Libe Gradstein1, Ronald M Hansen2, Gerald F Cox3,4, Pablo Altschwager2,5, Anne B Fulton6. 1. Department of Ophthalmology, Soroka Medical Center and Clalit Health Services, Faculty of Health Sciences, Ben Gurion University, Beer Sheva, Israel. 2. Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115-5737, USA. 3. Division of Genetics and Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. 4. Editas Medicine, 11 Hurley St., Cambridge, 02141, MA, USA. 5. Department of Ophthalmology, Pontificia Universidad Catolica de Chile, Santiago, Chile. 6. Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA, 02115-5737, USA. anne.fulton@childrens.harvard.edu.
Abstract
PURPOSE: We report for the first time electroretinographic (ERG) evidence of progressive retinal abnormalities in a girl who presented in infancy with ocular features of albinism and gradually developed choroidal sclerosis and patchy retinal atrophy leading to a diagnosis of Knobloch syndrome (KS, OMIM 267750, COL18A1). METHODS: At age 2 months, nystagmus and esotropia prompted ophthalmic evaluation. The appearance of choroidal sclerosis and atrophic retinal patches led to further evaluation at age 8 years. Genetics consultation was obtained in infancy and again at age 8 years as retinal findings evolved. Full field ERG responses in both scotopic and photopic conditions were recorded at both ages and compared to those in healthy control subjects. RESULTS: At age 2 months ERG response parameters were within normal limits for age and tyrosinase (TYR) gene sequencing revealed one novel mutation, p.S466F, and the temperature-sensitive polymorphism, p.R402Q, suggesting the diagnosis of oculocutaneous albinism type 1 (OCA1). At age 8 years, there was significant attenuation of both scotopic and photopic ERG responses. Genetic re-analysis led to the identification of a homozygous mutation, c.3213dupC, in the COL18A1 gene, thus confirming the diagnosis of Knobloch syndrome. CONCLUSIONS: Our patient with Knobloch syndrome developed abnormal ERG responses similar to those found in col18a1 knockout mice. Thus, we have documented progressive attenuation of the scotopic and photopic responses in KS.
PURPOSE: We report for the first time electroretinographic (ERG) evidence of progressive retinal abnormalities in a girl who presented in infancy with ocular features of albinism and gradually developed choroidal sclerosis and patchy retinal atrophy leading to a diagnosis of Knobloch syndrome (KS, OMIM 267750, COL18A1). METHODS: At age 2 months, nystagmus and esotropia prompted ophthalmic evaluation. The appearance of choroidal sclerosis and atrophic retinal patches led to further evaluation at age 8 years. Genetics consultation was obtained in infancy and again at age 8 years as retinal findings evolved. Full field ERG responses in both scotopic and photopic conditions were recorded at both ages and compared to those in healthy control subjects. RESULTS: At age 2 months ERG response parameters were within normal limits for age and tyrosinase (TYR) gene sequencing revealed one novel mutation, p.S466F, and the temperature-sensitive polymorphism, p.R402Q, suggesting the diagnosis of oculocutaneous albinism type 1 (OCA1). At age 8 years, there was significant attenuation of both scotopic and photopic ERG responses. Genetic re-analysis led to the identification of a homozygous mutation, c.3213dupC, in the COL18A1 gene, thus confirming the diagnosis of Knobloch syndrome. CONCLUSIONS: Our patient with Knobloch syndrome developed abnormal ERG responses similar to those found in col18a1 knockout mice. Thus, we have documented progressive attenuation of the scotopic and photopic responses in KS.
Authors: Alexander G Marneros; Douglas R Keene; Uwe Hansen; Naomi Fukai; Karen Moulton; Patrice L Goletz; Gennadiy Moiseyev; Basil S Pawlyk; Willi Halfter; Sucai Dong; Masao Shibata; Tiansen Li; Rosalie K Crouch; Peter Bruckner; Bjorn R Olsen Journal: EMBO J Date: 2003-12-11 Impact factor: 11.598
Authors: Boris Keren; Oscar T Suzuki; Marion Gérard-Blanluet; Dominique Brémond-Gignac; Monique Elmaleh; Luigi Titomanlio; Anne-Lise Delezoide; Maria Rita Passos-Bueno; Alain Verloes Journal: Am J Med Genet A Date: 2007-07-01 Impact factor: 2.802
Authors: Yaping Yang; Donna M Muzny; Fan Xia; Zhiyv Niu; Richard Person; Yan Ding; Patricia Ward; Alicia Braxton; Min Wang; Christian Buhay; Narayanan Veeraraghavan; Alicia Hawes; Theodore Chiang; Magalie Leduc; Joke Beuten; Jing Zhang; Weimin He; Jennifer Scull; Alecia Willis; Megan Landsverk; William J Craigen; Mir Reza Bekheirnia; Asbjorg Stray-Pedersen; Pengfei Liu; Shu Wen; Wendy Alcaraz; Hong Cui; Magdalena Walkiewicz; Jeffrey Reid; Matthew Bainbridge; Ankita Patel; Eric Boerwinkle; Arthur L Beaudet; James R Lupski; Sharon E Plon; Richard A Gibbs; Christine M Eng Journal: JAMA Date: 2014-11-12 Impact factor: 56.272