Progressive Retinal Degeneration in a Girl with Knobloch Syndrome Who Presented with Signs of Ocular Albinism

Overview

Journal Doc Ophthalmol

Specialty Ophthalmology

Date 2017 Feb 2

PMID 28144890

Citations 2

Authors

Libe Gradstein

Ronald M Hansen

Gerald F Cox

Pablo Altschwager

Anne B Fulton

Affiliations

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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.

Citing Articles

Knobloch Syndrome Associated with Novel Variants in Chinese Population.

Li S, Wang Y, Sun L, Yan W, Huang L, Zhang Z Genes (Basel). 2021; 12(10).

PMID: 34680907 PMC: 8536191. DOI: 10.3390/genes12101512.

Knobloch syndrome caused by homozygous frameshift mutation of the gene in a Chinese pedigree.

Zhang L, Li H, Zeng J, Yang Y, Ding C Int J Ophthalmol. 2018; 11(6):918-922.

PMID: 29977801 PMC: 6010381. DOI: 10.18240/ijo.2018.06.04.

References

King R, Townsend D, Oetting W, Summers C, Olds D, White J . Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism. J Clin Invest. 1991; 87(3):1046-53. PMC: 329899. DOI: 10.1172/JCI115064. View

Marneros A, Olsen B . Physiological role of collagen XVIII and endostatin. FASEB J. 2005; 19(7):716-28. DOI: 10.1096/fj.04-2134rev. View

Hood D, Birch D . Rod phototransduction in retinitis pigmentosa: estimation and interpretation of parameters derived from the rod a-wave. Invest Ophthalmol Vis Sci. 1994; 35(7):2948-61. View

Mordechai S, Gradstein L, Pasanen A, Ofir R, El Amour K, Levy J . High myopia caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2. Am J Hum Genet. 2011; 89(3):438-45. PMC: 3169819. DOI: 10.1016/j.ajhg.2011.08.003. View

Yang Y, Muzny D, Xia F, Niu Z, Person R, Ding Y . Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014; 312(18):1870-9. PMC: 4326249. DOI: 10.1001/jama.2014.14601. View

Mayer D, Beiser A, Warner A, Pratt E, Raye K, Lang J . Monocular acuity norms for the Teller Acuity Cards between ages one month and four years. Invest Ophthalmol Vis Sci. 1995; 36(3):671-85. View

Marneros A, Keene D, Hansen U, Fukai N, Moulton K, Goletz P . Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J. 2003; 23(1):89-99. PMC: 1271654. DOI: 10.1038/sj.emboj.7600014. View

Keren B, Suzuki O, Gerard-Blanluet M, Bremond-Gignac D, Elmaleh M, Titomanlio L . CNS malformations in Knobloch syndrome with splice mutation in COL18A1 gene. Am J Med Genet A. 2007; 143A(13):1514-8. DOI: 10.1002/ajmg.a.31784. View

Lamb T, Pugh Jr E . A quantitative account of the activation steps involved in phototransduction in amphibian photoreceptors. J Physiol. 1992; 449:719-58. PMC: 1176104. DOI: 10.1113/jphysiol.1992.sp019111. View

10.

Chiang P, Spector E, Chun-Hui Tsai A . Oculocutaneous albinism spectrum. Am J Med Genet A. 2009; 149A(7):1590-1. DOI: 10.1002/ajmg.a.32939. View

11.

Seaver L, Joffe L, Spark R, Smith B, Hoyme H . Congenital scalp defects and vitreoretinal degeneration: redefining the Knobloch syndrome. Am J Med Genet. 1993; 46(2):203-8. DOI: 10.1002/ajmg.1320460221. View

12.

Fulton A, Rushton W . The human rod ERG: correlation with psychophysical responses in light and dark adaptation. Vision Res. 1978; 18(7):793-800. DOI: 10.1016/0042-6989(78)90119-0. View

13.

Suzuki O, Kague E, Bagatini K, Tu H, Heljasvaara R, Carvalhaes L . Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome. Mol Vis. 2009; 15:801-9. PMC: 2671584. View

14.

Khan A, Aldahmesh M, Mohamed J, Al-Mesfer S, Alkuraya F . The distinct ophthalmic phenotype of Knobloch syndrome in children. Br J Ophthalmol. 2012; 96(6):890-5. DOI: 10.1136/bjophthalmol-2011-301396. View

15.

Hutton S, Spritz R . A comprehensive genetic study of autosomal recessive ocular albinism in Caucasian patients. Invest Ophthalmol Vis Sci. 2008; 49(3):868-72. DOI: 10.1167/iovs.07-0791. View

16.

Moskowitz A, Hansen R, Eklund S, Fulton A . Electroretinographic (ERG) responses in pediatric patients using vigabatrin. Doc Ophthalmol. 2012; 124(3):197-209. DOI: 10.1007/s10633-012-9320-7. View

17.

Fulton A, Hansen R, Moskowitz A, Akula J . The neurovascular retina in retinopathy of prematurity. Prog Retin Eye Res. 2009; 28(6):452-82. PMC: 2783268. DOI: 10.1016/j.preteyeres.2009.06.003. View

18.

Simeonov D, Wang X, Wang C, Sergeev Y, Dolinska M, Bower M . DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum Mutat. 2013; 34(6):827-35. PMC: 3959784. DOI: 10.1002/humu.22315. View