPS4-Gen OA1-Gen OA1-Gen Bislang Bislang bekannte bekannte Mutationen Mutationen Graphiken Graphiken mit mit freundlicher freundlicher Genehmigung Genehmigung von von Prof. Prof. Dr. Dr. R. R. King, King, Albinism Albinism Database, Database, Minneapolis Minneapolis TYR P OA TRP1 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Heredity •• All All oculocutaneous oculocutaneous forms: forms: •• autosomale-recessive autosomale-recessive Ocular Ocular albinism albinism :: X-chromosomale-recessive X-chromosomale-recessive –– –– Only Only boys boys affected affected Always Always conductor conductor signs signs in in mother mother –– Seldom Seldom mildly mildly affected affected mothers mothers Typical Typical pedigree pedigree of of aut.-recessive aut.-recessive heredity heredity // manifestation manifestation Gene frequency in Europa / Norhtern US (caucasian popul.) Gene frequency in Europa / Norhtern US (caucasian popul.) Heterogenous 11 :: 100 Heterogenous gene gene carrier: carrier: 100 Albinism: 11 :: 17.000 Albinism: 17.000 ~ BRD: BRD: ~ 4700 4700 affected affected persons persons Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Classic Classic autosomale-recessive autosomale-recessive heredity heredity in in OCA1A OCA1A One One sibling: sibling: Conductor, Conductor, very very pale pale skin skin complexion complexion Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Heredity Tipps Tipps for for an an orientating orientating counselling counselling •• Always Always recommend recommend counselling counselling at at an an Institute Institute of of Human Human Genetics! Genetics! •• Thumb Thumb rule: rule: –– With With one one affected affected child child •• 25% 25% morbidity morbidity risk risk for for every every further further child child (different (different phenotypes phenotypes possible) possible) •• 50% 50% risk risk of of heterozygote heterozygote gene gene carrier carrier (conduktor) (conduktor) •• 25% 25% probability probability of of genetical genetical normality normality –– –– 11 parent parent wirh wirh albinism: albinism: risk risk 1:200 1:200 to to have have an an affected affected child child 22 parents parents with with albinism albinism •• Genetically Genetically same same type: type: children children will will be be affected affected 100% 100% •• Genetically Genetically different different type: type: risk risk 1:200 1:200 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Moleculargenetic Moleculargenetic Analysis Analysis • • • Difficult!! Routine or prenatal analysis not possible in Europa / USA Reasons for problems of moleculargenetic analysis –– Even Even in in analysis analysis 1/3 1/3 of of patients patients without without results results •• further further up up to to now now unknown unknown gene gene loci loci are are probable probable –– Some Some of of the the 11 11 genes genes are are very very big big extensive extensive sequencing sequencing Own 2 studies in cooperation with Würzburg (79 pts.) and Lübeck (179 pts.) –– Specrtrum Specrtrum of of mutations mutations different different than than in in the the USA USA –– Many Many new new mutations mutations were were detected detected –– Up Up to to now: now: 22% 22% of of persons persons without without results results –– OCA4 OCA4 •• •• • Literature: Literature: one one description description worldwide worldwide Actual Actual study: study: 44 persons persons (2 (2 Germans, Germans, 11 Belgium, Belgium, 11 Luxembourg) Luxembourg) have have OCA4 OCA4 Praenatal diagnosis: not sensibly possible (exception: skin biopsy in known OCA1A as performed ion Corea and China) Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan The spectrum of albinism •• Table Table of of content content and and course course of of lecture lecture –– Types Types of of albinism albinism and and genetics genetics ••Oculocutaneous Oculocutaneous albinism albinism ••Ocular Ocular albinism albinism ••Syndromes Syndromes with with oculocutaneous oculocutaneous albinism albinism and and paediatric paediatric specialities specialities –– –– Ophthalmologic Ophthalmologic and and orthoptic orthoptic specialities specialities Neuroanatomic Neuroanatomic specialities specialities Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Albinism Albinism Syndromes Syndromes relevant relevant to to the the Paediatrician Paediatrician •• Paediatric Paediatric aspects aspects in in caring caring for for albinism albinism persons persons –– Syndromes Syndromes •• Hermansky-Pudlack-Syndrome Hermansky-Pudlack-Syndrome HPS HPS •• Chediak-Higashi-Syndrome Chediak-Higashi-Syndrome CHS CHS •• Prader-Willi-Syndrome Prader-Willi-Syndrome PWS PWS •• Angelman-Syndrome Angelman-Syndrome AS AS –– –– Always Always albinism albinism Occasionally Occasionally albinism albinism Hypopigmentation Hypopigmentation and and skin skin protection protection Socio-medical Socio-medical and and educational educational counselling counselling due due to to the the visual visual impairmant impairmant Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Hermansky-Pudlak-Syndrome Hermansky-Pudlak-Syndrome OMIM-Entry OMIM-Entry 203300; 203300; 44 Types, Types, 44 Genes, Genes, Chr. Chr. 3,5,10,22 3,5,10,22 •• Pigment Pigment forming forming OCA OCA with with variable variable degrees degrees of: of: –– –– –– –– –– –– –– Prolonged Prolonged bleeding bleeding time time Granulomatous Granulomatous colitis colitis Interstitial Interstitial lung lung fibrosis fibrosis Renal Renal insufficiency insufficiency Cardiomyopathy Cardiomyopathy Live Live expectancy expectancy possibly possibly reduced reduced Diagnostic Diagnostic proof: proof: •• missing missing dense dense bodies bodies in in thromocytes thromocytes –– Electron Electron microscopy microscopy Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Chediak-Higashi-Syndrome Chediak-Higashi-Syndrome OMIM-Entry OMIM-Entry 214500; 214500; Chr. Chr. 1: 1: CHS-Gene CHS-Gene •• Pigment Pigment forming forming OCA OCA with with variable variable degrees degrees of: of: –– –– –– –– –– –– –– High High risk risk of of infection infection // sepsis sepsis Hepato-Splenomegaly Hepato-Splenomegaly Muscular Muscular weakness weakness // atrophy atrophy Progressive Progressive mental mental impairment impairment Progressive Progressive neurologic neurologic degeneration, degeneration, brain brain atrophy atrophy Life Life expectancy expectancy always always reduced reduced Diagnostic Diagnostic proof: proof: •• Giant Giant granula granula in in muscle muscle and and nervous nervous tissue tissue Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Prader-Willi-Syndrome Prader-Willi-Syndrome OMIM-Entry OMIM-Entry 176270, 176270, Chr. Chr. 15, 15, 15-20% 15-20% have have OCA2 OCA2 •• Distinct Distinct retardation retardation of of mental mental and and motoric motoric development: development: –– Learning Learning and and mental mental impairment impairment –– PWS PWS = = one one of of the the most most frequent frequent forms forms of of learning learning impairments impairments –– –– –– –– –– Short Short statue statue Adipositas, Adipositas, pathognominic: pathognominic: always always hungry hungry Sociually Sociually unbalanced unbalanced behaviour behaviour Genital Genital hypoplasia hypoplasia Hypopigmentation Hypopigmentation –– In In 70% 70% pale pale skin skin and and fair fair hair hair –– In In 20% 20% eye eye symptoms symptoms and and clinical clinical OCA2 OCA2 Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Angelman-Syndrome Angelman-Syndrome Happy-Puppet-Syndrome Happy-Puppet-Syndrome OMIM-Entry OMIM-Entry 105830; 105830; Chr. Chr. 15, 15, seldom seldom associated associated with with OCA2 OCA2 •• Severe Severe mental mental impairment impairment and and pathognomonic pathognomonic paroxysmal paroxysmal laughing laughing bouts bouts with: with: –– –– –– –– –– –– Often Often inability inability to to learn learn to to speak speak Ataxia Ataxia Epileptic Epileptic seizures seizures Microbrachycephaly, Microbrachycephaly, Prognathia Prognathia Cutaneous Cutaneous hypopigmentation hypopigmentation Ocular Ocular hypopigmentation hypopigmentation –– Nystagmus Nystagmus and and visual visual impairment impairment in in approx. approx. 10% 10% Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Albinism Albinism –– Summary Summary of of Syndromes Syndromes •• HPS HPS and and CHS CHS –– –– –– Always Always pigment pigment forming forming OCA OCA rare, rare, HPS HPS > > CHS CHS Reduced Reduced life life expectancy expectancy possible possible •• PWS PWS und und AS AS –– –– PWS PWS frequent, frequent, AS AS rare rare Albinismus Albinismus in in ca ca 15% 15% •• in in all all cases cases of of mental mental impairment impairment PWS PWS and and AS AS and and visual visual impairment impairment need need to to be be ruled ruled out! out! Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan Ru/Ks Ru/Ks oder oder Ks/Ru. Ks/Ru. The The Spectrum Spectrum of of Albinism. Albinism. Name Name der der Tagung, Tagung, June June 2003, 2003, Kobe, Kobe, Japan Japan