Irene Gottlob - Academia.edu (original) (raw)

Papers by Irene Gottlob

Research paper thumbnail of Evaluation of the Retinal Pigmented Epithelium Layer in Human Albinism

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Research paper thumbnail of Visual field deficits in albinism

Investigative Ophthalmology & Visual Science, Apr 30, 2014

Research paper thumbnail of Analysis of Iris Abnormalities in Albinism using Anterior Segment Optical Coherence Tomography

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Research paper thumbnail of Association Between Retinal Abnormalities Measured Using Oct And Null-region Characteristics In Albinism

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Research paper thumbnail of Comparison of Retinal and Optic Nerve Head Structure in Albinism Imaged Using OCT with the Post Orbital Visual Pathway Imaged using MRI

Investigative Ophthalmology & Visual Science, Apr 30, 2014

Research paper thumbnail of The Diagnostic Potential of Iris Anterior Segment Optical Coherence Tomography in Albinism

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Research paper thumbnail of Abnormal Optic Nerve Head Topography in Albinism Imaged Using High Resolution Spectral Domain-Optical Coherence Tomography

Investigative Ophthalmology & Visual Science, Jun 16, 2013

Research paper thumbnail of Retinal Layer Abnormalities as Biomarkers of Schizophrenia

Schizophrenia Bulletin, Dec 19, 2017

Schizophrenia is associated with several brain deficits, as well as visual processing deficits, b... more Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectraldomain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. Methods: A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Results: Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = −.54, P = .001) and outer nuclear layer thickness (R = −.47, P = .005). Conclusions: Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.

Research paper thumbnail of Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles

International Journal of Molecular Sciences

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation dis... more Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduce...

Research paper thumbnail of Abnormal foveal morphology in carriers of oculocutaneous albinism

British Journal of Ophthalmology

Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) ... more Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.MethodsHandheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.ResultsFoveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL th...

Research paper thumbnail of Comparison of retinal and cortical structures with visual fields in albinism

Investigative Ophthalmology & Visual Science, 2016

Research paper thumbnail of Discordant phenotypes in twins with infantile nystagmus

Scientific Reports, 2021

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN h... more Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and...

Research paper thumbnail of Prediction Of Visual Acuity In Albinism Based On Objective Measurements Of Sensory And Motor Function

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Normal and abnormal foveal development

British Journal of Ophthalmology, 2020

Normal foveal development begins in utero at midgestation with centrifugal displacement of inner ... more Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal ...

Research paper thumbnail of SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization

Human Molecular Genetics, 2020

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosoma... more Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development...

Research paper thumbnail of Reliability and Recommended Settings for Pediatric Circumpapillary Retinal Nerve Fiber Layer Imaging Using Hand-Held Optical Coherence Tomography

Translational Vision Science & Technology, 2020

FA. Reliability and recommended settings for pediatric circumpapillary retinal nerve fiber layer ... more FA. Reliability and recommended settings for pediatric circumpapillary retinal nerve fiber layer imaging using hand-held optical coherence tomography.

Research paper thumbnail of Detection and characterisation of optic nerve and retinal changes in primary congenital glaucoma using hand-held optical coherence tomography

BMJ Open Ophthalmology, 2019

ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina w... more ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina with hand-held optical coherence tomography (HH-OCT) without sedation or anaesthesia in primary congenital glaucoma (PCG), (2) the characteristics of ON changes in comparison with adult primary open-angle glaucoma (POAG) in comparison with matched controls, (3) the sensitivity and specificity of ON parameters for diagnosis, and (4) changes of foveal morphology.Methods and analysisHH-OCT (Envisu 2300; Leica Microsystems) was used to investigate ON and foveal morphology of 20 children with PCG (mean age 4.64±2.79) and 10 adult patients with POAG (mean age 66.8±6.94), and compared with age-matched, gender-matched and ethnicity-matched healthy controls without sedation or anaesthesia.ResultsHH-OCT yielded useful data in 20 out of 24 young children with PCG. Patients with PCG had significantly deeper cup changes than patients with POAG (vs respective age-matched controls, p=0.014). ON changes ...

Research paper thumbnail of Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus

Brain, 2019

Herein we present a consanguineous family with three children affected by foveal hypoplasia with ... more Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C4T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr À/À mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Research paper thumbnail of Retinal and optic nerve changes in microcephaly: An optical coherence tomography study

Neurology, Jan 11, 2018

To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a pros... more To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients wit...

Research paper thumbnail of Altered whole-brain connectivity in albinism

Human Brain Mapping, 2016

Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, wh... more Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, white matter and cortical abnormalities occur in albinism, including a greater decussation of nerve fibres at the optic chiasm, foveal hypoplasia and nystagmus. Despite this, visual perception is largely preserved. We proposed that this may be attributable to reorganisation among cerebral networks, including an increased interhemispheric connectivity of the primary visual areas. We applied a graph-theoretic model to explore brain connectivity networks derived from resting-state functional and diffusion-tensor magnetic resonance imaging data in 23 people with albinism and 20 controls. We tested for group differences in connectivity between primary visual areas and in summary network organisation descriptors. We supplemented our main findings with analyses of control regions, brain volumes and white matter microstructure. We found significant functional interhemispheric hyperconnectivity of the primary visual areas in the albinism group (p=0.012). Tests of interhemispheric connectivity based on the diffusion-tensor data showed no significant group difference (p=0.713). Second, we found that a range of functional whole-brain network metrics were abnormal in people with albinism, including the clustering coefficient (p=0.005), although this may have been driven partly by overall differences in connectivity, rather than reorganisation. Based on our results, we suggest that changes occur in albinism at the whole-brain level, and not just within the visual processing pathways. We propose that our findings may reflect compensatory adaptations to increased chiasmic decussation, foveal hypoplasia and nystagmus.

Research paper thumbnail of Evaluation of the Retinal Pigmented Epithelium Layer in Human Albinism

Investigative Ophthalmology & Visual Science, Apr 17, 2010

Research paper thumbnail of Visual field deficits in albinism

Investigative Ophthalmology & Visual Science, Apr 30, 2014

Research paper thumbnail of Analysis of Iris Abnormalities in Albinism using Anterior Segment Optical Coherence Tomography

Investigative Ophthalmology & Visual Science, Apr 22, 2011

Research paper thumbnail of Association Between Retinal Abnormalities Measured Using Oct And Null-region Characteristics In Albinism

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Research paper thumbnail of Comparison of Retinal and Optic Nerve Head Structure in Albinism Imaged Using OCT with the Post Orbital Visual Pathway Imaged using MRI

Investigative Ophthalmology & Visual Science, Apr 30, 2014

Research paper thumbnail of The Diagnostic Potential of Iris Anterior Segment Optical Coherence Tomography in Albinism

Investigative Ophthalmology & Visual Science, Mar 26, 2012

Research paper thumbnail of Abnormal Optic Nerve Head Topography in Albinism Imaged Using High Resolution Spectral Domain-Optical Coherence Tomography

Investigative Ophthalmology & Visual Science, Jun 16, 2013

Research paper thumbnail of Retinal Layer Abnormalities as Biomarkers of Schizophrenia

Schizophrenia Bulletin, Dec 19, 2017

Schizophrenia is associated with several brain deficits, as well as visual processing deficits, b... more Schizophrenia is associated with several brain deficits, as well as visual processing deficits, but clinically useful biomarkers are elusive. We hypothesized that retinal layer changes, noninvasively visualized using spectraldomain optical coherence tomography (SD-OCT), may represent a possible "window" to these abnormalities. Methods: A Leica EnvisuTM SD-OCT device was used to obtain high-resolution central foveal B-scans in both eyes of 35 patients with schizophrenia and 50 demographically matched controls. Manual retinal layer segmentation was performed to acquire individual and combined layer thickness measurements in 3 macular regions. Contrast sensitivity was measured at 3 spatial frequencies in a subgroup of each cohort. Differences were compared using adjusted linear models and significantly different layer measures in patients underwent Spearman Rank correlations with contrast sensitivity, quantified symptoms severity, disease duration, and antipsychotic medication dose. Results: Total retinal and photoreceptor complex thickness was reduced in all regions in patients (P < .0001). Segmentation revealed consistent thinning of the outer nuclear layer (P < .001) and inner segment layer (P < .05), as well as a pattern of parafoveal ganglion cell changes. Low spatial frequency contrast sensitivity was reduced in patients (P = .002) and correlated with temporal parafoveal ganglion cell complex thinning (R = .48, P = .01). Negative symptom severity was inversely correlated with foveal photoreceptor complex thickness (R = −.54, P = .001) and outer nuclear layer thickness (R = −.47, P = .005). Conclusions: Our novel findings demonstrate considerable retinal layer abnormalities in schizophrenia that are related to clinical features and visual function. With time, SD-OCT could provide easily-measurable biomarkers to facilitate clinical assessment and further our understanding of the disease.

Research paper thumbnail of Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles

International Journal of Molecular Sciences

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation dis... more Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduce...

Research paper thumbnail of Abnormal foveal morphology in carriers of oculocutaneous albinism

British Journal of Ophthalmology

Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) ... more Background/aimsTo investigate the foveal morphology in carriers of oculocutaneous albinism (OCA) using spectral domain optical coherence tomography (SD-OCT). A cross-sectional, observational study.MethodsHandheld SD-OCT (Envisu C2300) was used to acquire horizontal scans through the centre of the fovea in biological parents of patients with OCA (n=28; mean age±SD=40.43±8.07 years) and age-matched and ethnicity-matched controls (n=28; mean age±SD=38.04±10.27 years). Sequence analysis was performed for variants in known genes associated with OCA. Best-corrected visual acuity (BCVA), presence of foveal hypoplasia and grade, foveal, parafoveal and perifoveal thickness measurements of total retinal layers (TRL), inner retinal layers (IRL) and outer retinal layers (ORL) thickness were measured.ResultsFoveal hypoplasia was identified in 32.14% of OCA carriers; grade 1 in all cases. OCA carriers demonstrated significant thicker TRL thickness (median difference: 13.46 µm, p=0.009) and IRL th...

Research paper thumbnail of Comparison of retinal and cortical structures with visual fields in albinism

Investigative Ophthalmology & Visual Science, 2016

Research paper thumbnail of Discordant phenotypes in twins with infantile nystagmus

Scientific Reports, 2021

Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN h... more Infantile nystagmus (IN) may result from aetiologies including albinism and FRMD7 mutations. IN has low prevalence, and twins with IN are rare. Whilst discordant presentation has been previously reported for IN, we present for the first time the comprehensive assessment of diagnostically discordant monozygotic twins. From a cohort of over 2000 patients, we identified twins and triplets discordant for nystagmus. Using next-generation sequencing, high-resolution infra-red pupil tracking and optical coherence tomography, we characterised differences in genotype and phenotype. Monozygotic twins (n = 1), dizygotic twins (n = 3) and triplets (n = 1) were included. The monozygotic twins had concordant TYR variants. No causative variants were identified in the triplets. Dizygotic twins had discordant variants in TYR, OCA2 and FRMD7. One unaffected co-twin demonstrated sub-clinical nystagmus. Foveal hypoplasia (FH) was noted in four of five probands. Both co-twins of the monozygotic pair and...

Research paper thumbnail of Prediction Of Visual Acuity In Albinism Based On Objective Measurements Of Sensory And Motor Function

Investigative Ophthalmology & Visual Science, 2011

Research paper thumbnail of Normal and abnormal foveal development

British Journal of Ophthalmology, 2020

Normal foveal development begins in utero at midgestation with centrifugal displacement of inner ... more Normal foveal development begins in utero at midgestation with centrifugal displacement of inner retinal layers (IRLs) from the location of the incipient fovea. The outer retinal changes such as increase in cone cell bodies, cone elongation and packing mainly occur after birth and continue until 13 years of age. The maturity of the fovea can be assessed invivo using optical coherence tomography, which in normal development would show a well-developed foveal pit, extrusion of IRLs, thickened outer nuclear layer and long outer segments. Developmental abnormalities of various degrees can result in foveal hypoplasia (FH). This is a characteristic feature for example in albinism, aniridia, prematurity, foveal hypoplasia with optic nerve decussation defects with or without anterior segment dysgenesis without albinism (FHONDA) and optic nerve hypoplasia. In achromatopsia, there is disruption of the outer retinal layers with atypical FH. Similarly, in retinal dystrophies, there is abnormal ...

Research paper thumbnail of SLC38A8 mutations result in arrested retinal development with loss of cone photoreceptor specialization

Human Molecular Genetics, 2020

Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosoma... more Foveal hypoplasia, optic nerve decussation defects and anterior segment dysgenesis is an autosomal recessive disorder arising from SLC38A8 mutations. SLC38A8 is a putative glutamine transporter with strong expression within the photoreceptor layer in the retina. Previous studies have been limited due to lack of quantitative data on retinal development and nystagmus characteristics. In this multi-centre study, a custom-targeted next generation sequencing (NGS) gene panel was used to identify SLC38A8 mutations from a cohort of 511 nystagmus patients. We report 16 novel SLC38A8 mutations. The sixth transmembrane domain is most frequently disrupted by missense SLC38A8 mutations. Ninety percent of our cases were initially misdiagnosed as PAX6-related phenotype or ocular albinism prior to NGS. We characterized the retinal development in vivo in patients with SLC38A8 mutations using high-resolution optical coherence tomography. All patients had severe grades of arrested retinal development...

Research paper thumbnail of Reliability and Recommended Settings for Pediatric Circumpapillary Retinal Nerve Fiber Layer Imaging Using Hand-Held Optical Coherence Tomography

Translational Vision Science & Technology, 2020

FA. Reliability and recommended settings for pediatric circumpapillary retinal nerve fiber layer ... more FA. Reliability and recommended settings for pediatric circumpapillary retinal nerve fiber layer imaging using hand-held optical coherence tomography.

Research paper thumbnail of Detection and characterisation of optic nerve and retinal changes in primary congenital glaucoma using hand-held optical coherence tomography

BMJ Open Ophthalmology, 2019

ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina w... more ObjectiveTo investigate (1) the feasibility of scanning the optic nerve (ON) and central retina with hand-held optical coherence tomography (HH-OCT) without sedation or anaesthesia in primary congenital glaucoma (PCG), (2) the characteristics of ON changes in comparison with adult primary open-angle glaucoma (POAG) in comparison with matched controls, (3) the sensitivity and specificity of ON parameters for diagnosis, and (4) changes of foveal morphology.Methods and analysisHH-OCT (Envisu 2300; Leica Microsystems) was used to investigate ON and foveal morphology of 20 children with PCG (mean age 4.64±2.79) and 10 adult patients with POAG (mean age 66.8±6.94), and compared with age-matched, gender-matched and ethnicity-matched healthy controls without sedation or anaesthesia.ResultsHH-OCT yielded useful data in 20 out of 24 young children with PCG. Patients with PCG had significantly deeper cup changes than patients with POAG (vs respective age-matched controls, p=0.014). ON changes ...

Research paper thumbnail of Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus

Brain, 2019

Herein we present a consanguineous family with three children affected by foveal hypoplasia with ... more Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C4T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr À/À mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Research paper thumbnail of Retinal and optic nerve changes in microcephaly: An optical coherence tomography study

Neurology, Jan 11, 2018

To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a pros... more To investigate the morphology of the retina and optic nerve (ON) in microcephaly. This was a prospective case-control study including 27 patients with microcephaly and 27 healthy controls. All participants underwent ophthalmologic examination and handheld optical coherence tomography (OCT) of the macula and ON head. The thickness of individual retinal layers was quantified at the foveal center and the parafovea (1,000 μm nasal and temporal to the fovea). For the ON head, disc diameter, cup diameter, cup-to-disc ratio, cup depth, horizontal rim diameter, rim area, peripapillary retinal thickness, and retinal nerve fiber layer thickness were measured. Seventy-eight percent of patients had ophthalmologic abnormalities, mainly nystagmus (56%) and strabismus (52%). OCT abnormalities were found in 85% of patients. OCT revealed disruption of the ellipsoid zone, persistent inner retinal layers, and irregular foveal pits. Parafoveal retinal thickness was significantly reduced in patients wit...

Research paper thumbnail of Altered whole-brain connectivity in albinism

Human Brain Mapping, 2016

Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, wh... more Albinism is a group of congenital disorders of the melanin synthesis pathway. Multiple ocular, white matter and cortical abnormalities occur in albinism, including a greater decussation of nerve fibres at the optic chiasm, foveal hypoplasia and nystagmus. Despite this, visual perception is largely preserved. We proposed that this may be attributable to reorganisation among cerebral networks, including an increased interhemispheric connectivity of the primary visual areas. We applied a graph-theoretic model to explore brain connectivity networks derived from resting-state functional and diffusion-tensor magnetic resonance imaging data in 23 people with albinism and 20 controls. We tested for group differences in connectivity between primary visual areas and in summary network organisation descriptors. We supplemented our main findings with analyses of control regions, brain volumes and white matter microstructure. We found significant functional interhemispheric hyperconnectivity of the primary visual areas in the albinism group (p=0.012). Tests of interhemispheric connectivity based on the diffusion-tensor data showed no significant group difference (p=0.713). Second, we found that a range of functional whole-brain network metrics were abnormal in people with albinism, including the clustering coefficient (p=0.005), although this may have been driven partly by overall differences in connectivity, rather than reorganisation. Based on our results, we suggest that changes occur in albinism at the whole-brain level, and not just within the visual processing pathways. We propose that our findings may reflect compensatory adaptations to increased chiasmic decussation, foveal hypoplasia and nystagmus.