ACO2 mutations: A novel phenotype associating severe optic atrophy and spastic paraplegia

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caractérisation génétique et phénotypique des déplétions de l'ADN mitochondrial

Les maladies mitochondriales forment le groupe le plus courant d'anomalies congénitales du métabolisme. Ces maladies représentent actuellement plus de 17% des consultations régulières de notre service de génétique médicale. Les déficits multiples de la chaîne respiratoire mitochondriale sont à l'origine d'un grand nombre de maladies mitochondriales. Ils se caractérisent par des atteintes multi-viscérales responsables la plupart du temps d'un décès précoce dans les premières années de vie des patients atteints par ce type de pathologie. Depuis une quinzaine d'années, notre laboratoire a recruté un très grand nombre de patients présentant un déficit multiple de la chaîne respiratoire (CR). En 2001, il a été mis en évidence qu'un tout nouveau type d'anomalie touchant l'ADN mitochondrial (ADNmt) pouvait être à l'origine de ces déficits multiples. Ces anomalies sont des modifications quantitatives de l'ADNmt connues sous le nom de déplétions de l'ADNmt. Le recrutement important de cas de déficits multiples et le faible rendement de diagnostic moléculaire établi nous a incité à considérer les déplétions de l'ADNmt comme origine potentielle de déficits multiples de la chaîne respiratoire. Le travail de recherche présenté dans ce manuscrit a eu pour objectif tout d'abord d'estimer l'incidence des déplétions de l'ADNmt dans notre cohorte de patients atteints de déficit multiple de la CR. Nous nous sommes ensuite attachés à définir les atteintes cliniques associées à ces déplétions de l'ADNmt. Enfin, l'étude des gènes connus de déplétion de l'ADNmt DGUOK, POLG1 et TK2 nous a permis de mieux caractériser ces patients. Par la suite, l'étude par cartographie génétique de nos familles consanguines avec déplétions de l'ADNmt et de mutation actuellement inconnue, nous a conduit à la première identification de mutations récessives dans le gène PEO1 responsables d'un syndrome hépatocérébral de déplétion de l'ADNmt. La dernière partie de ce manuscrit rapporte l'étude en cours de cartographie génétique et de séquençage de gènes candidats pour une famille consanguine présentant un autre type de syndrome hépatocérébral associé à un déficit multiple de la chaîne respiratoire. L'ensemble de ce travail a permis à notre laboratoire d'acquérir de meilleures connaissances de l'origine génétique des déficits multiples de la chaîne respiratoire associés à une déplétion de l'ADNmt et d'améliorer ainsi le conseil génétique d'une partie des maladies mitochondriales.Mitochondrial diseases are a common group of metabolism pathologies. Nowadays, they represent more than 17% of our clinical consultations. Multiple respiratory chain deficiency account for an important number of mitochondrial disease and are characterised by a multi-systemic organ involvement leading to early death. Since these last 15 years, we have recruited a large number of patients with multiple respiratory chain deficiency. In 2001, it has been shown that a mtDNA quantitative anomaly was at the origin of this defect also named mtDNA depletions. The large number of patients with multiple respiratory chain deficiency and the weak yield of molecular diagnosis prompt us to consider mtDNA depletion as a cause of multiple respiratory chain deficiency. The aim of this work was firstly to estimate the incidence of mtDNA depletion in our series of multiple respiratory chain cases. Then, we characterised the genetic and phenotypic features of mtDNA depletions. Finaly, the study of one family among our consanguineous and/or multiplex patients allowed us to identify a new gene responsible for mtDNA depletions associated with a hepatocerebral failure. This gene also named PEO1 encodes for the mitochondrial Twinkle helicase which has been ever known to cause adult onset PEO in a dominant transmission. Finally, we have studied another consanguineous family with multiple respiratory chain deficiency and hepatic failure. This work allowed us to improve the genetic counselling in our laboratory especially for all patients with multiple respiratory chain deficiency associated with a mtDNA depletion.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Optical Coherence Tomography: Imaging Mouse Retinal Ganglion Cells <em>In Vivo</em>

International audienceStructural changes in the retina are common manifestations of ophthalmic diseases. Optical coherence tomography (OCT) enables their identification in vivo-rapidly, repetitively, and at a high resolution. This protocol describes OCT imaging in the mouse retina as a powerful tool to study optic neuropathies (OPN). The OCT system is an interferometry-based, non-invasive alternative to common post mortem histological assays. It provides a fast and accurate assessment of retinal thickness, allowing the possibility to track changes, such as retinal thinning or thickening. We present the imaging process and analysis with the example of the Opa1delTTAG mouse line. Three types of scans are proposed, with two quantification methods: standard and homemade calipers. The latter is best for use on the peripapillary retina during radial scans; being more precise, is preferable for analyzing thinner structures. All approaches described here are designed for retinal ganglion cells (RGC) but are easily adaptable to other cell populations. In conclusion, OCT is efficient in mouse model phenotyping and has the potential to be used for the reliable evaluation of therapeutic interventions

Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy

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OPA1 gene therapy prevents retinal ganglion cell loss in a Dominant Optic Atrophy mouse model

Abstract Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable. Here, we tested the efficiency of gene therapy on a genetically-modified mouse model reproducing DOA vision loss. We performed intravitreal injections of an Adeno-Associated Virus carrying the human OPA1 cDNA under the control of the cytomegalovirus promotor. Our results provide the first evidence that gene therapy is efficient on a mouse model of DOA as the wild-type OPA1 expression is able to alleviate the OPA1-induced retinal ganglion cell degeneration, the hallmark of the disease. These results displayed encouraging effects of gene therapy for Dominant Optic Atrophy, fostering future investigations aiming at clinical trials in patients

Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!

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Optic neuropathy linked to ACAD9 pathogenic variants: a potentially riboflavin-responsive disorder?

International audienceMitochondrial complex I (CI) deficiencies (OMIM 252010) are the commonest inherited mitochondrial disorders in children. Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoenzyme involved chiefly in CI assembly and possibly in fatty acid oxidation. Biallelic pathogenic variants result in CI dysfunction, with a phenotype ranging from early onset and sometimes fatal mitochondrial encephalopathy with lactic acidosis to late-onset exercise intolerance. Cardiomyopathy is often associated. We report a patient with childhood-onset optic and peripheral neuropathy without cardiac involvement, related to CI deficiency. Genetic analysis revealed compound heterozygous pathogenic variants in ACAD9, expanding the clinical spectrum associated to ACAD9 mutations. Importantly, riboflavin treatment (15 mg/kg/day) improved long-distance visual acuity and demonstrated significant rescue of CI activity in vitro

SPACR Encoded by <i>IMPG1</i> Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium

Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1−/− mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1−/− mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants