title: Impairment of the transient pupillary light reflex in Rpe65(-/-) mice and humans with leber congenital amaurosis.
abstract: OBJECTIVE
  To determine the impairment of the transient pupillary light reflex (TPLR) due to severe retinal dysfunction and degeneration in a murine model of Leber congenital amaurosis (LCA) and in patients with the disease.
  
  
  METHODS
  Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control mice with full-field light stimuli (0.1 second duration) of increasing intensities (-6.6 to +2.3 log scot-cd. m(-2)). 9-cis-Retinal was administered orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the treatment. TPLR was also measured in a group of patients with LCA.
  
  
  RESULTS
  Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-) mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients with LCA had baseline pupillary diameters similar to normal, but the TPLR was abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted to the elevation of TPLR threshold, pupillary constriction kinetics in most patients were similar to those in normal subjects.
  
  
  CONCLUSIONS
  Pupillometry was used to quantify visual impairment and to probe transmission of retinal signals to higher nervous centers in a murine model of LCA and in patients with LCA. Mouse results were consistent with a dominant role of image-forming photoreceptors driving the early phase of the TPLR when elicited by short-duration stimuli. The objective and noninvasive nature of the TPLR measurement, and the observed post-treatment change toward normal in the animal model supports the notion that this may be a useful outcome measure in future therapeutic trials of LCA.
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
authors.forename: John D
authors.initials: JD
authors.lastname: Chico
authors.forename: Michele L
authors.initials: ML
authors.lastname: Scott
authors.forename: Andy Y
authors.initials: AY
authors.lastname: Cheung
authors.forename: Elizabeth A M
authors.initials: EA
authors.lastname: Windsor
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Furushima
authors.forename: T Michael
authors.initials: TM
authors.lastname: Redmond
authors.forename: Jean
authors.initials: J
authors.lastname: Bennett
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001766:Blindness / Q000150:complications* / Q000151:congenital; D002352:Carrier Proteins; D002648:Child; D002675:Child, Preschool; D003623:Dark Adaptation; D004224:Diterpenes; D004594:Electrophysiology; D005136:Eye Proteins; D005260:Female; D006801:Humans; D007223:Infant; D008027:Light; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011506:Proteins / Q000235:genetics*; D011681:Pupil Disorders / Q000209:etiology* / Q000503:physiopathology; D012025:Reflex, Pupillary / Q000502:physiology*; D012162:Retinal Degeneration / Q000150:complications* / Q000235:genetics; D012172:Retinaldehyde / Q000008:administration & dosage; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D004224:Diterpenes; D005136:Eye Proteins; D011506:Proteins; D012172:Retinaldehyde; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C031390:9-cis-retinal