Novel ATF6 homozygous variant in a Chinese patient with achromatopsia.

BACKGROUND: ATF6-associated Achromatopsia (ACHM) is a rare autosomal recessive disorder characterized by reduction of visual acuity, photophobia, nystagmus, and poor color vision. METHODS: Detailed ophthalmological examinations were performed in a Chinese patient with ACHM. Whole exome sequencing and Sanger sequencing were performed to detect the disease-causing gene in the patient. RESULTS: A 6-year-old girl presented photophobia, low vision and reduced color discrimination. Small yellow lesion in the macula of both eyes was observed. FAF demonstrated hypofluorescence in the macular fovea. OCT images revealed interruption of ellipsoid and interdigitation zone in the foveal area and a loss of the foveal pit. ERG showed relatively normal rod responses and unrecordable cone responses. Sequencing result identified a novel splicing variant c.354 + 6T>C in the ATF6 gene (NM_007348.4). CONCLUSIONS: We reported detailed clinical features and genetic analysis of a new Chinese ATF6-associated patient with ACHM.

Clinicopathologic and trichoscopic features of keratosis follicularis spinulosa decalvans: A case series study.

Keratosis follicularis spinulosa decalvans (KFSD) is a rare X-linked hereditary disorder characterized by the triad of follicular hyperkeratosis-photophobia-alopecia. The clinical heterogeneity makes the diagnosis difficult. To investigate the clinicopathologic and trichoscopic features of KFSD and to further clarify the essential requisites for the diagnosis, we conducted a retrospective study of patients with KFSD. The clinical information, histologic features, and trichoscopic findings were evaluated. Eight patients were from seven separate families. Two females were mother and daughter from the same family and the other six patients were male and represented sporadic cases. The average age of onset of alopecia was 21.25 years. Involvement of the scalp hairs leading to progressive scarring alopecia on the midline of the scalp with variable degrees of inflammation was the pathognomonic feature. It typically began after puberty. Vellus hair-associated follicular hyperkeratosis affected all of the patients. However, photophobia was not a constant feature. Histopathologic examination revealed disorders of the hair follicle with an acute-chronic inflammatory response. Follicular changes including fused infundibulum, the protrusion of the outer root sheath into the follicular canal, and a dilatation of the follicles at the isthmus level caused by the occlusion of keratin were observed. The trichoscopic features included perifollicular scaling, tufted hairs, and loss of follicular openings. In conclusion, terminal hair involvement, either scalp hairs, eyebrows, or eyelashes, and the hyperkeratosis of the follicle of vellus hairs is the diagnostic basis of KFSD. We hypothesize that follicular changes in histopathology are the primary event that trigger variable inflammation and further follicular destruction.

Blepharospasm With Photophobia Secondary to Midbrain Tuberculoma and Thalamic Infarct.

INTRODUCTION: Blepharospasm is a type of focal dystonia and categorized into primary and secondary forms, based on whether or not a cause can be established. Secondary blepharospasm is uncommon and can be associated with underlying brain lesions. Photophobia is a prominent complaint in blepharospasm patients. We are reporting a case of secondary blepharospasm with photophobia in a patient who had underlying midbrain tuberculoma and thalamic infarcts. This type of presentation has not been reported to the best of our knowledge. CASE REPORT: A 26-year-old man presented to us with the complaint of increased blinking and involuntary closure of both eyes for 1 year. He had a past history of tubercular meningitis 16 years back when he presented with bilateral ptosis, left up gaze palsy and right hemiparesis suggestive of Weber syndrome. His magnetic resonance images of the brain were suggestive of multiple intracranial tuberculomas, thalamic infarcts, and noncommunicating hydrocephalus. Following treatment he recovered significantly with no residual neurological deficit except mild bilateral ptosis. His recent magnetic resonance images of the brain was suggestive of calcified granuloma in the midbrain and chronic left thalamic lacunar infarcts. He was treated with injection Onabotulinum toxin and his symptoms improved significantly. CONCLUSIONS: Our patient had tuberculoma in the midbrain and chronic infarcts in the thalamus, and both lesions may cause blepharospasm and photophobia independently, so it is difficult to ascertain the causative lesion in our patient. However, it is possible that these heterogenous lesions are all part of a single functionally connected brain network and further studies are required to confirm this hypothesis.

Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice.

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

A novel mutation in MBTPS2 causes ichthyosis follicularis, alopecia, and photophobia syndrome.

BACKGROUND: The ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is a rare X-linked genodermatosis characterized by noninflammatory spiny follicular hyperkeratosis, severe photophobia, and non-scarring alopecia with variable severities. IFAP syndrome results from mutations in the gene encoding the membrane-bound transcription factor peptidase, site 2 (MBTPS2). METHODS: We present an 11-year-old male with typical clinical features of IFAP syndrome, including diffuse follicular hyperkeratosis, alopecia, photophobia, psoriasiform plaques, short statue, nail dystrophy, mental retardation, and seizures. RESULTS: A novel missense mutation (NM_015884.4: c.1298T > C; NP_056968.1: p. L433P) in the membrane-bound transcription factor peptidase, site 2 gene (MBTPS2) was identified in our patient. The heterozygous MBTPS2 mutation was identified in his mother but not his father. CONCLUSION: This study demonstrated a novel MBTPS2 mutation in a patient with IFAP syndrome and thus expands the known MBPTS2 molecular repertoire.

Case Report: Ocular Gnathostomiasis in Venezuela Most Likely Acquired in Texas.

A 69-year-old male dentist in Caracas, Venezuela, was referred to our Cornea Clinic with a history of pain, photophobia, and blurred vision on his left eye. Routine biomicroscopic examination with a slit lamp showed a worm in the corneal stroma of his left eye. The worm was surgically removed and was identified morphologically as Gnathostoma binucleatum.

An item response theory based integrated model of headache, nausea, photophobia, and phonophobia in migraine patients.

This study developed an integrated model of severity scores of migraine headache and the incidence of nausea, photophobia, and phonophobia to predict the natural time course of migraine symptoms, which are likely to occur by a common disease progression mechanism. Data were acquired from two phase 3 clinical trials conducted during the development of eletriptan. Only the placebo arm was used for analysis. A conventional proportional odds model was compared with an item response theory (IRT) based approach. Results suggested that the IRT based approach led to a better model fit, successfully revealing the difference in relief rates among different symptoms, which was the fastest in phonophobia and the slowest in headache. Simulation with the developed model suggested that using headache scores at 4 h post-dose attained greatest statistical power, yielding sample size of 100 per arm given drug effect of 40%, as compared to that of 200 per arm when 2 h post-dose scores were used as in the original eletriptan protocol. This work demonstrated the usefulness of an IRT based model as applied to analyzing multidimensional migraine symptoms and designing clinical trials. Our model can be similarly applied to analyzing other multiple endpoints sharing a common underlying mechanism.

Retinal phenotypic characterization of patients with ABCA4 retinopathydue to the homozygous p.Ala1773Val mutation.

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient. Results: Best-corrected visual acuities ranged from 20/200 to 4/200. The median age of the patients at diagnosis was 23.3 years. The majority of the patients had photophobia and nyctalopia, and were classified as Fishman stage 4 (widespread choriocapillaris atrophy, resorption of flecks, and greatly reduced ERG amplitudes). An atypical retinal pigmentation pattern was observed in the patients, and the majority showed cone-rod dystrophy on full-field ERG. In vivo retinal microstructure assessment with OCT demonstrated central retinal thinning, variable loss of photoreceptors, and three different patterns of structural retinal degeneration. Two dissimilar patterns of abnormal autofluorescence were observed. No apparent age-related differences in the pattern of retinal degeneration were observed. Conclusions: The results indicate that this particular mutation in ABCA4 is associated with a severe retinal phenotype and thus, could be classified as null. Careful phenotyping of patients carrying specific mutations in ABCA4 is essential to enhance our understanding of disease expression linked to particular mutations and the resulting genotype-phenotype correlations.

Subbasal Nerve Plexus Changes in Chronic Migraine.

PURPOSE: Migraine is a multifactorial disorder that presents with unilateral headache and several sensory symptoms. Photophobia is one of the ophthalmic manifestations that cause significant morbidity. The trigeminal pathway that innervates the cornea in the form of afferents has been implicated in photophobia associated with chronic migraine. This study investigates changes in the corneal subbasal nerve plexus (SBNP) in chronic migraine patients with and without photophobia. METHODS: Thirty-six patients with migraine and photophobia (group 1), 24 patients with migraine without photophobia (group 2), and 24 age- and sex-matched controls (group 3) were studied. A detailed history analysis and ophthalmic evaluation were performed on all subjects. In vivo confocal microscopy (IVCM) with automated CCMetrics software was used to quantify changes in the SBNP in all 3 groups. Measured parameters were compared using analysis of variance. RESULTS: Analysis of corneal SBNP features revealed a significant decrease in the corneal nerve fiber length (14.76 ± 3.98 mm/mm), total branch density (43.37 ± 21.63 branch points/mm), nerve branch density (30.19 ± 15.76 number of branches/mm), and fiber area (0.005 ± 0.001 total nerve fiber area/mm) in patients of group 1 compared with group 2 (P < 0.05). CONCLUSIONS: Structural changes in nociceptive corneal axons in the SBNP of patients with migraine with photophobia lend further support to the hypothesis that the trigeminal system plays a critical role in the pathogenesis of ocular symptoms in migraine. Our observations demonstrate that SBNP changes on IVCM may serve as a potential imaging marker for ocular symptoms of chronic migraine, and this warrants further investigation.

Understanding the phenotypic similarities between IFAP and Olmsted syndrome from a molecular perspective: the interaction of MBTPS2 and TRPV3.

Ichthyosis Follicularis, Atrichia, and Photophobia (IFAP) is a severe rare genetic disorder caused by mutations in the gene encoding the Membrane-Bound Transcription Factor Peptidase, Site 2 (MBTPS2). Olmsted syndrome is another rare genetic disease with overlapping clinical features caused by mutations in the gene encoding the Transient Receptor Potential Cation Channel, subfamily V (TRPV3). Mutations in MBTPS2 have been recently reported in Olmsted syndrome, underscoring the overlap and the confusion in separating Olmsted from IFAP syndrome. We studied a Lebanese family with IFAP syndrome both, clinically and molecularly, and investigated whether there is a cross relation between TRPV3 and MBTPS2. We identified a recurrent mutation designated p.F475S in MBTPS2 in the affected individuals. This mutation was not found in 100 control individuals from the same population. We determined that TRPV3 regulatory region is a target for MBTPS2. In addition, there was an increased cell death in the cells transfected with the mutant versus the wild-type MBTPS2. In conclusion, we identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway.

Fine-tuning light sensitivity in the starry flounder (Platichthys stellatus) retina: Regional variation in photoreceptor cell morphology and opsin gene expression.

Vertebrate color vision relies on the differential expression of visual pigment proteins (opsins) in cone photoreceptors of the retina. The diversity of opsins and their retinal expression patterns appear greatest for animals that experience variable light habitats, as is the case with flatfishes. Yet, opsin repertoires and expression patterns in this group of fishes are poorly described. Here, we unveil the visual opsin expression patterns of juvenile starry flounder (Platichthys stellatus) and describe the localization of cone types, their visual pigments and opsin expression. Juvenile starry flounder express eight opsins (Rh1, Sws1, Sws2A1, Sws2A2, Sws2B, Rh2A1, Rh2A2, Lws) and possess a corresponding number of photoreceptor visual pigments, with peak absorbance ranging from 369 to 557 nm. Retinal (vitamin A1) was the only chromophore detected in the retina. Intraretinal variation in opsin abundance consisted of greater expression of both RH2, and lesser expression of SWS1 and both SWS2A, opsin transcripts in the dorsal compared to the ventral retina. Overall cone density was greater in the dorsal retina which was also characterized by a larger proportion of unequal double cones compared with the ventral retina. Together, our results suggest that large opsin repertoires serve to optimize visual function under variable light environments by differential expression of opsin subsets with retinal location.

An experimental study of the neurophysical mechanisms of photophobia induced by subarachnoid hemorrhage.

BACKGROUND: Photophobia is defined as a painful psychosomatic discomfort triggered by intense light flow through the pupils to the brain, but the exact mechanism through which photophobia is induced by subarachnoid hemorrhage (SAH) is not well understood. In this study, we aimed to investigate whether there was any relationship between the mydriasis induced by the degeneration of the ciliary ganglion (CG) and photophobia in instances of SAH. MATERIALS AND METHODS: Five of a total of 25 rabbits were used as the intact control group; five were used in the sham-operated control group; and the remaining 15 were used as the SAH group, which was created by injecting autologous blood into their cisterna magna. All animals were examined daily for 20days to evaluate their level of photophobia, after which their brains, CGs and superior cervical ganglia (SCGs) were extracted bilaterally. The densities of normal and degenerated neurons in these ganglia were examined by stereological methods. RESULTS: In SAH animals with a high photophobia score, the mean pupil diameter and density of degenerated neurons density in the CG were greater than in cases with a low photophobia score (p<0.05). Further analysis revealed that the increase in the density of degenerated neurons in the CG following SAH resulted in the paralysis of the parasympathetic pathway of the pupillary muscles and mydriasis, which facilitates the excessive transfer of light to the brain and photophobia. CONCLUSION: Our findings indicate that SAH results in a high density of degenerated neurons in the CG, which induces mydriasis and is an important factor in the onset of photophobia. This phenomenon is likely due to more light energy being transferred through mydriatic pupils to the brain, resulting in vasospasm of the supplying arteries.

Interictal photosensitivity associates with altered brain structure in patients with episodic migraine.

BACKGROUND: Migraine attacks manifest with hypersensitivities to light, sound, touch and odor. Some people with migraine have photosensitivity between migraine attacks, suggesting persistent alterations in the integrity of brain regions that process light. Although functional neuroimaging studies have shown visual stimulus induced "hyperactivation" of visual cortex regions in migraineurs between attacks, whether photosensitivity is associated with alterations in brain structure is unknown. METHODS: Levels of photosensitivity were evaluated using the Photosensitivity Assessment Questionnaire in 48 interictal migraineurs and 48 healthy controls. Vertex-by-vertex measurements of cortical thickness were assessed in 28 people with episodic migraine who had interictal photosensitivity (mean age = 35.0 years, SD = 12.1) and 20 episodic migraine patients without symptoms of interictal photosensitivity (mean age = 36.0 years, SD = 11.4) using a general linear model design. RESULTS: Migraineurs have greater levels of interictal photosensitivity relative to healthy controls. Relative to migraineurs without interictal photosensitivity, migraineurs with interictal photosensitivity have thicker cortex in several brain areas including the right lingual, isthmus cingulate and pericalcarine regions, and the left precentral, postcentral and supramarginal regions. CONCLUSION: Episodic migraineurs with interictal photosensitivity have greater cortical thickness in the right parietal-occipital and left fronto-parietal regions, suggesting that persistent light sensitivity is associated with underlying structural alterations.

Genetic association of complement component 2 polymorphism with systemic lupus erythematosus.

Complement component 2 (C2), an early member of the classical pathway, mainly participates in apoptotic cell clearance. We hypothesize that C2 polymorphism may confer genetic susceptibility to complement dysfunction in systemic lupus erythematosus (SLE). The major aim of our study was to investigate the clinical and serological associations of C2 variants in Chinese patients with SLE. The single-nucleotide polymorphism (rs2844455, G/A SNP) located in the intron region of C2 gene was genotyped by direct sequencing in 95 SLE patients and 95 matched normal control subjects. The gene expression profiles were generated by quantitative real-time polymerase chain reaction (PCR) and reverse transcription PCR. Our results showed that the AA genotype was observed more frequently in SLE patients than in normal control subjects (22.1% vs 9.5%, P < 0.05). The A allele was strongly associated with the occurrence of hair loss, photosensitivity and anti-cardiolipin antibodies; whereas, the G allele was associated with lower frequencies of these clinical presentations. Relative expression levels were significantly lower in patients with the AA genotype [median: 18.86, interquartile range (IQR) 11.36-22.43, P = 0.002] than in those with the GG genotype (35.76, IQR: 19.33-49.71). As expected, we confirmed the A allele as a risk factor for SLE development in a Chinese population, in contrast, the G allele might be a protective factor against the pathogenic autoantibody formation and cutaneous manifestations in SLE patients.

Photophobia and corneal crystal density in nephropathic cystinosis: an in vivo confocal microscopy and anterior-segment optical coherence tomography study.

PURPOSE: To analyze the correlation between photophobia and corneal crystal density in nephropathic cystinosis using in vivo confocal microscopy (IVCM) and anterior-segment optical coherence tomography (AS-OCT). METHODS: Forty eyes of 20 patients with nephropathic cystinosis aged 7 to 37 years were included in this study. Ophthalmologic investigations included clinician-assessed and self-assessed evaluations of photophobia, slit-lamp biomicroscopy analysis, the depth of crystal deposition (DCD) and the central corneal thickness (CCT) in the central cornea measured with AS-OCT, and IVCM analysis of the crystal density score (IVCM-CysS), inflammatory cell density (IVCM-inf), and nerve damage (IVCM-N). Age, sex, intraleukocyte cystine concentrations (ICC), and the need for renal transplantation were also recorded. RESULTS: The average subjective and objective photophobia scores were 2.10 ± 1.28 and 1.70 ± 1.41, respectively. Using AS-OCT, the average percentage of crystal infiltration (OCT-CysP) and was 49.56 ± 27.31% (range, 11.45%-95.81%). The mean IVCM-CysS was 8.84 ± 4.34, the mean density of inflammatory cells (IVCM-inf) was 178.28 ± 173.00 cells/mm2, and the mean IVCM-N score was 3.11 ± 2.11. Clinician- and self-assessed estimations of photophobia were correlated (R2 = 0.61). No significant correlation was observed between clinician- and self-assessed photophobia scores and ICC or sex. There were significant correlations between clinician- and self-assessed photophobia scores and age, OCT-CysP, IVCM-CysS, IVCM-inf, and IVCM-N. The IVCM-CysS was also correlated with OCT-CysP (R2 = 0.27), IVCM-inf (R2 = 0.37), and IVCM-N (R2 = 0.56). CONCLUSIONS: In vivo confocal microscopy and AS-OCT are reliable tools to quantify cystinosis corneal crystals. In patients with nephropathic cystinosis, the intensity of photophobia is associated with the density of crystals, infiltration of inflammatory cells, and nerve damage within the cornea.

First reported case of systemic envenoming by the Sri Lankan keelback (Balanophis ceylonensis).

Envenoming by colubrid snakes is rarely reported. However, some colubrid snakes (e.g. Rhabdophis tigrinus and Rhabdophis subminiatus) have caused severe systemic envenoming. We report here the first case of a bite with systemic envenoming by Balanophis ceylonensis, an opisthoglyphous natricine colubrid, in Sri Lanka. A 33-year-old healthy male field biologist was bitten while handling the snake for photography. Within 5 min of the bite on the dorsum of the right hand, he reported severe occipital headache, photophobia, chills and transient loss of consciousness. He vomited blood-stained gastric contents and bled from venepuncture sites. He had a markedly elevated INR and positive D-dimer test suggestive of significant coagulopathy that was treated with infusions of fresh frozen plasma. He recovered and left hospital after 96 h and subsequent investigations, including electroencephalogram, were normal. We conclude that B. ceylonensis should be regarded as a medically significant venomous snake. This case highlights the need for further studies of the oral secretions (venoms) of colubrid snakes.

Assessment of corneal alterations by confocal microscopy in vernal keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a bilateral chronic, seasonally exacerbated inflammation of the ocular surface that especially affects male children and young boys. AIM: To evaluate the corneal microscopic features of patients affected by VKC and to assess whether some corneal changes were associated with specific ocular symptoms and/or signs. METHODS: 20 children aged between 4 and 14 years were enrolled. All patients underwent corneal confocal microscopy by Confoscan CS3 (Nidek). 350 images of the central cornea of each eye were obtained with a ×40 noncontact lens 3,5 micron gap in automode. RESULTS: Some alterations of the sub-basal and stromal corneal nerves were detected. These alterations were more evident in patients with higher severity of photophobia. On the other hand, there were scarce other signs of the anterior segment of the eye. CONCLUSIONS: Our preliminary findings show that there is another group of patients affected by VKC, characterized by an intense photophobia caused by corneal damage and without other significant ocular alterations. Therefore confocal microscopy may be useful for an early identification of corneal alterations before the onset of severe ocular symptoms and to set an appropriate therapeutic management.

Hypothalamic and basal ganglia projections to the posterior thalamus: possible role in modulation of migraine headache and photophobia.

Migraine attacks are typically described as unilateral, throbbing pain that is usually accompanied by nausea, vomiting, and exaggerated sensitivities to light, noise and smell. The headache phase of a migraine attack is mediated by activation of the trigeminovascular pathway; a nociceptive pathway that originates in the meninges and carries pain signals through meningeal nociceptors to the spinal trigeminal nucleus and from there to the cortex through relay neurons in the thalamus. Recent studies in our lab have identified a population of trigeminovascular neurons in the posterior (Po) and lateral posterior (LP) thalamic nuclei that may be involved in the perception of whole-body allodynia (abnormal skin sensitivity) and photophobia (abnormal sensitivity to light) during migraine. The purpose of the current study was to identify sub-cortical areas that are in position to directly regulate the activity of these thalamic trigeminovascular neurons. Such process begins with anatomical mapping of neuronal projections to the posterior thalamus of the rat by performing discrete injections of the retrograde tracer Fluorogold into the Po/LP region. Such injections yielded retrogradely labeled neurons in the nucleus of the diagonal band of Broca, the dopaminergic cells group A11/A13, the ventromedial and ventral tuberomammillary nuclei of the hypothalamus. We also found that some of these neurons contain acetylcholine, dopamine, cholecystokinin and histamine, respectively. Accordingly, we speculate that these forebrain/hypothalamic projections to Po and LP may play a role in those migraine attacks triggered by disrupted sleep, skipping meals and emotional reactions.