Visually induced syncope:a nonepileptic manifestation of visual sensitivity?

Visual sensitivity, defined as the “susceptibility toward experiencing seizures, which are triggered by the physical characteristics of visual stimuli and not by their perceptual properties,”1 can manifest in the context of various forms of generalized or focal, idiopathic or symptomatic epilepsies.2 We report a patient with no family or personal history of epilepsy who presented episodes of loss of consciousness exclusively triggered by visual stimuli unrelated to their emotional content, in which we have documented EEG-EKG characteristics suggestive of a neurally mediated syncope.

Higher-order aberrations in amblyopia:an analysis of pre- and post-wavefront-guided laser refractive correction

For more than a century it has been known that the eye is not a perfect optical system, but rather a system that suffers from aberrations beyond conventional prescriptive descriptions of defocus and astigmatism. Whereas traditional refraction attempts to describe the error of the eye with only two parameters, namely sphere and cylinder, measurements of wavefront aberrations depict the optical error with many more parameters. What remains questionable is the impact these additional parameters have on visual function. Some authors have argued that higher-order aberrations have a considerable effect on visual function and in certain cases this effect is significant enough to induce amblyopia. This has been referred to as ‘higher-order aberration-associated amblyopia’. In such cases, correction of higher-order aberrations would not restore visual function. Others have reported that patients with binocular asymmetric aberrations display an associated unilateral decrease in visual acuity and, if the decline in acuity results from the aberrations alone, such subjects may have been erroneously diagnosed as amblyopes. In these cases, correction of higher-order aberrations would restore visual function. This refractive entity has been termed ‘aberropia’. In order to investigate these hypotheses, the distribution of higher-order aberrations in strabismic, anisometropic and idiopathic amblyopes, and in a group of visual normals, was analysed both before and after wavefront-guided laser refractive correction. The results show: (i) there is no significant asymmetry in higher-order aberrations between amblyopic and fixing eyes prior to laser refractive treatment; (ii) the mean magnitude of higher-order aberrations is similar within the amblyopic and visually normal populations; (iii) a significant improvement in visual acuity can be realised for adult amblyopic patients utilising wavefront-guided laser refractive surgery and a modest increase in contrast sensitivity was observed for the amblyopic eye of anisometropes following treatment (iv) an overall trend towards increased higher-order aberrations following wavefront-guided laser refractive treatment was observed for both visually normal and amblyopic eyes. In conclusion, while the data do not provide any direct evidence for the concepts of either ‘aberropia’ or ‘higher-order aberration-associated amblyopia’, it is clear that gains in visual acuity and contrast sensitivity may be realised following laser refractive treatment of the amblyopic adult eye. Possible mechanisms by which these gains are realised are discussed.

Defining response to anti-VEGF therapies in neovascular AMD

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient’s age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as ‘responder status’ after treatment for n-AMD, ‘tachyphylaxis’ and ‘recalcitrant’ n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

Misophonia:current perspectives

Misophonia is characterized by a negative reaction to a sound with a specific pattern and meaning to a given individual. In this paper, we review the clinical features of this relatively common yet underinvestigated condition, with focus on co-occurring neurodevelopmental disorders. Currently available data on the putative pathophysiology of the condition can inform our understanding and guide the diagnostic process and treatment approach. Tinnitus retraining therapy and cognitive behavior therapy have been proposed as the most effective treatment strategies for reducing symptoms; however, current treatment algorithms should be validated in large population studies. At the present stage, competing paradigms see misophonia as a physiological state potentially inducible in any subject, an idiopathic condition (which can present with comorbid psychiatric disorders), or a symptomatic manifestation of an underlying psychiatric disorder. Agreement on the use of standardized diagnostic criteria would be an important step forward in terms of both clinical practice and scientific inquiry. Areas for future research include phenomenology, epidemiology, modulating factors, neurophysiological underpinnings, and treatment trials.

The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction

PurposeTo develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication.MethodsA panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability.ResultsThis classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables.ConclusionsWe present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies.

Reply: 'Myopic foveoschisis: An ectatic retinopathy, not a schisis'

Full text: We thank Tsilimbaris et al1 for their comments on the appropriateness of the term ‘myopic foveoschisis’ to describe the condition that is characterized by the separation of neural retina layers associated with high myopia and posterior staphyloma. They have proposed the term ‘myopic ectatic retinopathy’ as a more literal and functionally more accurate descriptor of the condition to avoid the use of the word ‘schisis’, which may be misleading because it is also used to describe other conditions where there is separation of neural retina layers without the presence of staphyloma.2 Using the word ‘ectatic’ for this condition would imply that we are fairly certain about the pathogenesis and mechanistic factors that underlie its development and progression. However, this is not the case, unfortunately, as our review of the literature has shown. There are several theories ranging from vitreous traction to sclerosing changes of retinal vessels to progression of staphylomas as possible etiological factors. Therefore, it is likely to be multifactorial in nature—hence the success reported with different procedures that address either the vitreous traction factor using vitrectomy, peel plus tamponade or the scleral ectasia factor using posterior buckling techniques. In the absence of a good understanding of underlying pathogenesis, it is probably best to use purely descriptive names rather than mechanistic terms. The use of descriptive terms, even though similar, do not necessarily cause confusion as long as they are widely accepted as differentiating terminology, for example, postoperative pseudophakic cystoid macular edema (Irvine–Gass syndrome) vs cystoid macular edema associated with posterior uveitis in a phakic patient. The introduction of too many mechanistic or pathogenetic terms in the absence of clear understating of etiology can in fact cause more confusion, for example, serous chorioretinopathy vs central serous retinopathy vs serous choroidopathy. The confinement to broad descriptive terms can enhance communication and reduce confusion without committing to any presumption about etiology until it is better understood. This approach is probably best illustrated by the recent advances in the understanding of mactel21, a condition initially described and classified, using descriptive nomenclature, by Don Gass as bilateral, idiopathic acquired juxtafoveolar telangiectasis (Group2A) and as distinctly different from unilateral, congenital parafoveolar telangiectasis (Group 1A; Gass,3 pp 504–506 vs 127–128). Finally, it is worthy to note that for myopic foveoschisis associated with a staphyloma that is associated with outer layer macular detachment, Don Gass also descriptively included the additional observation (before the advent of OCT) that the retinal profile was concave rather than convex in shape, thereby differentiating it from rhegmatogenous detachments with recruitment of subretinal fluid that is associated with posteriorly located breaks and macular holes in myopic eyes. References 1.Tsilimbaris MK, Vavvas DG, Bechrakis NE. Myopic foveoschisis: an ectatic retinopathy, not aschisis. Eye 2016; 30: 328–329. 2.Powner MB, Gillies MC, Tretiach M, Scott A, Guymer RH, Hageman GS et al. Perifoveal müller cell depletion in a case of macular telangiectasia type 2. Ophthalmology 2010; 117(12): 2407–2416. 3.Gass DM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment, 4th edn. Mosby-Yearbook: St. Louis, 1997.

Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Background The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF. Methods Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro. Results A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization. Conclusions This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese.

El mirto, la rosa y el álamo : El simbolismo del escenario en Pervigilium Veneris

Pervigilium Veneris, datado entre los siglos II y IV d.C., de autor anónimo, es un poema dedicado a la primavera como estación de Venus, al amor y a la deidad que lo patrocina. Describe el ritual de vigilia nocturna destinado a reactualizar el origen del mundo y su regeneración periódica, marcada por el devenir de las estaciones. El poema, dividido en dos grandes partes -canto a la llegada de la primavera y epílogo personal del autor- presenta dos escenarios construidos con diversos símbolos vinculados con la vegetación. Entre uno y otro hay un continuum espacial vinculado con la renovación-procreación y con la muerte-esterilidad. La diferencia entre ambos radica en el tipo de vegetación que acompaña a cada situación: el mirto (myrteo) y la rosa (rosa) en el escenario que narra la llegada de Venus y el álamo (p?p?lus) en el que se refiere al mito de Procne y Tereo. En esta ponencia analizaremos el simbolismo de las plantas antes mencionadas y de los términos utilizados para referirse al bosque -nemus, lucus, saltus y silva-, a las flores -flos, papilla y gemma purpura- y aquellos términos que los acompañan. Partimos de la propuesta de Mircea Elíade para la interpretación del simbolismo religioso en el marco procedimental de la ciencia de las religiones. Entendemos por símbolo una ?cifra? que conforma un ?sistema? y cuyo valor está relacionado con la existencia humana y la cósmica. Intentaremos demostrar que los escenarios creados por los símbolos de la vegetación coinciden con el tono de cada parte del poema, festivo o melancólico, respectivamente.

"Ad nostram scientiam referatur": la supervisión administrativa imperial de la aplicación de las leyes durante la dinastía constantiniana

Constantino y sus sucesores, Constancio II, Constante y Juliano, expresaron su particular interés por supervisar la aplicación de determinadas leyes imperiales mediante el uso de la fórmula ad nostram scientiam referatur y de otras similares. Constantino fue el príncipe que la empleó con más frecuencia, especialmente durante el período de 313-324, exceptuando el intervalo de 315-316, cuando la confrontación con Licinio le obligó a renunciar a atender directamente las cuestiones administrativas. La progresiva disminución de la inclusión de estas cláusulas en los textos legales imperiales a partir de la unificación del Imperio en 324 se debe poner en relación con la aparición de los curiosi y luego de los agentes in rebus, como oficiales encargados de vigilar la observancia de las normas vigentes.

Hypoxia-induced DNA hypermethylation in human pulmonary fibroblasts is associated with Thy-1 promoter methylation and the development of a pro-fibrotic phenotype

BACKGROUND: Pulmonary fibrosis is a debilitating and lethal disease with no effective treatment options. Understanding the pathological processes at play will direct the application of novel therapeutic avenues. Hypoxia has been implicated in the pathogenesis of pulmonary fibrosis yet the precise mechanism by which it contributes to disease progression remains to be fully elucidated. It has been shown that chronic hypoxia can alter DNA methylation patterns in tumour-derived cell lines. This epigenetic alteration can induce changes in cellular phenotype with promoter methylation being associated with gene silencing. Of particular relevance to idiopathic pulmonary fibrosis (IPF) is the observation that Thy-1 promoter methylation is associated with a myofibroblast phenotype where loss of Thy-1 occurs alongside increased alpha smooth muscle actin (α-SMA) expression. The initial aim of this study was to determine whether hypoxia regulates DNA methylation in normal human lung fibroblasts (CCD19Lu). As it has been reported that hypoxia suppresses Thy-1 expression during lung development we also studied the effect of hypoxia on Thy-1 promoter methylation and gene expression.

METHODS: CCD19Lu were grown for up to 8 days in hypoxia and assessed for global changes in DNA methylation using flow cytometry. Real-time PCR was used to quantify expression of Thy-1, α-SMA, collagen I and III. Genomic DNA was bisulphite treated and methylation specific PCR (MSPCR) was used to examine the methylation status of the Thy-1 promoter.

RESULTS: Significant global hypermethylation was detected in hypoxic fibroblasts relative to normoxic controls and was accompanied by increased expression of myofibroblast markers. Thy-1 mRNA expression was suppressed in hypoxic cells, which was restored with the demethylating agent 5-aza-2'-deoxycytidine. MSPCR revealed that Thy-1 became methylated following fibroblast exposure to 1% O2.

CONCLUSION: These data suggest that global and gene-specific changes in DNA methylation may play an important role in fibroblast function in hypoxia.

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.

Role of Vascular Smooth Muscle Cell PiT-2 in Basal Ganglia Calcification

Thesis (Master's)--University of Washington, 2016-08

Évaluation du contrôle sensorimoteur chez les patients ayant une scoliose idiopathique de l'adolescent - Vers un biomarqueur des troubles sensorimoteur basé sur la stimulation vestibulaire galvanique

La scoliose est la pathologie déformante du rachis la plus courante de l’adolescence. Dans 80 % des cas, elle est idiopathique, signifiant qu’aucune cause n’a été associée. Les scolioses idiopathiques répondent à un modèle multifactoriel incluant des facteurs génétiques, environnementaux, neurologiques, hormonaux, biomécaniques et de croissance squelettique. Comme hypothèse neurologique, une anomalie vestibulaire provoquerait une asymétrie d’activation des voies vestibulospinales et des muscles paravertébraux commandés par cette voie, engendrant la déformation scoliotique. Certains modèles animaux permettent de reproduire ce mécanisme. De plus, des anomalies liées au système vestibulaire, comme des troubles de l’équilibre, sont observées chez les patients avec une scoliose. La stimulation vestibulaire galvanique permet d’explorer le contrôle sensorimoteur de l’équilibre puisqu’elle permet d’altérer les afférences vestibulaires. L’objectif de cette thèse est d’explorer le contrôle sensorimoteur en évaluant la réaction posturale provoquée par cette stimulation chez les patients et les participants contrôle. Dans la première étude, les patients sont plus déstabilisés que les contrôles et il n’y a pas de lien entre l’ampleur de l’instabilité et la sévérité de la scoliose. Dans la deuxième étude, à l’aide d’un modèle neuromécanique, un poids plus grand aux signaux vestibulaires a été attribué aux patients. Dans la troisième étude, un problème sensorimoteur est également observé chez les jeunes adultes ayant une scoliose, excluant ainsi que le problème soit dû à la maturation du système nerveux. Dans une étude subséquente, des patients opérés pour réduire leur déformation du rachis, montrent également une réaction posturale de plus grande amplitude à la stimulation comparativement à des participants contrôle. Ces résultats suggèrent que l’anomalie sensorimotrice ne serait pas secondaire à la déformation. Finalement, un algorithme a été développé pour identifier les patients ayant un problème sensorimoteur. Les patients montrant un contrôle sensorimoteur anormal ont également une réponse vestibulomotrice plus grande et attribuent plus de poids aux informations vestibulaires. Globalement, les résultats de cette thèse montrent qu’un déficit sensorimoteur expliquerait l’apparition de la scoliose mais pas sa progression. Le dysfonctionnement sensorimoteur n’est pas présent chez tous les patients. L’algorithme permettant une classification de la performance sensorimotrice pourrait être utile pour de futures études cliniques.

Visual results with the use of prismatic lenses in the treatment of congenital nystagmus: a clinical case

Purpose: It is important to establish a differential diagnosis between the different types of nystagmus, in order to give the appropriate clinical approach to every situation and to improve visual acuity. The nystagmus is normally blocked when the eyes are positioned in a particular way. This makes the child adopt a posture of ocular torticollis that reduces the nistagmiformes movements, improving the vision in this position. A way to promote the blocking of the nystagmic movements is by using prismatic lenses with opposite bases, to block or minimize the oscillatory movements. This results in a vision improvement and it reduces the anomalous head position. There is limited research on the visual results in children with nystagmus after using prisms with opposing bases. Our aim is to describe the impact on the visual acuity (VA ) of theprescription prism lenses in a nystagmus patient starting at 3 months of age. Methods: Case report on thirty month old caucasian male infant, with normal growth and development for their age, with an early onset of horizontal nystagmus at 3 months of age. Ophthalmic examination included slit lamp examination, fundus, refractive study, electrophysiological and magnetic resonance tests, measurement of VA over time with the Teller Acuity Cards (TAC ) in the distance agreed for the age. At age ten months, the mother noted a persistent turn to the right of the child’s head, which became increasingly more severe along the months. There’s no oscillopcia. At 24 months, an atropine refraction showed the following refractive error: 0D.: -1,50, OS: -0,50 and prismatic lens adapting OD 8 Δ nasal base and OE 8 Δ temporal base. Results: Thirty month old child, with adequate development for their age, with onset of idiopatic horizontal nystagmus, at 3 months of age. Normal ocular fundus and magnetic ressoance without alterations, sub-normal results in electrophysiological tests and VA with values below normal for age. At 6 months OD 20/300; OE 20/400; OU 20/300. At 9 months OD 20/250; OE 20/300; OU 20/150 (TAC a 38 cm). At 18 months OD 20/200; OE 20/100; OU 20/80 (TAC at 38 cm), when the head is turned to the right and the eyes in levoversão, the nystagmus decreases in a “neutral” area. At 24 month, with the prismatic glasses, OD 20/200 OE 20/100, OU20/80 (TAC at 54 cm, reference value is 20/30 – 20/100 para OU e 20/40 – 20/100 monocular), there was an increase in the visual acuity. The child did visual stimulation with multimedia devices and using glasses. After adaptation of prisms: at 30 months VA (with Cambridge cards) OD e OE = 6/18. The child improved the VA and reduced the anomalous head position. There is also improvement in mobility and fine motricity. Conclusion: Prisms with opposing bases., were used in the treatment of idiopathic nystagmus. Said prisms were adapted to reduce the skewed position of the head, and to improve VA and binocular function. Monitoring of visual acuity and visual stimulation was done using electronic devices. Following the use of prismatic, the patient improved significantly VA and the anomalous head position was reduced.

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.