Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions.

Detailed functional and structural characterization of a macular lesion in a rhesus macaque.

PURPOSE: Animal models are powerful tools to broaden our understanding of disease mechanisms and to develop future treatment strategies. Here we present detailed structural and functional findings of a rhesus macaque suffering from a naturally occurring bilateral macular dystrophy (BMD), partial optic atrophy and corresponding reduction of central V1 signals in visual fMRI experiments when compared to data in a healthy macaque (CTRL) of similar age. METHODS: Retinal imaging included infrared and autofluorescence recordings, fluorescein and indocyanine green angiography and spectral domain optical coherence tomography (OCT) on the Spectralis HRA + OCT platform. Electroretinography included multifocal and Ganzfeld-ERG recordings. Animals were killed and eyes analyzed by immunohistochemistry. RESULTS: Angiography showed reduced macular vascularization with significantly larger foveal avascular zones (FAZ) in the affected animal (FAZBMD = 8.85 mm(2) vs. FAZCTRL = 0.32 mm(2)). OCT showed bilateral thinning of the macula within the FAZ (total retinal thickness, TRTBMD = 174 ± 9 µm) and partial optic nerve atrophy when compared to control (TRTCTRL = 303 ± 45 µm). Segmentation analysis revealed that inner retinal layers were primarily affected (inner retinal thickness, IRTBMD = 33 ± 9 µm vs. IRTCTRL = 143 ± 45 µm), while the outer retina essentially maintained its thickness (ORTBMD = 141 ± 7 µm vs. ORTCTRL = 160 ± 11 µm). Altered macular morphology corresponded to a preferential reduction of central signals in the multifocal electroretinography and to a specific attenuation of cone-derived responses in the Ganzfeld electroretinography, while rod function remained normal. CONCLUSION: We provided detailed characterization of a primate macular disorder. This study aims to stimulate awareness and further investigation in primates with macular disorders eventually leading to the identification of a primate animal model and facilitating the preclinical development of therapeutic strategies.

Neuropathology and craniofacial lesions of osteopetrotic Red Angus calves.

Inherited osteopetrosis was identified in cattle herds in Wyoming, Nebraska, and Missouri in 2008 to 2010. Ten affected Red Angus calves were examined to characterize lesions in brain, teeth, and skull. Six affected aborted or stillborn calves were homozygous for the recently characterized deletion mutation in SLC4A2. Four affected calves were heterozygous for the SLC4A2 mutation and survived 1 to 7 days after birth. Gross lesions were similar in all 10 calves. Brains were rectangular and dorsoventrally compressed, with concave depressions in the parietal cortex owing to thickened parietal bone. Cerebellar hemispheres were compressed with herniation of the cerebellar vermis into the foramen magnum. Moderate bilateral chromatolysis affected multiple cranial nerve nuclei and, in some calves, the red nucleus. There was loss of retinal ganglion cells with severe atrophy of optic nerves. Periventricular corpora amylacea were in the thalamus, caudate nucleus, and midbrain. Vessels and neuropil in the dorsomedial aspect of the thalamus were mineralized. Dysplastic change in premolar and molar teeth comprised intra-alveolar intermingling of dentin, enamel, cementum, and bone, contributing to dental ankylosis. Changes in the heads of osteopetrotic calves are similar to those in children with malignant forms of homozygous recessive osteopetrosis.

Blindness, optic atrophy and sinusitis in the horse.

OBJECTIVE: The case histories described each presented with a visual deficit, varying from permanent total blindness with ophthalmoscopic evidence of optic atrophy to variable and transient visual disturbances, including occasional blindness, but with absence of ophthalmoscopic or any other ocular abnormality. ANIMALS STUDIED: Three horses of widely different age and type, but all with an original history of upper respiratory tract infection. PROCEDURE: All three cases were examined by a specialist veterinary ophthalmologist. In addition, magnetic resonance imaging (MRI) and, where possible, postmortem and histopathological examinations were performed. RESULTS: The common factor to all three cases proved to be infection of the spheno-palatine sinuses with subsequent distension and compression of adjacent optic nerve(s) and optic chiasm. CONCLUSIONS: Specialist veterinary ophthalmological examination proved of extremely limited value. The importance of MRI (and CT) scans for accurate diagnosis, and therefore possible successful treatment, is emphasized. Our cases were compared with similar cases in man, where visual disturbances due to spheno-palatine sinus involvement are recognized, but rare, in similar situation.

Idiopathic bilateral optic atrophy in the rhesus macaque.

PURPOSE: To document the existence of idiopathic bilateral optic atrophy (BOA) in rhesus macaque monkeys and to characterize the structural and functional consequences of this condition. METHODS: In vivo assessment of retinal and optic nerve structure included fundus biomicroscopy and stereophotography. Functional analyses included transient pattern-reversal electroretinography (PERG) and full-field flash ERG, with both white flashes while dark adapted and red flashes on a blue background used to assess the photopic negative response (PhNR). Also measured were visual evoked cortical potentials (VEPs) and multifocal (mf)ERGs, with both a standard fast and slowed (7F) stimulation sequence. Post mortem histologic evaluation was performed on a subset of five animals with BOA and compared with data from 22 healthy normal animals. Blood tests, including vitamin E, B(12), folate, lead, and complete blood cell count with differential were obtained on the four animals that remained alive. RESULTS: Animals with BOA showed temporal pallor of the optic nerve head and thinning of the retinal nerve fiber layer (RNFL) between the temporal vascular arcades (i.e., of the papillomacular bundle). Severity of optic atrophy and RNFL loss varied between animals from mild to severe, but was similar in the two eyes of each animal. Functional changes included greater loss of the PERG N95, compared with the P50 component and substantial reduction of mfERG high-frequency components. The mfERG low-frequency components were slightly larger than normal. None of the full-field flash ERG amplitudes (a-wave, b-wave, oscillatory potentials, or PhNR) was significantly different from normal. There were no consistent abnormalities found in the results of any blood test. Histologic findings included axonal loss and gliosis limited to the temporal optic nerve, reduction of nuclei within the retinal ganglion cell layer, and thinning of the temporal retinal RNFL. CONCLUSIONS: The existence of BOA in nonhuman primates warrants caution on the part of investigators who use these animals in experimental models of ophthalmic disease.

Multifocal chorioretinal lesions in Borzoi dogs.

OBJECTIVES: To identify the prevalence of Borzoi chorioretinopathy in western Canada, characterize lesions with fluorescein angiography, determine if lesions were progressive, clarify the association of progressive retinal atrophy and investigate the etiology. MATERIALS AND METHODS: Serial ophthalmic examination, fundus photography, electroretinography, and fluorescein angiography were used to evaluate Borzoi dogs with lesions of Borzoi chorioretinopathy. Pedigree analysis and test breeding of two affected dogs were completed to determine the heritability of Borzoi chorioretinopathy. RESULTS: One hundred three Borzoi dogs were examined between 1998 and 2003. Focal, peripheral, tapetal, hyper-reflective and pigmented areas consistent with focal retinal degeneration and RPE pigmentation were identified in 12 dogs between 7 months and 7 years of age. Seven males and five female dogs were affected. Ophthalmoscopy and fundus photography over 5 years revealed individual lesions that did not progress or coalesce in 12 affected dogs. Electroretinography of affected and normal Borzoi dogs confirmed that retinal function was similar in normal and affected dogs up to 7 years of age. Fluorescein angiography was performed in three affected dogs and confirmed intact blood-ocular barriers, focal retinal pigment epithelium hypertrophy, and focal absence of choroiocapillaris corresponding to chronic, focal lesions. Pedigree analysis precluded simple dominant, X-linked dominant, or X-linked recessive inheritance. One male dog from the test-bred litter developed bilateral lesions at 14 months of age. Simple recessive, polygenetic, and acquired etiologies of these lesions cannot be ruled out at this time. CONCLUSIONS: Borzoi chorioretinopathy is an acquired condition that initially manifests as focal retinal edema and loss of choriocapillaris and tapetum. With time the retina degenerates becoming hyper-reflective and with RPE hyper-pigmentation and clumping within the borders of the tapetal lesions. Choriocapillaris remains hypofluorescent on fluorescein angiography. Progressive retinal atrophy was excluded as an etiology of multifocal chorioretinopathy in Borzois dogs. This condition is not inherited by simple autosomal dominant or sex-linked modes of inheritance.

Arsanilic acid-induced blindness in swine: electroretinographic and visually evoked responses.

Arsanilic acid (1,000 ppm) caused blindness in pigs within 25 to 30 days. The visually evoked response was "nonrecordable" in blind pigs, but was consistently recordable in normal pigs. The electroretinographic response was recordable in both normal and blind pigs, and significant differences were not apparent between results of tests of the 2 groups. Optic disk atrophy was noted ophthalmoscopically; lesions of the optic nerve are probably responsible for the nonrecordable visually evoked response.

Uniocular vascular occlusion in a paraplegic hybrid monkey. A clinicopathologic study.

One eye of a hybrid monkey showed ophthalmoscopic, fluorescein angiographic, and electroretinographic evidence of ophthalmic artery occlusive disease. Histopathologic examination of that eye revealed widespread atrophy of the choroid, retina and optic nerve. An associated paraplegia was presumed to be the result of vascular occlusive disease as well.