Phenotypic variability related to dominant UCHL1 mutations: about three families with optic atrophy and ataxia.

INTRODUCTION: Ubiquitin C-terminal hydrolase L1 (UCHL1) has been associated with a severe, complex autosomal recessive spastic paraplegia (HSP79) [1] [2] [3] [4]. More recently, UCHL1 loss of function (LoF) variants have been associated to an autosomal dominant disease characterized by late-onset spastic ataxia, neuropathy, and frequent optic atrophy [5]. METHODS: Routine clinical care whole-genome (WGS) and exome (ES) sequencing. RESULTS: We present three families with autosomal dominant UCHL1-related disorder. The clinical phenotype mainly associated optic atrophy, mixed cerebellar and sensory ataxia, and possible hearing loss. We delineated two major phenotypes, even within the same family: (1) juvenile severe optic atrophy followed by a later-onset ataxia, or (2) late-onset ataxia with asymptomatic or mild optic atrophy. The families harboured three novel heterozygous variants in UCHL1: two loss of function (p.Lys115AsnfsTer40; c.171_174 + 7del11), and one missense (p.Asp176Asn) involving the catalytic site of the protein and potentially altering the adjacent splice site. DISCUSSION: We confirm the existence of dominantly inherited UCHL1 pathogenic variants. We describe a considerable intrafamilial phenotypic variability, with two main phenotypes. Optic atrophy was consistently present, but with varying degrees of severity. Neither delayed motor or intellectual development, nor dysmorphic features were part of the dominant phenotype in comparison with the autosomal recessive form. The molecular mechanism appears to be haploinsufficiency. UCHL1 monoallelic variants should therefore be considered in any case of early-onset optic atrophy or in late-onset complex ataxic syndrome with asymptomatic optic atrophy.

Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

[Hereditary optic neuropathies: from clinical signs to diagnosis]. / Les neuropathies optiques héréditaires: du signe clinique au diagnostic.

Inherited optic atrophy must be considered when working up any optic nerve involvement and any systemic disease with signs of optic atrophy, even with a negative family history. There are two classical forms: dominant optic atrophy, characterized by insidious, bilateral, slowly progressive visual loss and temporal disc pallor, and Leber's optic atrophy, characterized by acute loss of central vision followed by the same event in the fellow eye within a few weeks to months, with disc hyperemia in the acute phase. Family history is critical for diagnosis. In the absence of family history, the clinician must rule out an identifiable acquired cause, i.e. toxic, inflammatory, perinatal injury, traumatic or tumoral, with orbital and brain imaging (MRI). Recessive optic atrophies are more rare and more severe and occur as part of multisystemic disorders, particularly Wolfram syndrome (diabetes mellitus, diabetes insipidus, and hearing loss). Effective treatments are limited; alcohol and smoking should be avoided. A cyclosporine trial (taken immediately upon visual loss in the first eye) is in progress in Leber's optic atrophy to prevent involvement of the fellow eye.

[Screening for retinal detachment using wide-field retinal imaging]. / Dépistage du décollement de rétine par l'utilisation d'une imagerie panrétinienne.

PURPOSE: The wide-field retinal imaging device (200°) (P200 Optomap Plus, Optos, Edinburgh, Scotland, UK), using a scanning laser ophthalmoscope (SLO), makes it possible to visualize a wide retinal area including the retinal periphery. The present study was designed to evaluate the ability to detect peripheral rhegmatogenous lesions using SLO wide-field image reading. METHODS: Between 2 November 2007 and 30 April 2008, all patients presenting with a retinal detachment were prospectively enrolled. Retinal ophthalmoscopy and drawing of retinal detachment, breaks, and holes were performed by a single retinal surgeon. SLO imaging was performed by an orthoptist and image reading by a senior resident. The orthoptist and the resident were both unaware of the results of the clinical examination. The extension of the retinal detachment in clock hours as well as the number of breaks and holes were compared between the retinal drawing and the image reading results. RESULTS: During the study period, 6053 images were taken, in 56 eyes with retinal detachment documented. Retinal breaks and holes were detected in seven of 10 cases with SLO image reading, only those situated superiorly between 11 and 1 o'clock and inferiorly between 5 and 7 o'clock were missed. Retinal detachments (one situated superiorly and one situated inferiorly) were detected in nine of 10 cases. CONCLUSIONS: The sensitivity of retinal detachment detection with the wide-field imaging device appears to be satisfactory for screening purposes, although it cannot replace retinal ophthalmoscopy.

Ocular alterations in dogs naturally infected by Leishmania (Leishmania) chagasi

Ocular conditions, anti-Leishmania antibodies and total protein of the aqueous humor were studied in dogs naturally infected by Leishmania (Leishmania) chagasi. Fifty dogs were analyzed and assigned into two groups of 25 animals each. All animals were submitted to routine ophthalmic exam. Results showed that 76 percent of the affected animals presented ocular signs, being uveitis the predominant. The mean of total protein in the aqueous humor of animals with uveitis was higher (P<0.05) when compared to the mean of animals with other ocular signs or no clinical sign. The anti-Leishmania chagasi antibody values in plasma were superior to those found in the aqueous humor (P<0.05).

Estudaram-se as condições oculares, os anticorpos anti-Leishmania e os valores de proteína total no humor aquoso de cães infectados naturalmente por Leishmania (Leishmania) chagasi. Analisaram-se 50 cães, divididos em dois grupos de 25 animais. Todos os animais foram submetidos a exame oftálmico rotineiro. Os resultados mostraram que 76 por cento dos cães infectados apresentaram sinais oculares, sendo a uveíte a alteração predominante. A média de proteína total no humor aquoso dos animais com uveíte foi maior (P<0,05), que a dos animais com outros sinais oculares ou sem qualquer sinal. Os valores de anticorpos anti-L. chagasi obtidos no plasma foram estatisticamente superiores aos encontrados no humor aquoso (P<0,05).

[Transpupillary thermotherapy and age-related macular degeneration]. / Thermothérapie transpupillaire et dégénérescence maculaire liée à l'âge.

Transpupillary thermotherapy (TTT) has been proposed over the last a few years for the treatment of subfoveal occult choroidal neovessels resulting from age-related degeneration (AMD) when they are symptomatic and associated with exudation. Several pilot studies have shown how this technique can decrease or slow down the progression of exudation related to choroidal neovessels. Based on these pilot studies, a randomized study (TTT4CNV) is in progress to evaluate the efficacy of TTT. While the inclusion of the patients in this study has come to an end, the therapeutic context of AMD has recently been changed with a permit to market Visudyn for photodynamic therapy (PDT) for some types of subfoveal occult choroidal neovessels. Moreover, the clinical studies in progress on photodynamic therapy and antiangiogenic drugs now make it possible to consider combined treatments possibly including TTT. This paper aims to provide a report on the current place and potential of TTT within the therapeutics available or soon available for subfoveal occult choroidal neovessels of AMD.

[Intraocular lens implantation in the first year of life]. / Implantation chez l'enfant avant l'âge d'un an.

We evaluated 36 eyes in 23 infants between one and eleven months old who had primary posterior chamber intraocular lens implantation for congenital cataracts. All eyes had a capsulorhexis of anterior and posterior capsulae and anterior vitrectomy. In order to obtain an emmetropia at age 5 years, we chose a 35% undercorrection of lens power for infants less than six months old, and 25% for infants between seven and eleven months old. The average follow-up was 15.3 months. Nine eyes developed posterior synechiae and eight developed a posterior opacification. The average postoperative refraction was +5.81 dioptries at one month, +4.56 at four months, +1.5, at one year, and +0.19 at two years. There was a marked subjective visual improvement in 34 eyes.

[Vascular diseases of the retina]. / Affections vasculaires de la rétine.

Retinal venous occlusion are usually associated with hypertension and arteriosclerosis; visual loss can be mild or severe. Two complications are related with a poor visual outcome: macular oedema and severe retinal ischaemia. Retinal artery occlusion is responsible for a sudden visual loss, usually caused by embolism. In cases without early reperfusion, visual loss is irretrievable. Retinal vasculitides, characterized by inflammation of blood vessels, are isolated or associated with systemic diseases. Visual prognosis is usually poor, particularly in cases of vascular occlusions or retinal necrosis.

Imaging of chorioretinal anastomoses in vascularized retinal pigment epithelium detachments.

OBJECTIVE: To identify specific features of pigment epithelium detachments with limited hyperfluorescent lesions (hot spots). DESIGN: One hundred eighty-two consecutive patients (186 eyes) who had vascularized pigment epithelium detachments and recent onset of symptoms were examined with indocyanine green and fluorescein videoangiography using the scanning laser ophthalmoscope. The choroidal neovascularization complex and macular retinal vessels were studied. The natural history and the effect of laser treatment were evaluated. RESULTS: Fifty-four eyes had hot spots on indocyanine green angiography. In 50 of these 54 eyes, the video analysis showed an anastomosis of one or more retinal vessels, with the choroidal neovascularization within the hot spot. One or two retinal veins or arteries or both filled with both dyes and were seen to enter into the hot spot. Results of indocyanine green-guided photocoagulation of the hot spot in 28 eyes were disappointing. CONCLUSION: Continuous recording of the early phases of fluorescein and indocyanine green angiography allowed identification of chorioretinal anastomoses in vascularized pigment epithelium detachments with hot spots at an early exudative stage of age-related macular degeneration in 50 (26.8%) of 186 eyes. The poor outcome of laser photocoagulation could be related not only to the development of an overlying pigment epithelium detachment, but also to the retinal and choroidal vascularization of the lesion.

Evaluation of new benzoporphyrin derivatives with enhanced PDT efficacy.

A first report on the biological evaluation of a series of isomerically pure benzoporphyrin derivatives (cis- and trans-isomers) as methyl esters is described. In preliminary in vivo studies, the n-hexyl ether analogues of both cis- and trans-isomers of benzoporphyrin derivatives were found to be more active than the industrially prepared benzoporphyrin derivative, a mixture of monocarboxylic acids (BPDMA, Quadralogic Technologies, Vancouver). Further studies with 4-de-vinyl-4- (1-hexyloxyethyl) benzoporphyrin derivative showed that, like BPDMA, it had reduced residual skin phototoxicity compared in mice with Photofrin. The uptake and clearance characteristics of BPDMA were also compared with the 4-(1-hexyloxyethyl)-derivative by in vivo reflection spectroscopy.

[Effect of rheological factors on diabetic microangiopathies: is there an effective medical treatment for diabetic retinopathy?]. / Influence des facteurs rhéologiques sur la microangiopathie diabétique: existe t-il un traitement médical efficace de la rétinopathie diabétique?

Rheologic abnormalities, observed in type I and type II diabetes, have been implicated in the onset and progression of microangiopathy and of diabetic retinopathy. This theory of pathogenesis, proposed by Farhaeus in 1921, and developed by Little, takes into account complex abnormalities of blood viscosity, platelet and erythrocyte aggregation, fibrinolysis, coagulation and oxygen fixation by hemoglobin. The correction of these abnormalities might delay or prevent the onset or the progression of diabetic microangiopathy, most notably of retinopathy. No study, however, has demonstrated an therapeutic effect of molecules acting on the different rheologic factors. In contrast, strict long-term control of glycemia leads to a partial or complete correction of some of these rheologic abnormalities.

[Laser photocoagulation treatment of diabetic maculopathy]. / Traitement par photocoagulation au laser de la maculopathie diabétique.

Diabetic retinopathy is the main cause of decreased visual acuity in non-proliferative or proliferative diabetic retinopathy. The frequency of maculopathy rises with age and the duration of diabetes, and now represents the major therapeutic problem following the control of neovascular proliferation through pan-retinal photocoagulation. Oedematous maculopathy, focal or diffuse, and cystoid macular oedema are improved by laser photocoagulation, either focal or grid. Laser photocoagulation is not indicated for predominantly ischaemic maculopathy. The laser treatment should be carried out early in the stage of clinically significant oedema, and applied either focally or in a grid depending on the clinical and angiographic features of the diabetic maculopathy. If pan-retinal photocoagulation is also indicated it should be performed after the focal macular treatment. Laser treatment should always be accompanied by a general medical assessment, emphasising optimal glycemic control and control of associated risk factors, especially arterial hypertension.

Visual function and course of basal laminar drusen combined with vitelliform macular detachment.

Basal laminar drusen (BLD) are small round yellow drusen that are more easily visualised angiographically than biomicroscopically, with a 'stars in the sky' pattern. Patients with BLD are predisposed to macular vitelliform detachment. Little is known about the course of the disease, but the prognosis for retention of useful central vision for patients with BLD is thought to be better than for patients with typical drusen. A retrospective analysis of clinical and angiographic charts of 19 patients with BLD combined with a vitelliform macular detachment was performed to precisely describe their course. In addition, nine patients were re-examined to allow an analysis of their visual function--that is, central visual field, contrast sensitivity, and colour vision. Eyes without choroidal new vessels retained a fair visual acuity (mean final visual acuity 0.5; follow up 4 to 69 months, mean 24 months). In 11 of these eyes visual function assessment disclosed a reduction of contrast sensitivity in high and medium spatial frequencies in nine eyes (81%), a blue-yellow dyschromatopsia in nine eyes (81%), and a mild reduction of foveal threshold in seven eyes (63%). Choroidal neovascularisation (CNV) was observed in 12 eyes (31%) with a poor final outcome (mean final visual acuity 0.1). Two thirds of cases of CNV were observed at the time of presentation; thus this finding may be a bias of a referring centre. However, the high prevalence of CNV suggests the need for a close follow up of patients with BLD.

[Surgery of macular neovascular subretinal membranes]. / Chirurgie des membranes néovasculaires sous-rétiniennes maculaires.

Vitreoretinal surgical techniques were recently used to eradicate subfoveal choroidal neovascularization which is usually associated with a poor visual prognosis. A series of 102 patients who underwent this surgery with a small retinotomy was reviewed. There were 62 eyes with age-related macular degeneration, 35 eyes with presumed ocular histoplasmosis, and five eyes with other etiologies. Retinal pigment epithelium patches were associated in seven eyes. Significant improvement in vision was achieved in 33% of eyes with age-related macular degeneration. Final visual acuity was 20/200 or worse in 84% of eyes. Visual prognosis was unchanged in eyes with retinal epithelium patches. In presumed ocular histoplasmosis, response to surgery seemed better: visual improvement was achieved in 44% of eyes and final visual acuity was 20/70 or more in 33% of eyes. During a one year follow-up, recurrent choroidal neovascularization, macular pucker and retinal detachment were observed in 27%, 11% and 5.6% of eyes respectively. Long term follow-up and randomized clinical trials comparing laser and surgical treatments are required for evaluation of surgical removal. At present, surgical removal does not reduce rates of choroidal neovascularization recurrence.