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.

A novel nonsense variant in REEP6 is involved in a sporadic rod-cone dystrophy case.

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is the most common form of progressive inherited retinal disorders secondary to photoreceptor degeneration. It is a genetically heterogeneous disease characterized by night blindness, followed by visual field constriction and, in most severe cases, total blindness. The aim of our study was to identify the underlying gene defect leading to severe RCD in a 60-year-old woman. The patient's DNA was investigated by targeted next generation sequencing followed by whole exome sequencing. A novel nonsense variant, c.267G>A p.(Trp89*), was identified at a homozygous state in the proband in REEP6 gene, recently reported mutated in 7 unrelated families with RCD. Further functional studies will help to understand the physiopathology associated with REEP6 mutations that may be linked to a protein trafficking defect.

ARL2BP mutations account for 0.1% of autosomal recessive rod-cone dystrophies with the report of a novel splice variant.

We report a novel ARL2BP splice site mutation after whole-exome sequencing (WES) applied to a Moroccan family including two sisters affected with autosomal recessive rod-cone dystrophy (arRCD). Subsequent analysis of 844 index cases did not reveal further pathogenic chances in ARL2BP indicating that mutations in ARL2B are a rare cause of arRCD (about 0.1%) in a large cohort of French patients.

Multimodal imaging and functional correlations identify unusual cases of macular retinal pigment epithelium hypopigmentation occurring without functional loss.

PURPOSE: Patients with unusual macular retinal pigment epithelium (RPE) hypopigmentation are described and analyzed using retinal multimodal imaging. METHODS: We report three cases of patients with unilateral (2) or bilateral (1) macular lesions discovered incidentally on fundoscopy. A comprehensive ophthalmic examination including visual acuity, fundoscopy, spectral-domain optical coherence tomography (SD-OCT), short-wavelength light and near-infrared autofluorescence, fluorescein angiography, microperimetry, multifocal electroretinogram, adaptive optics (AO), and OCT-angiography (OCT-A) has been performed. RESULTS: Visual acuity was 20/20 in both eyes of all patients. The lesion appeared hyperautofluorescent on short-wavelength light and hypoautofluorescent on near-infrared light. Fluorescein angiography revealed a sharply demarcated macular hyperfluorescence without any leakage, suggesting a window defect. Interestingly, SD-OCT revealed only a choroidal hyperreflectivity in relation to the lesions without any abnormality of the outer retinal layers. Microperimetry was normal except for 1 patient with bilateral lesion and subtle decrease in macular sensitivity. Mf ERG was normal in all three patients. AO showed a well-preserved cone mosaic, suggesting that the abnormality was localized under the photoreceptor layers. OCT-A revealed hyperreflectivity just below the RPE layer, corresponding to the macular lesion observed on fundoscopy and the choroidal hyperreflectivity seen on SD-OCT. CONCLUSIONS: Macular RPE hypopigmentation should be considered in case of an isolated macular lesion without functional visual impairment or anatomical defect on SD-OCT.

Next-generation sequencing confirms the implication of SLC24A1 in autosomal-recessive congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous retinal disorder which represents rod photoreceptor dysfunction or signal transmission defect from photoreceptors to adjacent bipolar cells. Patients displaying photoreceptor dysfunction show a Riggs-electroretinogram (ERG) while patients with a signal transmission defect show a Schubert-Bornschein ERG. The latter group is subdivided into complete or incomplete (ic) CSNB. Only few CSNB cases with Riggs-ERG and only one family with a disease-causing variant in SLC24A1 have been reported. Whole-exome sequencing (WES) in a previously diagnosed icCSNB patient identified a homozygous nonsense variant in SLC24A1. Indeed, re-investigation of the clinical data corrected the diagnosis to Riggs-form of CSNB. Targeted next-generation sequencing (NGS) identified compound heterozygous deletions and a homozygous missense variant in SLC24A1 in two other patients, respectively. ERG abnormalities varied in these three cases but all patients had normal visual acuity, no myopia or nystagmus, unlike in Schubert-Bornschein-type of CSNB. This confirms that SLC24A1 defects lead to CSNB and outlines phenotype/genotype correlations in CSNB subtypes. In case of unclear clinical characteristics, NGS techniques are helpful to clarify the diagnosis.

[CRISPR/Cas9: From research to therapeutic application]. / CRISPR/Cas9 : de la recherche à l'application thérapeutique.

For several decades, genome engineering has raised interest among many researchers and physicians in the study of genetic disorders and their treatments. Compared to its predecessors, zinc-finger nucleases (ZFN) and transcription activator-like effectors (TALEN), clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) is currently the most efficient molecular tool for genome editing. This system, originally identified as a bacterial adaptive immune system, is capable of cutting and modifying any gene of a large number of living organisms. Numerous trials using this technology are being developed to provide effective treatment for several diseases, such as cancer, cardiovascular and ophthalmic disorders. In research, this technology is increasingly used for genetic disease modelling, providing meaningful models of relevant studies as well as a better understanding of underlying pathological mechanisms. Many molecular tools are now available to put this technique into practice in laboratories, and despite the technical and ethical issues raised by manipulation of the genome, CRIPSR/Cas9 offers a new breath of hope for therapeutic research around the world.

First identification of ITM2B interactome in the human retina.

Integral Membrane Protein 2 B (ITM2B) is a type II ubiquitous transmembrane protein which role remains unclear. ITM2B mutations have been associated with different disorders: mutations leading to longer mutant proteins have been reported in two distinct Alzheimer-like autosomal dominant disorders with early-onset progressive dementia and cerebellar ataxia. Both disorders share neurological features including severe cerebral amyloid angiopathy, non-neuritic plaques, and fibrillary tangles as in Alzheimer disease. Our group reported a missense mutation in ITM2B, in an unusual retinal dystrophy with no dementia. This finding suggests a specific role of ITM2B in the retina. As the identification of retinal-specific ITM2B partners could bring new insights into the cellular functions of ITM2B, we performed quantitative proteomics of ITM2B interactome of the human retina. Overall, 457 ITM2B partners were identified with 8 of them involved in visual transduction. In addition, bulk Gene Ontology analyses showed that many ITM2B partners are involved in several other biological functions, such as microtubule organization, protein translation and interestingly, mitochondrial homeostasis. These data represent the first report of the ITM2B interactome in the human retina and may serve as a valuable inventory of new potential ITM2B partners for future investigations of ITM2B physiological functions and dysfunctions.

[Variability of chloroquine and hydroxychloroquine retinopathy among various ethnicities]. / Différences ethniques parmi les patients souffrant de toxicité maculaire aux antipaludéens de synthèse.

INTRODUCTION: Current screening recommendations for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy are based on central 10°C static perimetry and a high-resolution SD-OCT with a special attention to the inferior part of the macula where the toxicity usually starts by ellipsoid zone disruption. However, Melles and Marmor, have recently shown a great variability in the topography of the initial toxicity observed among various ethnicities, which is important to keep in mind so as not to miss early toxicity in certain subgroups of patients. METHODS: Review of the literature. RESULTS: Ethnic differences have been shown regarding the topography of the initial retinal toxicity of CQ and HCQ, particularly between Caucasian and Asian subjects. In Caucasians, the first signs of toxicity are more often localized in the inferior para-foveal area associated with a decrease in retinal sensitivity in the upper 10°C visual field. However, in Asian subjects, the first signs of toxicity appear more pericentral (still inferior) with an extramacular pattern that could be missed by the usual 10°C visual field screening. DISCUSSION/CONCLUSION: The pathophysiology of these ethnic differences is unknown and may be due to distinct genetic predisposition to CQ and HCQ toxicity. Screening strategies should be adjusted to the ethnicity and performed in Asian subjects with larger visual fields (30°C), along with SD-OCT, looking for ellipsoid disruption≥8°C from the fovea. The recognition of this pericentral topography and an adjusted screening protocol should avoid late diagnosis in Asians treated with CQ and HCQ.

[Update on recommendations for screening for hydroxychloroquine retinopathy]. / Mise à jour des recommandations sur la toxicité rétinienne des antipaludéens de synthèse.

INTRODUCTION: Recommendations for screening for chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy have recently been changed by the American Academy of Ophthalmology, taking into account new published data on toxicity prevalence, risk factors, location of onset in the retina and the efficacy of screening tests. METHODS: Literature review. RESULTS AND DISCUSSION: The risk of developing CQ or HCQ retinopathy depends on the daily dose and duration of treatment. At recommended doses, the risk is<1 % at 5 years, <2 % at 10years but increases to about 20 % after 20years of treatment. The maximum recommended daily dose is 5.0mg/kg for HCQ and 2.3mg/kg for CQ. The two main risk factors are the daily dose and duration of treatment. The presence of kidney failure and treatment with tamoxifen are also significant risk factors. A baseline examination should be performed at the initiation of treatment to rule out pre-existing maculopathy. The screening is then annual and starts from the 5th year of treatment. The two tests recommended for screening are the automated visual field and spectral domain OCT. Multifocal ERG and autofluorescence fundus imaging are only carried out secondarily to confirm the pathology.

[Management of congenital microphthalmos and anophthalmos]. / Prise en charge des microphtalmies et anophtalmies congénitales.

PURPOSE: To better characterize congenital anophthalmos and microphthalmos in order to distinguish which patients need surgical treatment. MATERIALS AND METHODS: A retrospective study of 42 cases with congenital anophthalmos and microphthalmos over a 16 years period was performed. Seven anophthalmos, 20 microphthalmic globes with no associated colobomatous orbital cyst and 15 microphthalmic globes associated with colobomatous orbital cyst were observed. Complete history, pediatrical and ophthalmological examination, electrophysiological feature, oculo-cerebral imagery and karyotype on each of the patients were reviewed. RESULTS: Among all patients, lack of development of the lids was observed in 45% of cases. In our group of anophthalmos, 100% had micro-orbit. In our group of microphthalmic globes with no associated colobomatous orbital cyst, 30% had micro-orbit and in our group of microphthalmic globes associated with colobomatous orbital cyst, 6% had micro-orbit. 75% of patients had ocular anomalies and 39% had systemic anomalies, mostly on the face. Aetiology were found in 36% of cases. Visual evoked potentials and retinal electric feature were useful to better determine visual function. CONCLUSION: Expandable orbital prosthesis would appear to be the most effective therapy for certain cases of anophthalmos and microphthalmos with micro-orbit.