Albinism
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Presented by Thomas Hahn Bioinformatics Ph.D. program [email protected] February 27 th , 2013 Albinism Albinism
Transcript of Albinism
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OutlineOutline• What is Albinism? • Causes of Albinism?• What are the symptoms? • How is vision affected?
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Facts about Albinism 1:17,000 in US1:17,000 in US Can affect all Can affect all vertebratesvertebrates
Reduced or no melanin Tyrosinase defect Autsomal recessive
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Types of Albinism Ocular Albinism (OA) (affecting only brain and eyes)
Oculocutaneous Albinism (OCA) (affecting brain, eyes, skin and hair (systemic)
OCA type 2: slight pigmentation OCA type 1: no pigmentation (worse)
There are a few more but very rare types of Albinism (type 3 and 4)
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Phenotype variations
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Melanin pathway
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Mutations causing OCA1
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Bioinformatics and Albinism
Bioinformatics is now used to analyze deep RNA sequencing results of the transcriptome in Albinism, which – in addition to DNA analysis – also reveals abnormalities in gene splicing.
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SymptomsSymptomsReduced or absence of pigmentation Reduced or absence of pigmentation (coloration) of brain, skin, hair, (coloration) of brain, skin, hair, retina and iris is causing varying retina and iris is causing varying degrees ofdegrees of Vision lossVision loss Light sensitivity (photophobia)Light sensitivity (photophobia) Rapid eye movements (nystagmus)Rapid eye movements (nystagmus) Crossed eyes (strabismus)Crossed eyes (strabismus) Abnormal vision nerve routingAbnormal vision nerve routing UV sensitivity of skin (sunburn)UV sensitivity of skin (sunburn)
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Anatomy of the eyeAnatomy of the eye
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Visual abnormalities Visual abnormalities All types of albinism show variability All types of albinism show variability
in:in: Iris transilluminationIris transillumination Hypopigmentation of the retinal Hypopigmentation of the retinal pigment epitheliumpigment epithelium
Foveal hypoplasia / dysplasiaFoveal hypoplasia / dysplasia Optic nerve head morphologyOptic nerve head morphology
Variability depends on:Variability depends on: GenotypeGenotype Ethnical backgroundEthnical background
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Visual Acuity in Albinism
OCA1 OCA2 OA
Type of Albinism
0,00
0,10
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OU VA Median
n=72 n=122 n=48
OCA 1 shows significanty
lower values of visual
acuity than OCA 2 and OA
Visual Acuity in Albinism
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Comparing IrisesComparing IrisesNormalNormal Albino Albino
Iris Iris isis transparent transparent
Iris Iris should‘t beshould‘t be transparent transparent
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Degrees of Iris Translucency
Completely Completely transparent transparent
Mostly pigmented Mostly pigmented Completely pigmented Completely pigmented
Mostly Mostly transparent transparent
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Retina AnatomyRetina Anatomy
Normal Ophthalmoscopy Findings
Optic Nerve Head ONHDiameter 1,5 to 2,1mm Macula Diameter 3,5mm
Fovea approx. 1,2mm
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Pigmented aspectPigmented aspectNormal foveal Normal foveal appearanceappearance
Albinotic fundus,macula dysplasia
Comparing retinasComparing retinas
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Comparing vision nerves
NormalNormal Albino
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Brain abnormalities in Albinism
Melanin, dopamine, tyrosinase and tyrosine are involved in embryonal, fetal and postnatal neural differentiation in mammalian individuals.
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Neurological abnormalities
Aberration of retino-neural topography
Optic nerve hypoplasia is frequent
Atypical chiasmal crossing of the optic nerve fibres
Atypical architecture of primary and associative visual cortex
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Chiasmal Crossing in normally Chiasmal Crossing in normally Pigmented IndividualsPigmented Individuals
Crossing: 30 - 40% of fibers (nasal hemiretina) cross
60 - 70% of fibers (temporal hemiretina) do not cross
Temporal hemiretina (fovea!) is larger than nasal hemiretina
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Chiasmal crossing in pigmented and hypopigmented / albinotic
persons
Partial explanation: Albinism has foveal hypoplasia less ganglion cells
Fiber course; both eyes are left eyes
BUT: Other congenital visual impairments with foveal hypoplysia do not have atypic chiasmal crossing!
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Clinical Trial
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You just drew your maculaYou just drew your macula
Normal Ophthalmoscopy Findings
Macula Diameter 3,5mmFovea approx. 1,2mm
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Special Thanks to:Dr. Barbara Käsmann-Kellner MD PhD
Department of Paediatric Ophthalmology
University Eye Hospital Homburg (Saar), Germany
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References• [1] Karen Grønskov, Jakob Ek and Karen Brondum-Nielsen. Oculocutaneous
albinism. Orphanet Journal of Rare Diseases 2007, 2:43 doi:10.1186/1750-1172-2-43
• [2] Johan W. Stjernschantz, Daniel M. Albert, Dan-Ning Hu, MD, Filippo Drago, and Per J. Wistrand. Mechanism and Clinical Significance of Prostaglandin-Induced Iris Pigmentation. Survey of Ophthalmology. Volume 47. 2002:S162–S175.
• [3] Annagiusi Gargiulo, Ciro Bonetti, Sandro Montefusco, Simona Neglia, Umberto Di Vicino, Elena Marrocco, Michele Della Corte, Luciano Domenici, Alberto Auricchio and Enrico M Surace. AAV-mediated Tyrosinase Gene Transfer Restores Melanogenesis and Retinal Function in a Model of Oculo-cutaneous Albinism Type I (OCA1). Molecular Therapy. 2009. 17(8):1347-54. doi: 10.1038/mt.2009.112.
• [4] C. Zühlke, A. Stell, B. Käsmann-Kellner. Genetik bei okulokutanem Albinismus. Ophthalmologe. 2007. 104:674–680. doi: 10.1007/s00347-007-1590-1
• [5] Ighovie F. Onojafe, David R. Adams, Dimitre R. Simeonov, Jun Zhang, Chi-Chao Chan, Isa M. Bernardini, Yuri V. Sergeev, Monika B. Dolinska, Ramakrishna P. Alur, Murray H. Brilliant, William A. Gahl, and Brian P. Brooks. Nitisinone improves eye and skin
• [6]pigmentation defects in a mouse model of oculocutaneous albinism. the Journal of Clinical Investigation. 2011;121(0):3914–3923. doi:10.1172/JCI59372
• [7] Prashiela Manga and Seth J. Orlow. Informed reasoning: repositioning of nitisinone to treat oculocutaneous albinism. the Journal of Clinical Investigation. 2011; 121(10):3828–3831. doi:10.1172/JCI59763
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References continued• [8] B. Käsmann-Kellner · B. Seitz. Phänotyp des visuellen Systems bei
okulokutanem und okulärem Albinismus. Ophthalmologe. 2007. 104:648–661. DOI 10.1007/s00347-007-1571-4
• [9] William S. Oetting. The Tyrosinase Gene and Oculocutaneous Albinism Type 1 (OCA1): A Model for Understanding the Molecular Biology of Melanin Formation. PIGMENT CELL Volume 13, Issue5, pp320–325. 2000
• [10] C. Gail Summers, Vision in Albinism. Transaction American Ophthalmology Society. 1996; 94: 1095–1155.
• [11] Nagata A, Mishima HK, Kiuchi Y, Hirota A, Kurokawa T, Ishibashi S. Binding of antiglaucomatous drugs to synthetic melanin and their hypotensive effects on pigmented and nonpigmented rabbit eyes. Japanese Journal of Ophthalmology. 1993;37(1):32-8.
• [12] Clinical Trials. http://clinicaltrials.gov/show/NCT01176435• [13] Eisenhofer, G., Tian, H., Holmes, C., Matsunaga, J., Roffler-Tarlov,
S., Hearing, V. J. Tyrosinase: A Developmentally Specific Major Determinant of Peripheral Dopamine. FASEB J. 17, 1248–1255 (2003)
• [14] Joseph H. Nadeau. Modifier Genes in Mice and Humans. Nature Reviews Genetics 2, 165-174, 2001. doi:10.1038/35056009
• ]15] E. Lasseaux, F. Morice-Picard, C. Rooryck-Thambo, A. Rouault, C. Plaisant, P. Fergelot, D. Lacombe, B. Arveiler . Bioinformatics tools to predict splicing mutation effect in genetic diagnosis of oculocutaneous albinism. http://www.ifpcs.org/ipcc2011/programme/abstract/195/Bioinformatics%20tools%20to%20predict%20splicing%20mutation%20effect%20in%20genetic%20diagnosis%20of%20oculocutaneous%20albinism.html
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Questions??
