Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Albinism describes a heterogeneous group of genetically determined disorders characterized by disrupted synthesis of melanin and a range of developmental ocular abnormalities. The main ocular features common to both oculocutaneous albinism (OCA), and ocular albinism (OA) include reduced visual acuity, refractive errors, foveal hypoplasia, congenital nystagmus, iris and fundus hypopigmentation and visual pathway misrouting, but clinical signs vary and there is phenotypic overlap with other pathologies. This study reviews the prevalence, genetics and ocular manifestations of OCA and OA, including abnormal development of the optic chiasm. The role of visual electrophysiology in the detection of chiasmal dysfunction and visual pathway misrouting is emphasized, highlighting how age-associated changes in visual evoked potential (VEP) test results must be considered to enable accurate diagnosis, and illustrated further by the inclusion of novel VEP data in genetically confirmed cases. Differential diagnosis is considered in the context of suspected retinal and other disorders, including rare syndromes that may masquerade as albinism.

To describe the trans-occipital asymmetries of pattern and flash visual evoked potentials (VEPs), in an infant with MRI findings of unilateral optic nerve aplasia and hemi-chiasm dysplasia.
A child with suspected left cystic microphthalmia, left microcornea, left unilateral optic nerve aplasia, and hemi-chiasm underwent a multi-channel VEP assessment with pattern reversal, pattern onset, and flash stimulation at the age of 16 weeks.
There was no VEP evidence of any post-retinal visual pathway activation from left eye with optic nerve aplasia. The VEP trans-occipital distribution from the functional right eye was skewed markedly across the midline, in keeping with significant misrouting of optic nerve fibres at the chiasm. This was supported by the anatomical trajectory of the optic chiasm and tracts seen on MRI.
This infant has chiasmal misrouting in association with unilateral optic nerve aplasia and unilateral microphthalmos. Chiasmal misrouting has not been found in patients with microphthalmos or anophthalmos, but has been reported after early eye loss in animal models. Our findings contribute to our understanding of the discrepancy between the visual pathway physiology of human unilateral microphthalmia and animal models.

An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, from protein synthesis in the endoplasmic reticulum to delivery to the PM, stressing the main repercussions of processing failures and their physiological consequences in pathologies, and we summarize the recent proposed therapeutic strategies to rescue misassembled proteins through different types of chaperones and/or small molecule drugs that safeguard protein quality control and regulate proteostasis.

The purpose of this study was to assess chiasmal misrouting in a cohort of children with albinism with no nystagmus using hemifield visual evoked potentials (VEP) measures.
METHODS: Monocular VEPs were recorded and analyzed from three electrodes (O1, Oz, and O2 referred to Fz) from 16 children with albinism without nystagmus. Pattern reversal (full field and hemifield stimulation), full field pattern appearance and flash stimuli were used to evoke VEPs for each eye.
RESULTS: The amplitude of the pattern reversal VEPs to stimulation of the hemifield corresponding to the crossing pathways were as expected significantly larger than those to the non-crossing in each eye ((right eye p = 0.000004), (left eye p = 0.001)). Pattern reversal VEPs recorded from the left hemisphere were also larger than those from the right and most evident when comparing the crossing pathways of each eye (p = 0.004).
CONCLUSIONS: This study has demonstrated electrophysiological differences in visual pathway function of the left and right hemisphere in subjects with albinism like that previously described in controls. Nasal field stimulation activated crossing and non-crossing pathways in patients with albinism and as a result, nasal hemifield VEPs in albinism are less lateralized compared to what is found in normal subjects.

Due to an increased crossing of the optic nerve fibers at the optic chiasm in albinism, the visual cortex receives largely monocular input from the contralateral eye. Here we investigated whether this obstruction of binocular integration at the cortical input stage also impacts on interocular information exchange at the high processing level of visual memory. Interocular transfer (IOT) of visual memory retrieval was tested psychophysically after monocular encoding in 8 albinotic participants and 24 healthy controls. The retrieval performance (hit rate, reaction time, d\') was determined when using the same or different eye at encoding. To assess the effect of reduced visual acuity (VA) on recognition, we simulated interocular acuity differences (IOA) in two healthy control groups (each n = 8), i.e., with large (VA: 0.89 vs. 0.12) and small simulated interocular difference (VA: 0.25 vs. 0.12), with the latter matched to that observed in the albinotic participants (VA: 0.20 vs. 0.15). A significant decrease in retrieval performance was observed in controls with simulated strongly reduced VA in one eye (p < 0.0001). For the other conditions and groups, including the albinotic participants, no dependence on VA and no significant difference between using the same or different eye was observed. This indicates interocular transfer and hence interocular information exchange in human albinism. These findings thus provide insights into the scope of plasticity of binocular information processing and inter-hemispherical information flow.

BACKGROUND: Conformational diseases are caused by structurally abnormal proteins that cannot fold properly and achieve their native conformation. Misfolded proteins frequently originate from genetic mutations that may lead to loss-of-function diseases involving a variety of structurally diverse proteins including enzymes, ion channels, and membrane receptors. Pharmacoperones are small molecules that cross the cell surface plasma membrane and reach their target proteins within the cell, serving as molecular scaffolds to stabilize the native conformation of misfolded or well-folded but destabilized proteins, to prevent their degradation and promote correct trafficking to their functional site of action. Because of their high specificity toward the target protein, pharmacoperones are currently the focus of intense investigation as therapy for several conformational diseases. Areas covered: This review summarizes data on the mechanisms leading to protein misfolding and the use of pharmacoperone drugs as an experimental approach to rescue function of distinct misfolded/misrouted proteins associated with a variety of diseases, such as lysosomal storage diseases, channelopathies, and G protein-coupled receptor misfolding diseases. Expert commentary: The fact that many misfolded proteins may retain function, offers a unique therapeutic opportunity to cure disease by directly correcting misrouting through administering pharmacoperone drugs thereby rescuing function of disease-causing, conformationally abnormal proteins.