Genetic Landscape of Joubert syndrome in French Canadians

Le syndrome de Joubert est une maladie récessive caractérisée par une malformation congénitale distincte du tronc cérébral et du cervelet, associée à une anomalie des mouvements oculaires (apraxie oculomotrice), une respiration irrégulière, un retard de développement, et une ataxie à la démarche. Au cours de la dernière décennie, plus de 20 gènes responsables ont été identifiés, tous ayant un rôle important dans la structure et la fonction des cils primaires. Ainsi, le syndrome de Joubert est considéré une ciliopathie. Bien que le Syndrome de Joubert ait été décrit pour la première fois dans une famille canadienne-française en 1969, le(s) gène(s) causal demeurait inconnu dans presque tous les cas de syndrome de Joubert recensés en 2010 dans la population canadienne-française, soit début de mon projet doctoral. Nous avons identifié un total de 43 individus canadiens-français (35 familles) atteints du syndrome de Joubert. Il y avait un regroupement de familles dans la région du Bas-Saint-Laurent de la province de Québec, suggérant la présence d'un effet fondateur. L’objectif de ce projet était de caractériser la génétique du syndrome de Joubert dans la population canadienne-française. Notre hypothèse était qu’il existait un effet fondateur impliquant au moins un nouveau gène JBTS. Ainsi, dans un premier temps, nous avons utilisé une approche de cartographie par homozygotie. Cependant, nous n’avons pas identifié de région d’homozygotie partagée parmi les individus atteints, suggérant la présence d’une hétérogénéité génétique ou allélique. Nous avons donc utilisé le séquençage exomique chez nos patients, ce qui représente une approche plus puissante pour l’étude de conditions génétiquement hétérogènes. Nos travaux ont permis l’identification de deux nouveaux gènes responsables du syndrome de Joubert: C5orf42 et TMEM231. Bien que la localisation cellulaire et la fonction de C5orf42 soient inconnus au moment de cette découverte, nos résultats génétiques combinés avec des études ultérieures ont établi un rôle important de C5orf42 dans la structure et la fonction ciliaire, en particulier dans la zone de transition, qui est une zone de transition entre le cil et le reste de la cellule. TMEM231 avait déjà un rôle établi dans la zone de transition ciliaire et son interaction avec d’autres protéines impliquées dans le syndrome de Joubert était connu. Nos études ont également identifié des variants rares délétères chez un patient JBTS dans le gène ciliaire CEP104. Nous proposons donc CEP104 comme un gène candidat JBTS. Nous avons identifié des mutations causales dans 10 gènes, y compris des mutations dans CC2D2A dans 9 familles et NPHP1 dans 3 familles. Au total, nous avons identifié les mutations causales définitives chez 32 des 35 familles étudiées (91% des cas). Nous avons documenté un effet fondateur complexe dans la population canadienne-française avec de multiples mutations récurrentes dans quatre gènes différents (C5orf42, CC2D2A, TMEM231, NPHP1). Au début de ce projet de recherche, l’étiologie génétique était inconnue chez les 35 familles touchées du syndrome de Joubert. Maintenant, un diagnostique moléculaire définitif est identifié chez 32 familles, et probable chez les 3 autres. Nos travaux ont abouti à la caractérisation génétique du syndrome de Joubert dans la population canadienne-française grâce au séquençage exomique, et révèlent la présence d'un effet fondateur complexe avec une l'hétérogénéité allélique et intralocus importante. Ces découvertes ont éclairé la physiologie de cette maladie. Finalement, l’identification des gènes responsables ouvre de nouvelles perspectives diagnostiques ante-natales, et de conseils génétique, très précieuses pour les familles.

Strategies and biases in location memory in Williams syndrome

Individuals with Williams syndrome (WS) demonstrate impaired visuo-spatial abilities in comparison to their level of verbal ability. In particular, visuo-spatial construction is an area of relative weakness. It has been hypothesised that poor or atypical location coding abilities contribute strongly to the impaired abilities observed on construction and drawing tasks [Farran, E. K., & Jarrold, C. (2005). Evidence for unusual spatial location coding in Williams syndrome: An explanation for the local bias in visuo-spatial construction tasks? Brain and Cognition, 59, 159-172; Hoffman, J. E., Landau, B., & Pagani, B. (2003). Spatial breakdown in spatial construction: Evidence from eye fixations in children with Williams syndrome. Cognitive Psychology, 46, 260-301]. The current experiment investigated location memory in WS. Specifically, the precision of remembered locations was measured as well as the biases and strategies that were involved in remembering those locations. A developmental trajectory approach was employed; WS performance was assessed relative to the performance of typically developing (TD) children ranging from 4- to 8-year-old. Results showed differential strategy use in the WS and TD groups. WS performance was most similar to the level of a TD 4-year-old and was additionally impaired by the addition of physical category boundaries. Despite their low level of ability, the WS group produced a pattern of biases in performance which pointed towards evidence of a subdivision effect, as observed in TD older children and adults. In contrast, the TD children showed a different pattern of biases, which appears to be explained by a normalisation strategy. In summary, individuals with WS do not process locations in a typical manner. This may have a negative impact on their visuo-spatial construction and drawing abilities. (c) 2007 Elsevier Ltd. All rights reserved.

I see happy people: attention bias towards happy but not angry facial expressions in Williams syndrome

Introduction: Observations of behaviour and research using eye-tracking technology have shown that individuals with Williams syndrome (WS) pay an unusual amount of attention to other people’s faces. The present research examines whether this attention to faces is moderated by the valence of emotional expression. Method: Sixteen participants with WS aged between 13 and 29 years (Mean=19 years 9 months) completed a dot-probe task in which pairs of faces displaying happy, angry and neutral expressions were presented. The performance of the WS group was compared to two groups of typically developing control participants, individually matched to the participants in the WS group on either chronological age or mental age. General mental age was assessed in the WS group using the Woodcock Johnson Test of Cognitive Ability Revised (WJ-COG-R; Woodcock & Johnson, 1989; 1990). Results: Compared to both control groups, the WS group exhibited a greater attention bias for happy faces. In contrast, no between-group differences in bias for angry faces were obtained. Conclusions: The results are discussed in relation to recent neuroimaging findings and the hypersocial behaviour that is characteristic of the WS population.

Collagen dysplasia (cutaneous asthenia) in a cat

Hereditary collagen dysplasias comprise a complex group of connective-tissue disorders that result in the reduced tensile strength of affected tissues. These processes are called cutaneous asthenia in the skin of dogs and cats. We report here the case of a crossbred male cat, aged 6 months, that presented with two skin wounds in the region of the right thorax and right iliac tuberosity. The skin of these regions and of the animal's dorsum was hyperextensible, smooth to the touch, and easily torn with minor trauma. Microscopic examination of skin samples revealed reduced dermal connective tissue consisting of shortened and fragmented collagen fibers. Normal fibers were intermingled with altered fibers. Ultrastructural changes in collagen fibers included disorientation of fibrils within the same bundle, marked spacing differences, and variation in the diameter of transverse sections. The fibrils maintained the transverse striations characteristic of normal collagen.

Uveodermatologic syndrome in a Brazilian Fila dog

A 5-year-old Brazilian Fila dog was presented with a history of vision loss, alopecia, and generalized depigmentation of the skin and hair. Clinical examination confirmed generalized depigmentation and pyodermitis. on ophthalmic examination there was depigmentation at the eyelid mucocutaneous junction, associated with anterior uveitis, and bilateral posterior synechia at 360degrees. Both the complete blood count and skin scraping were normal. Skin biopsy showed histiocytary lichenoid interface dermatitis with an absence of pigment within the queratinocytes, and a moderate lymphomononuclear infiltrate and predominance of histiocytes in the papilar derma suggestive of uveodermatologic syndrome. Clinical management consisted of oral and topical administration of prednisone, associated with 1% indometacine eye drops. Methylprednisone was also used twice via the subconjunctival route, at an interval of 15 days. To prevent the development of secondary glaucoma due to posterior synechiae, dorzolamide and timolol eye drops were indicated. Both dermatologic and ophthalmic signs showed good improvement, vision was preserved, and some repigmentation of the skin and hair occurred.

Clinical manifestations and oral findings in fraser syndrome

This article is the first known case report of Fraser syndrome in the dental literature. Its purpose was to present the clinical manifestations, oral findings, and dental treatment of a 14-year, 10-month-old female patient. Fraser syndrome is a rare recessive autosomal genetic disorder characterized by multisystemic malformation, usually comprising cryptophthalmos, syndactyly, and renal defects. The child presented with: (1) hydrocephaly; (2) face asymmetry; (3) low-inserted ears; (4) flat nose bridge; (5) cryptophthalmos; (6) bilateral absence of eyeballs; (7) hypertelorism; (8) syndactyly on the left fingers and toes; (9) skeletal defects; and (10) lower limb asymmetry. The intraoral examination revealed: (1) complete primary denture; (2) malocclusion; (3) tooth crowding; (4) ogival palate; (5) normal labial frena; (6) absence of lingual frenum (not compromising the tongue movements); (7) parched lips; (8) supragingival calculus adhered to all tooth surfaces; and (9) moderate gingivitis. The dental treatment consisted of periodic monitoring of the patient's oral health status and supragingival scaling associated with topical applications of 0.12% chlorhexidine digluconate gel at 2-week intervals to reduce gingivitis.

Swimmer syndrome affecting an entire litter of kittens

Swimmer syndrome is a developmental abnormality characterized by a delay in the ability to walk and move about and is manifested in newborns between 15 and 20 days of age. These animals exhibit constant coxofemoral articulation abduction, and their pelvic limbs move caudally and laterally. This case reports a litter of three crossbreeds kittens (26 days old) with swimmer syndrome. Each animal was treated with physical therapy and shackle bandages that kept their pelvic limbs bent and close to the body. After seven days, all of the animals exhibited normal ambulation, indicating that this treatment had a curative effect on the kittens.

Risk factors for computer visual syndrome (CVS) among operators of two call centers in Sao Paulo, Brazil

The aims of this study were to investigate work conditions, to estimate the prevalence and to describe risk factors associated with Computer Vision Syndrome among two call centers' operators in Sao Paulo (n = 476). The methods include a quantitative cross-sectional observational study and an ergonomic work analysis, using work observation, interviews and questionnaires. The case definition was the presence of one or more specific ocular symptoms answered as always, often or sometimes. The multiple logistic regression model, were created using the stepwise forward likelihood method and remained the variables with levels below 5% (p < 0.05). The operators were mainly female and young (from 15 to 24 years old). The call center was opened 24 hours and the operators weekly hours were 36 hours with break time from 21 to 35 minutes per day. The symptoms reported were eye fatigue (73.9%), "weight" in the eyes (68.2%), "burning" eyes (54.6%), tearing (43.9%) and weakening of vision (43.5%). The prevalence of Computer Vision Syndrome was 54.6%. Associations verified were: being female (OR 2.6, 95% CI 1.6 to 4.1), lack of recognition at work (OR 1.4, 95% CI 1.1 to 1.8), organization of work in call center (OR 1.4, 95% CI 1.1 to 1.7) and high demand at work (OR 1.1, 95% CI 1.0 to 1.3). The organization and psychosocial factors at work should be included in prevention programs of visual syndrome among call centers' operators.

Ocular manifestations of Noonan syndrome

Purpose: To describe the ophthalmological characteristics in a group of Noonan syndrome patients with proven mutations in the PTPN11 gene. Methods: Thirty-five Noonan syndrome patients with PTPN11 gene mutations underwent ophthalmological exams, which consisted of external inspection, slit-lamp biomicroscopy examination and an ophthalmoscopic examination after instillation of 1.0% tropicamide or 1.0% cyclopentolate. Results: All 35 patients had at least one abnormality upon ophthalmological examination. The eyelid and external eye abnormalities were the prevailing features, followed by prominent corneal nerves on slit-lamp exam. Fundus changes were detected in 8% of the subjects, mainly associated with high myopia. No statistically significant differences were observed among the patients presenting specific mutations in the PTPN11 gene. Conclusions: The current study further supports the finding that ocular symptoms account for a large fraction of the clinical manifestations of NS. Additional characteristics are described here. The roles for the various mutations of PTPN11 in ocular development are yet to be established.

Expanding the differential diagnosis of inherited neuropathies with non-uniform conduction: Andermann syndrome

Uniform conduction slowing has been considered a characteristic of inherited demyelinating neuropathies. We present an 18-year-old girl, born from first cousins, that presented a late motor and psychological development, cerebellar ataxia, facial diplegia, abnormal eye movement, scoliosis, and corpus callosum agenesis, whose compound muscle action potentials were slowed and dispersed. A mutation was found on KCC3 gene, confirming Andermann syndrome, a disease that must be included in the differential diagnosis of inherited neuropathies with non-uniform conduction slowing.

Congenital Nystagmus eye movements analysis and oculomotor system models evaluation

The term Congenital Nystagmus (Early Onset Nystagmus or Infantile Nystagmus Syndrome) refers to a pathology characterised by an involuntary movement of the eyes, which often seriously reduces a subject’s vision. Congenital Nystagmus (CN) is a specific kind of nystagmus within the wider classification of infantile nystagmus, which can be best recognized and classified by means of a combination of clinical investigations and motility analysis; in some cases, eye movement recording and analysis are indispensable for diagnosis. However, interpretation of eye movement recordings still lacks of complete reliability; hence new analysis techniques and precise identification of concise parameters directly related to visual acuity are necessary to further support physicians’ decisions. To this aim, an index computed from eye movement recordings and related to the visual acuity of a subject is proposed in this thesis. This estimator is based on two parameters: the time spent by a subject effectively viewing a target (foveation time - Tf) and the standard deviation of eye position (SDp). Moreover, since previous studies have shown that visual acuity largely depends on SDp, a data collection pilot study was also conducted with the purpose of specifically identifying eventual slow rhythmic component in the eye position and to characterise in more detail the SDp. The results are presented in this thesis. In addition, some oculomotor system models are reviewed and a new approach to those models, i.e. the recovery of periodic orbits of the oculomotor system in patients with CN, is tested on real patients data. In conclusion, the results obtained within this research consent to completely and reliably characterise the slow rhythmic component sometimes present in eye position recordings of CN subjects and to better classify the different kinds of CN waveforms. Those findings can successfully support the clinicians in therapy planning and treatment outcome evaluation.

Analysis of cerebral and autonomic response to respiratory events in patients with Sleep Apnea Syndrome

The arousal scoring in Obstructive Sleep Apnea Syndrome (OSAS) is important to clarify the impact of the disease on sleep but the currently applied American Academy of Sleep Medicine (AASM) definition may underestimate the subtle alterations of sleep. The aims of the present study were to evaluate the impact of respiratory events on cortical and autonomic arousal response and to quantify the additional value of cyclic alternating pattern (CAP) and pulse wave amplitude (PWA) for a more accurate detection of respiratory events and sleep alterations in OSAS patients. A retrospective revision of 19 polysomnographic recordings of OSAS patients was carried out. Analysis was focused on quantification of apneas (AP), hypopneas (H) and flow limitation (FL) events, and on investigation of cerebral and autonomic activity. Only 41.1% of FL events analyzed in non rapid eye movement met the AASM rules for the definition of respiratory event-related arousal (RERA), while 75.5% of FL events ended with a CAP A phase. The dual response (EEG-PWA) was the most frequent response for all subtypes of respiratory event with a progressive reduction from AP to H and FL. 87.7% of respiratory events with EEG activation showed also a PWA drop and 53,4% of the respiratory events without EEG activation presented a PWA drop. The relationship between the respiratory events and the arousal response is more complex than that suggested by the international classification. In the estimation of the response to respiratory events, the CAP scoring and PWA analysis can offer more extensive information compared to the AASM rules. Our data confirm also that the application of PWA scoring improves the detection of respiratory events and could reduce the underestimation of OSAS severity compared to AASM arousal.

Ophthalmological findings in Joubert syndrome

Joubert syndrome (JS) is an autosomal-recessive inherited complex malformation of the midbrain-hindbrain. It has been associated with ocular and oculomotor abnormalities. The aim of our study was to extend the ophthalmic knowledge in JS and to add new findings.

Modified temporal approach for a rostro-temporal basal meningioma in a cat

An 11-year-old neutered female domestic shorthair indoor cat was presented to our hospital for treatment of a left-sided rostro-temporal basal meningioma. Focal seizures in the facial muscles had been observed sporadically for 1 year. Two weeks prior to presentation the cat had developed generalised seizures and was treated with symptomatic anticonvulsive treatment. Focal facial seizures, especially on the right side, persisted after medical therapy. From the computed tomography scan, a basal meningioma was suspected by the treating veterinarian. A left-sided suprazygomatical temporobasal approach to the zygomatic arch was chosen because it causes less soft tissue damage. After craniotomy, durotomy and gentle dorsal retraction of the left piriform lobe, the meningioma was removed. Postoperative magnetic resonance imaging confirmed complete excision of the tumour. One day after surgery the cat was alert and a left-sided facial nerve palsy was noticed. Otherwise the neurological examination was normal. Anticonvulsive and eye moistening therapy was continued for 3 months. Six months after surgery the cat was clinically normal without any recurrence of seizures.

Cutaneous lesions associated with dual infection caused by canine distemper virus and orthopoxvirus in a domestic cat.

BACKGROUND Within the context of an increased epidemiological pressure caused by canine distemper virus (CDV) in Switzerland together with a potential re-emergence of endemic pathogens such as orthopoxviruses (OPXV), dual infections are possible among susceptible species. OBJECTIVE To describe a case of concurrent CDV and OPXV infection in a cat. ANIMAL A 5-year-old, neutered male cat was presented with erythema, crusts and ulcerations around the left eye. High-grade pruritus and a severe conjunctivitis were also present. METHODS Formalin-fixed skin biopsy samples were obtained from lesional skin. Histopathology, CDV immunohistochemistry and CDV and OPXV RT-PCR were performed. RESULTS Histopathological examination showed severe epidermal necrosis extending to the follicular walls and a dermal infiltration, predominantly eosinophilic. Intranuclear and intracytoplasmic eosinophilic inclusion bodies were visible in the wall of affected hair follicles, with occasional formation of syncytia. The RT-PCR revealed the contextual presence of both CDV and OPXV. Scattered cells stained positive for CDV by immunohistochemistry. CONCLUSION AND DISCUSSION Dual infections with CDV and OPXV, although rare, may occur and represent additional differential diagnoses for ulcerative skin lesions in cats.