Biomedical subjects

Jeremiah Brown

Publications and source records attributed to Jeremiah Brown.

6 recordsLinked to original sources

PubMed2005

A novel GCAP1 missense mutation (L151F) in a large family with autosomal dominant cone-rod dystrophy (adCORD).

PURPOSE: To elucidate the phenotypic and biochemical characteristics of a novel mutation associated with autosomal dominant cone-rod dystrophy (adCORD). METHODS: Twenty-three family members of a CORD pedigree underwent clinical examinations, including visual acuity tests, standardized full-field ERG, and fundus photography. Genomic DNA was screened for mutations in GCAP1 exons using DNA sequencing and single-strand conformational polymorphism (SSCP) analysis. Function and stability of recombinant GCAP1-L151F were tested as a function of [Ca(2+)], and its structure was probed by molecular dynamics. RESULTS: Affected family members experienced dyschromatopsia, hemeralopia, and reduced visual acuity by the second to third decade of life. Electrophysiology revealed a nonrecordable photopic response with later attenuation of the scotopic response. Affected family members harbored a C-->T transition in exon 4 of the GCAP1 gene, resulting in an L151F missense mutation affecting the EF hand motif 4 (EF4). This change was absent in 11 unaffected family members and in 100 unrelated normal subjects. GCAP1-L151F stimulation of photoreceptor guanylate cyclase was not completely inhibited at high physiological [Ca(2+)], consistent with a lowered affinity for Ca(2+)-binding to EF4. CONCLUSIONS: A novel L151F mutation in the EF4 hand domain of GCAP1 is associated with adCORD. The clinical phenotype is characterized by early cone dysfunction and a progressive loss of rod function. The biochemical phenotype is best described as persistent stimulation of photoreceptor guanylate cyclase, representing a gain of function of mutant GCAP1. Although a conservative substitution, molecular dynamics suggests a significant change in Ca(2+)-binding to EF4 and EF2 and changes in the shape of L151F-GCAP1.

Adolescent↗

PubMed2004

Micro-optic fabrication with subdomain masking.

An innovative fabrication technique is introduced that is based on multiple-exposure techniques for micro-optics fabrication. This approach is compatible with conventional lithography systems used in integrated circuit manufacturing and can be applied to thick and thin photoresists and is based on additive lithographic techniques introduced elsewhere [Appl. Opt. 41, 6176 (2002)]. We chose a simple subdomain basis set to transform the two-dimensional basis patterns into a family of various three-dimensional micro-optic elements using exposure control to modulate the third dimension. We demonstrate the capability to sculpt the photoresist into a variety of three-dimensional micro-optic elements by performing multiple exposures using elements from the subdomain basis set, without resorting to multiple etching steps.

Journal Article↗

PubMed2004

Assessment of alleged retinal laser injuries.

Accidental retinal laser injuries are easily diagnosed when there are known laser sources, typical macular injuries, and visual deficits consistent with retinal findings. Decisions are more difficult when retinal findings are subtle or absent, despite reported visual problems and somatic complaints. Inaccurate diagnosis of an ocular laser injury can precipitate a costly, lengthy sequence of medical and legal problems. Analysis of laser-tissue interactions and the characteristics of unambiguous retinal laser injuries provide 6 key questions to facilitate difficult diagnoses. Case reports demonstrate the usefulness of answering these questions before making diagnostic decisions. Retinal laser lesions that cause serious visual problems are readily apparent ophthalmoscopically and angiographically. Accidental, intentional, or clinical retinal laser lesions do not cause chronic eye, face, or head pains. Diagnosis of a retinal laser injury should be evidence based, not a matter of conjecture or speculation.

Accidents, Occupational↗

PubMed2004

Laser-induced macular holes demonstrate impaired choroidal perfusion.

PURPOSE: To evaluate choroidal perfusion following creation of a laser-induced macular hole in a nonhuman primate model. METHODS: Six rhesus monkeys underwent macular exposures delivered by a Q-switched Nd:YAG laser. The lesions were evaluated with fluorescein angiography and indocyanine green angiography using scanning laser ophthalmoscopy. RESULTS: Each lesion produced vitreous hemorrhage and progressed to a full-thickness macular hole. Indocyanine green angiography revealed no perfusion of the choriocapillaris beneath the lesion centers. Fluorescein angiography demonstrated mild enlargement of the foveal avascular zone due to loss of perifoveal capillaries. Histopathologic evaluation showed replacement of the choriocapillaris with fibroblasts and connective tissue. CONCLUSIONS: Nd:YAG laser-induced macular holes result in long-term impairment of choroidal perfusion at the base of the hole due to choroidal scarring and obliteration of the choriocapillaris. Evaluation of choroidal perfusion may be useful in assessment of laser-injured patients. Impairment in choroidal perfusion may have functional implications for surviving photoreceptors.

Animals↗

PubMed2003

Comparison of the clinical expression of retinitis pigmentosa associated with rhodopsin mutations at codon 347 and codon 23.

PURPOSE: To examine the difference in expression of retinitis pigmentosa from mutations at codon 23 and codon 347 or rhodopsin; to report a novel mutation in rhodopsin. METHODS: Goldmann perimetry (solid angle of I4e isopter) and electroretinographic amplitudes (square root transform of a response ratio) were analyzed for 24 patients with mutations at codon 347 (15 with Pro347Ala, 2 with Pro347Gln, 6 with Pro347Leu, and 1 with a novel Pro347Cys change) and 41 patients with mutations at codon 23 (6 with Pro23Ala; 35 with Pro23His). RESULTS: When all patients with mutations at codons 347 and 23 were compared, loss of visual fields was significantly worse in patients with codon 347 changes (P =.0003). Only rod responses of the electroretinograms were significantly different between the two groups (P =.048). Specific comparison of Pro347Ala with Pro23Ala using regression analysis demonstrated significant differences in severity between codon 23 and codon 347 patients for b-wave amplitudes of rod (P =.0069), cone (P =.039) and maximum combined response (P =.049). The solid angle of the I4e isopter was also significantly different (P =.025) between the groups after controlling for age. Modeling age by group for Pro347Ala comparison produced an R(2) of.44. CONCLUSION: We reconfirmed that rhodopsin-related retinitis pigmentosa from mutations involving codon 347 produces a more severe phenotype than that involving codon 23. Accurate modeling of disease was shown to be possible by incorporating the effects of a patient's age and specific genotype. Therefore, both of these variables must be considered in prognostic counseling and subject recruitment for future therapeutic trials.

Adolescent↗

PubMed2003

Posterior chorioretinal atrophy and vitreous phenotype in a family with Stickler syndrome from a mutation in the COL2A1 gene.

PURPOSE: To report posterior chorioretinal atrophy (PCRA) and correlate the vitreous phenotype with inheritance of the disease mutation in a family with vitreoretinal dystrophy. DESIGN: Prospective observational case series. METHODS: Twenty-four members of a family with 14 affected individuals were examined, and genetic linkage analysis was performed at the COL2A1, COL11A1, and Wagner disease loci. The vitreous phenotype was prospectively graded as optically empty with retrolenticular membrane, fibrillar, or normal. Ocular ultrasonography and optical coherence tomography (OCT) were performed on selected individuals to study the vitreous structure and vitreoretinal interface. RESULTS: The 6-year-old proband had PCRA and optically empty vitreous without systemic features, suggestive of Wagner disease. The family history was negative for systemic disease, except for one cousin with cleft palate. However, when examined, clinical features of the 14 affected subjects included 5 with small chin, 4 with at least submucosal cleft palate, and 9 with a myopic refractive error greater than 5 diopters. Lens opacity or previous cataract extraction was found in 13 family members. All affected individuals in whom the vitreous could be examined had an optically empty vitreous with retrolental membrane. Posterior chorioretinal atrophy was found in eight of the affected subjects. The finding was not limited to highly myopic subjects, nor did all the high myopes have PCRA. Ultrasonography and OCT revealed vitreous adherent to the retina, but without apparent retinal distortion or edema of the macula. Significant linkage was established to the COL2A1 locus; the other loci were excluded. A single nucleotide insertion mutation (c.2012 2013insC) was identified in exon 34, leading to a downstream premature stop codon in the COL2A1 gene. CONCLUSIONS: Although posterior chorioretinal atrophy and vitreoretinal degeneration have been classically associated with Wagner disease, we demonstrate its presence in a family with typical Stickler syndrome. On the basis of clinical, ultrasonographic, and OCT studies, the etiology of PCRA in this family does not seem to be attributable to vitreomacular traction or myopia. The vitreous findings in this large family confirm reports that mutations in the COL2A1 gene lead to the optically empty vitreous with retrolenticular membrane phenotype.

Adolescent↗