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Biomedical subjects

Joseph Carroll

Publications and source records attributed to Joseph Carroll.

11 recordsLinked to original sources
PubMed2026

Small Copy Number Neutral Intrachromosomal Translocation of PAX6 and Aniridia.

IMPORTANCE: Approximately 5% to 10% of individuals with classic aniridia do not receive a molecular diagnosis after clinical testing for variants in PAX6 and its downstream regulatory region. OBJECTIVE: To apply optical genome mapping (OGM) and long-read whole-genome sequencing (lrWGS) to diagnose an individual with unexplained classic aniridia. DESIGN, SETTING, AND PARTICIPANTS: High-quality DNA was extracted from the blood of a 16-year-old male patient with classic aniridia and prior negative clinical test results that included sequencing and copy number analysis of PAX6 exons and downstream regulatory region as well as genomic analysis via short-read whole-genome sequencing (srWGS) and analyzed using OGM and lrWGS. All analyses were performed in a research laboratory in Wisconsin from January 2019 to September 2025. INTERVENTIONS: OGM and lrWGS. MAIN OUTCOMES AND MEASURES: Identification of a structural variant disrupting PAX6 expression in an individual with classic aniridia, following negative prior testing including srWGS. RESULTS: OGM identified a 55-kb deletion on 11p13 encompassing all PAX6 exons and exon 12 of ELP4, with insertion of this segment into 11q21. lrWGS delineated the exact breakpoints, confirming that the downstream regulatory region, required for normal PAX6 expression, remained at the 11p13 locus. Consequently, the translocated copy of PAX6 at 11q21 is expected to lack expression due to the loss of its essential regulatory elements. CONCLUSIONS AND RELEVANCE: These findings in an individual with classic aniridia harboring an intrachromosomal rearrangement at the PAX6 locus identified by OGM and lrWGS may represent the smallest reported structural variant to separate the PAX6 coding sequence from its downstream regulatory region. This structural variant may have fallen below the detection threshold of srWGS due to its balanced nature and small size, suggesting OGM and lrWGS would be needed for definitive identification.

Aniridia↗
PubMed2006

High-resolution retinal imaging of cone-rod dystrophy.

PURPOSE: This study examines a patient with cone-rod dystrophy using high-resolution adaptive optics retinal imaging. Conventional ophthalmoscopes provide limited resolution due to their inability to overcome the eye's optical aberrations. In contrast, adaptive optics ophthalmoscopes correct these aberrations to provide noninvasive high-resolution views of the living retina. To date, adaptive optics ophthalmoscopy has been used mainly to examine the normal retina. Here we use adaptive optics ophthalmoscopy to image cone-rod dystrophy in vivo and compare these results with standard clinical tests. DESIGN: Observational case report. METHODS: High-resolution retinal images of a patient with cone-rod dystrophy were obtained with the University of Rochester adaptive optics flood-illuminated ophthalmoscope and the adaptive optics scanning laser ophthalmoscope located at the University of Houston and compared with standard clinical tests, including fundus photography, Goldmann visual fields, fluorescein angiography, optical coherence tomography, electroretinography, and multifocal electroretinography. MAIN OUTCOME MEASURES: Direct measurement of cone density and diameter and comparison of adaptive optics images with standard clinical imaging and functional tests. RESULTS: Adaptive optics images were acquired at multiple retinal locations throughout a clinically detected bull's-eye lesion. Within the atrophic regions, we observed large areas devoid of wave-guiding cones. In contrast, regions that appeared relatively spared by clinical examination contained a completely tiled cone mosaic. However, in these areas the cones were abnormally large, resulting in a 6.6-fold reduction from the normal peak cone density (patient peak density: 30 100 cones/mm2, normal peak density: 199 200 cones/mm2). Multifocal electroretinography confirmed a 5.5-fold reduction in amplitude of the central peak (10.8 nanovolts/degree2 vs. 59.8 nanovolts/degree2). CONCLUSIONS: Adaptive optics ophthalmoscopy is a noninvasive technique to observe a patient's retinal pathology directly at a cellular level. It can provide a quantitative measurement of photoreceptor loss in retinal disease.

Adult↗
PubMed2006

Retinal microscotomas revealed with adaptive-optics microflashes.

PURPOSE: To develop a sensitive psychophysical test for detecting visual defects such as microscotomas. METHODS: Frequency-of-seeing curves were measured with 0.75' and 7.5' spots. On each trial, from 0 to 4 stimuli were randomly presented at any of eight equally spaced loci 0.5 degrees from fixation. By correcting the aberrations of the eye, adaptive optics produced retinal images of the 0.75' spot that were 3.0 microm wide at half height, small enough to be almost entirely confined within the typical cone diameter at this eccentricity. Data were collected from a patient with deuteranopia (AOS1) whose retina, imaged with adaptive optics, suggested that approximately 30% of his cones were missing or abnormal. Patients with protanomalous trichromacy (1 subject), deuteranopia (1 subject), and trichromacy (5 subjects) served as controls (all had normal cone density and complete cone mosaics). Psychophysical results were modeled by a Monte Carlo simulation incorporating measured properties of the cone mosaic. RESULTS: Frequency-of-seeing curves for AOS1 obtained with 0.75' spots showed lower asymptote, slope, and sensitivity than for controls. The 7.5' results showed that these differences were the result of the small spot size, which on some trials was confined mostly to the locus of the putatively missing cones. A two-parameter model satisfactorily described the data and was highly sensitive to the proportion of missing cones simulated. CONCLUSIONS: Adaptive-optics microperimetry is a powerful psychophysical test for assessing the loss of neural elements, even in retinas that appear otherwise normal in standard clinical tests. This technique may prove useful in estimating the proportion of missing cones in different patients and in detecting other visual losses such as those associated with glaucoma.

False Positive Reactions↗
PubMed2005

Organization of the human trichromatic cone mosaic.

Using high-resolution adaptive-optics imaging combined with retinal densitometry, we characterized the arrangement of short- (S), middle- (M), and long- (L) wavelength-sensitive cones in eight human foveal mosaics. As suggested by previous studies, we found males with normal color vision that varied in the ratio of L to M cones (from 1.1:1 to 16.5:1). We also found a protan carrier with an even more extreme L:M ratio (0.37:1). All subjects had nearly identical S-cone densities, indicating independence of the developmental mechanism that governs the relative numerosity of L/M and S cones. L:M cone ratio estimates were correlated highly with those obtained in the same eyes using the flicker photometric electroretinogram (ERG), although the comparison indicates that the signal from each M cone makes a larger contribution to the ERG than each L cone. Although all subjects had highly disordered arrangements of L and M cones, three subjects showed evidence for departures from a strictly random rule for assigning the L and M cone photopigments. In two retinas, these departures corresponded to local clumping of cones of like type. In a third retina, the L:M cone ratio differed significantly at two retinal locations on opposite sides of the fovea. These results suggest that the assignment of L and M pigment, although highly irregular, is not a completely random process. Surprisingly, in the protan carrier, in which X-chromosome inactivation would favor L- or M-cone clumping, there was no evidence of clumping, perhaps as a result of cone migration during foveal development.

Color Perception↗
PubMed2005

The locus of fixation and the foveal cone mosaic.

High-resolution retinal imaging with adaptive optics was used to record the position of a light stimulus on the cone mosaic, with an error at least five times smaller than the diameter of the smallest foveal cones. We discuss the factors that limit the accuracy with which absolute retinal position can be determined. In five subjects, the standard deviation of fixation positions measured in discrete trials ranged from 2.1 to 6.3 arcmin, with an average of 3.4 arcmin (about 17 microm), in agreement with previous studies (R. W. Ditchburn, 1973; R. M. Steinman, G. M. Haddad, A. A. Skavenski, & D. Wyman, 1973). The center of fixation, based on the mean retinal position for each of three subjects, was displaced from the location of highest foveal cone density by an average of about 10 arcmin (about 50 microm), indicating that cone density alone does not drive the location on the retina selected for fixation. This method can be used in psychophysical studies or medical applications requiring submicron registration of stimuli with respect to the retina or in delivering light to retinal features as small as single cells.

Adult↗
PubMed2004

Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness.

There is enormous variation in the X-linked L/M (long/middle wavelength sensitive) gene array underlying "normal" color vision in humans. This variability has been shown to underlie individual variation in color matching behavior. Recently, red-green color blindness has also been shown to be associated with distinctly different genotypes. This has opened the possibility that there may be important phenotypic differences within classically defined groups of color blind individuals. Here, adaptive optics retinal imaging has revealed a mechanism for producing dichromatic color vision in which the expression of a mutant cone photopigment gene leads to the loss of the entire corresponding class of cone photoreceptor cells. Previously, the theory that common forms of inherited color blindness could be caused by the loss of photoreceptor cells had been discounted. We confirm that remarkably, this loss of one-third of the cones does not impair any aspect of vision other than color.

Adult↗
PubMed2002

Color perception is mediated by a plastic neural mechanism that is adjustable in adults.

An intensely debated issue concerning visual-experience-dependent neural plasticity is whether experience is required only to maintain function or whether information from experience is used actively, relieving the necessity to hard-wire all connections and allowing adaptive adjustments. Here, an active role for experience is demonstrated in circuits for color vision. Chromatic experience was altered using colored filters. Over days there was a shift in color perception, as measured by the wavelength of unique yellow, which persisted 1-2 weeks after the filters were discontinued. Moreover, color-deficient adults were shown to have altered weightings of inputs to chromatic channels, demonstrating a large neural adjustment to their inherited photopigment defect. Thus, a neural normalization mechanism for color perception, determined by visual experience, operates to compensate for large genetic differences in retinal architecture and for changes in chromatic environment.

Adaptation, Physiological↗
PubMed2002

Estimates of L:M cone ratio from ERG flicker photometry and genetics.

Estimates of L:M cone ratio for males with normal color vision were derived using the flicker-photometric electroretinogram (ERG). These were obtained by best fitting ERG spectral sensitivity functions to a weighted sum of long (L)- and middle (M)-wavelength-sensitive cone spectral absorption curves. Using the ERG, measurements can be made with extremely high precision, which leaves variation in the wavelength of maximal sensitivity (lambda(max)) of the cone photopigments as the major remaining source of inaccuracy in determining the ratio of cone contributions. Here that source of inaccuracy was largely eliminated through the use of individualized L-cone spectral absorption curves deduced from L-pigment gene sequences. The method was used on 62 normal males as part of an effort to obtain a true picture of how normal variations in L:M cone ratio are distributed. The percentage of L cones in the average eye was 65%L [where %L = 100 X L / (L+M)]. There were huge individual differences ranging from 28%-93%L, corresponding to more than a 30-fold range in L:M ratio (0.4-13). However, the most extreme values were relatively rare; 80% of the subjects fell within +/-15 %L of the mean, corresponding to a 4-fold range in L:M ratio (1-4). The method remedies major weaknesses inherent in earlier applications of flicker photometry to estimate cone ratio; however, it continues to depend on the assumption that the average L cone produces a response with an identical amplitude to that of the average M cone. A comparison of the ERG results with the distribution of cone ratios estimated from cone pigment messenger RNA in cadaver eyes indicates that the assumption generally holds true. However, there may be a small number of exceptions in which individuals have normally occurring (but relatively rare) amino acid substitutions in one of their pigments that significantly affect the physiology of the cone class containing that pigment, so as to reduce the amplitude of its contribution to the ERG. Consistent with this possibility, extreme cone contribution ratios were found to be associated with atypical L-pigment amino acid combinations.

Adolescent↗
PubMedDate not supplied

Variety of genotypes in males diagnosed as dichromatic on a conventional clinical anomaloscope.

The hypothesis that dichromatic behavior on a clinical anomaloscope can be explained by the complement and arrangement of the long- (L) and middle-wavelength (M) pigment genes was tested. It was predicted that dichromacy is associated with an X-chromosome pigment gene array capable of producing only a single functional pigment type. The simplest case of this is when deletion has left only a single X-chromosome pigment gene. The production of a single L or M pigment type can also result from rearrangements in which multiple genes remain. Often, only the two genes at the 5' end of the array are expressed; thus, dichromacy is also predicted to occur if one of these is defective or encodes a defective pigment, or if both of them encode pigments with identical spectral sensitivities. Subjects were 128 males who accepted the full range of admixtures of the two primary lights as matching the comparison light on a Neitz or Nagel anomaloscope. Strikingly, examination of the L and M pigment genes revealed a potential cause for a color-vision defect in all 128 dichromats. This indicates that the major component of color-vision deficiency could be attributed to alterations of the pigment genes or their regulatory regions in all cases, and the variety of gene arrangements associated with dichromacy is cataloged here. However, a fraction of the dichromats (17 out of 128; 13%) had genes predicted to encode pigments that would result in two populations of cones with different spectral sensitivities. Nine of the 17 were predicted to have two pigments with slightly different spectral peaks (usually < or = 2.5 nm) and eight had genes which specified pigments identical in peak absorption, but different in amino acid positions previously associated with optical density differences. In other subjects, reported previously, the same small spectral differences were associated with anomalous trichromacy rather than dichromacy. It appears that when the spectral difference specified by the genes is very small, the amount of residual red-green color vision measured varies; some individuals test as dichromats, others test as anomalous trichromats. The discrepancy is probably partly attributable to testing method differences and partly to a difference in performance not perception, but it seems there must also be cases in which other factors, for example, cone ratio, contribute to a person's ability to extract a color signal from a small spectral difference.

Amino Acid Sequence↗