Tetsuhisa Hatase

Dominant Mutations in RP1L1 Are Responsible for Occult Macular Dystrophy

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

Clinical characteristics of occult macular dystrophy in family with mutation of RP1l1 gene.

Purpose: To report the clinical characteristics of occult macular dystrophy (OMD) in members of one family with a mutation of the RP1L1 gene. Methods: Fourteen members with a p.Arg45Trp mutation in the RP1L1 gene were examined. The visual acuity, visual fields, fundus photographs, fluorescein angiograms, full-field electroretinograms, multifocal electroretinograms, and optical coherence tomographic images were examined. The clinical symptoms and signs and course of the disease were documented. Results: All the members with the RP1L1 mutation except one woman had ocular symptoms and signs of OMD. The fundus was normal in all the patients during the entire follow-up period except in one patient with diabetic retinopathy. Optical coherence tomography detected the early morphologic abnormalities both in the photoreceptor inner/outer segment line and cone outer segment tip line. However, the multifocal electroretinograms were more reliable in detecting minimal macular dysfunction at an early stage of OMD. Conclusion: The abnormalities in the multifocal electroretinograms and optical coherence tomography observed in the OMD patients of different durations strongly support the contribution of RP1L1 mutation to the presence of this disease.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin‐4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia–neuron interaction in NMOsd.

Early morphological recovery of the optic chiasm is associated with excellent visual outcome in patients with compressive chiasmal syndrome caused by pituitary tumors.

Abstract Objectives: The study objectives are (1) to identify factors predicting the excellent visual recovery after transsphenoidal removal of pituitary tumors and (2) to describe the association of excellent visual recovery and early restoration of symmetry of the decompressed optic chiasm. Methods: Thirty-five patients with visual symptoms due to pituitary tumors underwent endoscopic endonasal surgery. All patients received perioperative diagnostic magnetic resonance (MR) imaging and ophthalmological assessments within 2 weeks before surgery, within 2 weeks after surgery, and 3 months or later after surgery. Preoperative best-corrected visual acuity (BCVA ≧ 20/20), degree of visual field deficit (VFD, less than half of VF), thickness of retinal nerve fiber layer (RNFL) measured by optical coherence tomography (OCT), and thickness of ganglion cell complex (GCC) measured by OCT were considered for statistical analysis as predictive factors of VF outcome. Multivariate logistic regression models were used in statistical evaluation of data. Results: In the multivariate analysis, RNFL (odds ratio  =  62·137, P < 0·001) and preoperative VFD (odds ratio  =  8·244, P < 0·02) proved to be effective as factors predicting sufficient VF recovery. Postoperative restoration of symmetry of the optic chiasm was related to sufficient VF recovery (P < 0·0001, Fisher’s exact test) and RNFL (P < 0·0001, Fisher’s exact test). Discussion: Early decompression is crucial for sufficient VF recovery, in particular, while RNFL preserves normal or borderline thickness and while VFD keeps within hemianopia. Morphological reversibility is associated with functional reversibility in the optic chiasm compressed by a pituitary tumor. In particular, early morphological recovery suggests functional recovery, which indicates neurocyte reserve in the compressed optic pathway with functional recovery.

Superior segmental optic nerve hypoplasia in youth.

PurposeThe clinical characteristics of superior segmental optic nerve hypoplasia (SSOH) in youth were investigated to help establish diagnostic criteria.MethodsEleven eyes of seven young patients (male/female ratio, 3/4; age, 15.1 ± 3.4 years) who had good visual acuity and inferior visual field defects (VFDs) were evaluated. Goldmann and Humphrey perimetries and optic disc morphology were analyzed, and the patients were prospectively followed for a long period.ResultsVisual field defects were wedge shaped and oriented to the blind spot, but discontinuous in mild cases. Nerve fiber layer defects (NFLDs) were consistent with the VFDs. The optic disc appearance was variable, with double ring signs in seven eyes, small discs in three eyes, and an incomplete topless disc in one eye. The mothers of none of the patients had gestational diabetes. Visual field defects did not progress during the prospective 8.3 ± 1.3 years follow-up.ConclusionsCharacteristic VFD patterns on Goldmann perimetry and corresponding NFLDs are important in the diagnosis of SSOH, but not optic disc morphology.

Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy

Purpose To report the clinical characteristics of asymptomatic cases with RP1L1 gene mutations in four families with occult macular dystrophy (OMD). Methods Four asymptomatic cases from four families were selected from a cohort of 40 subjects (16 families) with RP1L1 pathogenic variants. Clinical data of the four asymptomatic cases and three symptomatic patients in the same families were reviewed. The three asymptomatic cases did not have any visual symptoms in either eye, and one was unilaterally affected. Ophthalmologic examinations, including spectral-domain optical coherence tomography (OCT) were performed, and the morphologic characteristics of the photoreceptor layer of the asymptomatic cases were compared to those of the symptomatic patients within the same family. Results The OCT images demonstrated photoreceptor abnormalities in the parafoveal regions in all of the four asymptomatic cases (i.e., absence of the interdigitation zone and blurring of the ellipsoid zone). However, these microstructures were preserved at the foveal center. The longitudinal reflectivity profiles clearly identified this distinct pattern in the asymptomatic cases. In contrast, no distinct abnormalities were detected by other examinations including perimetry, fundus autofluorescence images, and multifocal electroretinograms (ERGs). Conclusions The sparing of the central foveal photoreceptor layer accounts for the well-preserved visual acuity in the asymptomatic patients. The sparing may represent either the initial phase of typical OMD or a subtype of macular lesion associated with OMD. It is necessary to examine asymptomatic subjects in families with OMD because some of them may progress to the typical phenotype of OMD.

Evaluation of the optic nerve complex in the orbit using coronal Fast Magnetic resonance Imaging

Recently available coronal fast magnetic resonance imaging (MRI) has very high spatial resolution with good contrast between the optic nerves and cerebrospinal fluid (CSF). The aim of this study was to evaluate the diagnostic value of coronal fast imaging in optic nerve diseases. Thirty-five patients with various Neuro-ophthalmic conditions including 9 with optic neuritis, 6 with optic atrophy, 5 with glaucoma, 4 with segmental optic nerve hypoplasia and 11 with other optic neuropathies including orbital apex syndrome were evaluated with the three-dimensional fast imaging employing steady-state acquisition (FIESTA) sequence in addition to standard MRI protocols. The optic nerve complexes were evaluated on coronal images of the orbits. Detailed demonstration of the optic nerve complex—the optic nerve, the perineural CSF space and dural sheath—could be readily obtained with FIESTA sequence. The acute phase of both optic neuritis and perineuritis showed enlargement of the perineural CSF space; the optic nerve was swollen in optic neuritis but not in perineuritis. Cases of optic atrophy and glaucoma showed perineural CSF space enlargement with normal optic sheath circumference and a thinner optic nerve, while optic nerve hypoplasia showed a smaller dural sheath circumference without perineural CSF space enlargement. In the cases of orbital apex syndrome optic nerve compression by the extraocular muscles was clearly shown. Coronal FIESTA imaging of the orbit is capable of delineating detailed structural changes in the optic nerve complex and is of diagnostic value for the differentiation of optic nerve diseases.