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Clinical Course and Visual Function in a Family With Mutations in the RPE65 Gene
Joost Felius, PhD;
Debra A. Thompson, PhD;
Naheed W. Khan, PhD;
Eve L. Bingham;
Jeffrey A. Jamison;
Jennifer A. Kemp;
Paul A. Sieving, MD, PhD
Arch Ophthalmol. 2002;120:55-61.
Objective To evaluate the phenotype of affected and carrier members of a family
with mutations in RPE65 (a retinal pigment epithelium
gene).
Methods RPE65 mutation screening was performed on DNA
from 2 affected brothers, 1 unaffected brother, both parents, and 3 surviving
grandparents using cycle sequencing. Ophthalmic examinations included ophthalmoscopic
fundus examination; visual function testing; 2-color, static, dark-adapted
threshold perimetry; and rod electroretinographic a-wave phototransduction
analysis.
Results The 2 affected brothers carried RPE65 mutations
in compound heterozygous form: a maternal Y368H (1156T C) missense mutation
and a paternal IVS1 + 5ga splice-site mutation. Severe visual deficits
and an absence of rod and cone electroretinographic responses were diagnosed
in both affected boys before the age of 5 years. Visual acuities of about
20/100 during grade school declined to hand movements by the teenage years,
and only a rudimentary peripheral temporal visual field remained by the ages
of 25 and 29 years. Both parents had normal central visual function, as measured
by visual acuity, contrast sensitivity, color vision, and Humphrey 10-2 fields.
However, the 50-year-old father showed hundreds of tiny whitish hard drusen
in both eyes and had abnormal peripheral function on dark-adapted perimetry,
with extended field defects of 15 to 20 dB outside 30° eccentricity. His
rod photoreceptor sensitivity and amplitude, calculated by fitting the rod
a waves by a model of activation of phototransduction, were normal, but the
flicker electroretinographic response was delayed.
Conclusions The RPE65 mutations Y368H and IVS1 + 5ga
present in compound heterozygous form cause severe visual compromise in childhood
and progress to nearly total vision loss by the second to third decades of
life. The retinal and functional changes in the father carrying a presumed
functional null allele suggest that some RPE65 heterozygous
carriers may manifest visual symptoms.
From the Departments of Ophthalmology and Visual Sciences (Drs Felius,
Thompson, Khan, and Sieving, Mss Bingham and Kemp, and Mr Jamison) and Biological
Chemistry (Dr Thompson), University of Michigan Medical School, Ann Arbor.
Dr Sieving is now with the National Eye Institute, Bethesda, Md.
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