Retinal projections in tyrosinase-negative albino cats

Journal ArticleRetinal projections were examined in two tyrosinase-negative albino cats using autoradiographic techniques. Cats from this colony have pink eyes; their retinal pigment epithelium, ciliary body, and iris epithelium are completely devoid of melanin pigment. Test breeding for five generations indicates that these cats are true albinos (cc). The most striking feature of the albino cats' visual pathways was a reduction in ipsilateral input which was more severe than that reported for Siamese cats. The only evidence of ipsilateral input to the laminated dorsal lateral geniculate nucleus of the albino was a small lateral normal segment and a small projection to the lateral portion of lamina C1. Ipsilateral projections to the medial interlaminar nucleus, retinal recipient zone of the pulvinar complex, ventral lateral geniculate nucleus, superior colliculus, and pretectum also were reduced. Ipsilateral projections to the suprachiasmatic nucleus appeared to be normal in the albino cats studied. Our findings indicate that, compared to the normal cat as well as to the tyrosine-positive Siamese cat, the tyrosinase-negative albino has reduced ipsilateral retinal projections. The albino cat is a model system analogous to tyrosinase-negative albinism found in mammals

Role of Melanin Pigment in Retina and Inner Ear

Melanin pigment is normally present in the outermost layer of the retina of the eye, the inner ear adjacent to capillaries in stria vascularis near hair cells, and vestibular organs. Significant reduction in melanin pigment in mammals is associated with embryonic miswiring and disruption of visual and auditory functions. The consequences for the visual system include abnormal development of the retina and misrouting of optic pathways into the brain impairing visual acuity, eye movement, and stereovision. Lack of melanin pigment in the inner ear is associated with greater susceptibility to noise damage and poorer localization of sound in space

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Multifocal Electroretinograms

The most important development in ERGs is the multifocal ERG (mfERG). Erich Sutter adapted the mathematical sequences called binary m-sequences creating a program that can extract hundreds of focal ERGs from a single electrical signal. This system allows assessment of ERG activity in small areas of retina. With this method one can record mfERGs from hundreds of retinal areas in a several minutes (Sutter, 2010). ERG electrodes are used to record ERGs from the cornea from a dilated eye. Small scotomas in retina can be mapped and degree of retinal dysfunction quantified.EXAMmultier

Visual Evoked Responses (Webvision)

WebVision: The terms visually evoked potential (VEP), visually evoked response (VER) and visually evoked cortical potential (VECP) are equivalent. They refer to electrical potentials, initiated by brief visual stimuli, which are recorded from the scalp overlying visual cortex, VEP waveforms are extracted from the electro-encephalogram (EEG) by signal averaging. VEPs are used primarily to measure the functional integrity of the visual pathways from retina via the optic nerves to the visual cortex of the brain. VEPs better quantify functional integrity of the optic pathways than scanning techniques such as magnetic resonance imaging (MRI). See Webvision for complete information: http://webvision.med.utah.edu/book/electrophysiology/visually-evoked-potentials

Not All That Flickers Is Snow

A woman presented with bilateral visual disturbances that had been diagnosed as visual snow. Dilated ophthalmic examination and multimodal imaging were strongly suggestive of birdshot chorioretinopathy, meriting initiation of systemic immunomodulatory therapy. Visual snow requires a thorough ophthalmologic exam to exclude other ocular diseases

The Electroretinogram and Electro-oculogram: Clinical Applications

The global or full-field electroretinogram (ERG) is a mass electrical response of the retina to photic stimulation. The ERG is a test used worldwide to assess the status of the retina in eye diseases in human patients and in laboratory animals used as models of retinal disease.EXAMer

The Multifocal Electroretinogram: Clinical Applications

The most important development in ERGs is the multifocal ERG (mfERG). Erich Sutter adapted the mathematical sequences called binary m-sequences creating a program that can extract hundreds of focal ERGs from a single electrical signal. This system allows assessment of ERG activity in small areas of retina. With this method one can record mfERGs from hundreds of retinal areas in a several minutes (Sutter, 2010). ERG electrodes are used to record ERGs from the cornea from a dilated eye. Small scotomas in retina can be mapped and degree of retinal dysfunction quantified. See Hood et al. (2012) for recommended ISCEV International Standard mfERG protocol.EXAMmultier