Disease boundaries in the retina of patients with Usher syndrome caused by MYO7A gene mutations.
OBJECTIVE
To study retinal microstructure in Usher Syndrome type 1B (USH1B) caused by MYO7A mutations as a prelude to treatment initiatives.


METHODS
Patients with MYO7A-USH1B (n=17; ages 5-61) were studied with optical coherence tomography. Retinal laminae across horizontal and vertical meridians were measured. Colocalized visual sensitivity was measured with automated perimetry to enable comparisons of function and structure in the transition zones.


RESULTS
Laminar architecture of the central retina in MYO7A-USH1B ranged from normal to severely abnormal. Within the transition zone between normal and abnormal retina, the first detectable abnormality was an increase in prominence of the OLM (outer limiting membrane). Declining ONL thickness was accompanied by increased thickness of the OPL and normal or increased INL. Undetectable ONL and OPL and hyperthick INL were features of severe laminopathy at further eccentricities into the transition zone. Visual sensitivity in the transition zone declined with the decrease in ONL thickness.


CONCLUSIONS
Patients with MYO7A-USH1B can have regions of structurally and functionally normal retina with definable transitions to severe laminopathy and visual loss. The earliest detectable structural markers of disease may represent Müller glial cell response to photoreceptor stress and apoptosis. Visual losses were predictably related to a decline in ONL thickness. The prospect of focal treatment of MYO7A-USH1B, such as subretinal gene therapy, prompts the need to identify retinal locations that warrant consideration for treatment in early phase trials. The transition zones are candidate sites for treatment, and laminar architecture and visual sensitivity are possible outcomes to assess safety and efficacy.
Jacobson
Samuel G
SG
Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. jacobsos@mail.med.upenn.edu
Aleman
Tomas S
TS
Sumaroka
Alexander
A
Cideciyan
Artur V
AV
Roman
Alejandro J
AJ
Windsor
Elizabeth A M
EA
Schwartz
Sharon B
SB
Rehm
Heidi L
HL
Kimberling
William J
WJ
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics*; D012160:Retina / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D041623:Tomography, Optical Coherence; D052245:Usher Syndromes / Q000235:genetics* / Q000473:pathology; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D009218:Myosins