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1.
Biomed Res Int ; 2019: 8397521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828134

RESUMO

Retinal ganglion cell (RGC) death is the central and irreversible endpoint of optic neuropathies. Current management of optic neuropathies and glaucoma focuses on intraocular pressure-lowering treatment which is insufficient. As such, patients are effectively condemned to irreversible visual impairment. This review summarizes experimental treatments targeting RGCs over the last decade. In particular, we examine the various treatment modalities and determine their viability and limitations in translation to clinical practice. Experimental RGC treatment can be divided into (1) cell replacement therapy, (2) neuroprotection, and (3) gene therapy. For cell replacement therapy, difficulties remain in successfully integrating transplanted RGCs from various sources into the complex neural network of the human retina. However, there is significant potential for achieving full visual restoration with this technique. Neuroprotective strategies, in the form of pharmacological agents, nutritional supplementation, and neurotrophic factors, are viable strategies with encouraging results from preliminary noncomparative interventional case series. It is important to note, however, that most published studies are focused on glaucoma, with few treating optic neuropathies of other etiologies. Gene therapy, through the use of viral vectors, has shown promising results in clinical trials, particularly for diseases with specific genetic mutations like Leber's hereditary optic neuropathy. This treatment technique can be further extended to nonhereditary diseases, through transfer of genes promoting cell survival and neuroprotection. Crucially though, for gene therapy, teratogenicity remains a significant issue in translation to clinical practice.


Assuntos
Atrofia Óptica Hereditária de Leber/terapia , Doenças do Nervo Óptico/terapia , Células Ganglionares da Retina/transplante , Pesquisa Médica Translacional/tendências , Animais , Terapia Baseada em Transplante de Células e Tecidos/tendências , Modelos Animais de Doenças , Terapia Genética/tendências , Glaucoma/genética , Glaucoma/patologia , Glaucoma/terapia , Humanos , Fármacos Neuroprotetores/uso terapêutico , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Doenças do Nervo Óptico/genética , Doenças do Nervo Óptico/patologia , Retina/patologia , Células Ganglionares da Retina/patologia
2.
Adv Exp Med Biol ; 1185: 513-517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884663

RESUMO

Inherited retinal dystrophies (IRDs) are a broad group of neurodegenerative disorders associated with reduced or deteriorating visual system. In the retina, cells are under constant oxidative stress, leading to elevated reactive oxygen species (ROS) generation that induces mitochondrial dysfunction and alteration of the mitochondrial network. This mitochondrial dysfunction combined with mutations in mitochondrial DNA and nuclear genes makes photoreceptors and retinal ganglion cells more susceptible to cell death. In this minireview, we focus on mitochondrial dynamics and their contribution to neuronal degeneration underlying IRDs, with particular attention to Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA), and propose targeting cell resilience and mitochondrial dynamics modulators as potential therapeutic approaches for retinal disorders.


Assuntos
Mitocôndrias/fisiologia , Atrofia Óptica Autossômica Dominante/patologia , Atrofia Óptica Hereditária de Leber/patologia , Estresse Oxidativo , Retina/citologia , DNA Mitocondrial/genética , Humanos
3.
Cells ; 8(6)2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31234430

RESUMO

The mitochondrial genetic disorder, Leber's hereditary optic neuropathy (LHON), is caused by a mutation in MT-ND4 gene, encoding NADH dehydrogenase subunit 4. It leads to the progressive death of retinal ganglion cells (RGCs) and causes visual impairment or even blindness. However, the precise mechanisms of LHON disease penetrance and progression are not completely elucidated. Human-induced pluripotent stem cells (hiPSCs) offer unique opportunities to investigate disease-relevant phenotypes and regulatory mechanisms underlying LHON pathogenesis at the cellular level. In this study, we successfully generated RGCs by differentiation of LHON patient-specific hiPSCs. We modified the protocol of differentiation to obtain a more enriched population of single-cell RGCs for LHON study. Based on assessing morphology, expression of specific markers and electrophysiological activity, we found that LHON-specific hiPSC-derived were more defective in comparison with normal wild-type RGCs. Based on our previous study, whereby by using microarray analysis we identified that the components of glutamatergic synapse signaling pathway were significantly downregulated in LHON-specific RGCs, we focused our study on glutamate-associated α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors. We found that the protein expression levels of the subunits of the AMPA receptor, GluR1 and GluR2, and their associated scaffold proteins were decreased in LHON-RGCs. By performing the co-immunoprecipitation assay, we found several differences in the efficiencies of interaction between AMPA subunits and scaffold proteins between normal and LHON-specific RGCs.


Assuntos
Ácido Glutâmico/farmacologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Atrofia Óptica Hereditária de Leber/metabolismo , Atrofia Óptica Hereditária de Leber/patologia , Receptores de AMPA/metabolismo , Células Ganglionares da Retina/metabolismo , Transdução de Sinais , Sequência de Bases , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Células Ganglionares da Retina/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/metabolismo
4.
J Mol Neurosci ; 68(4): 640-646, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31077085

RESUMO

Autosomal recessive optic neuropathies (IONs) are extremely rare disorders affecting retinal ganglion cells and the nervous system. RTN4IP1 has recently been identified as the third known gene associated with the autosomal recessive ION optic atrophy 10 (OPA10). Patients with RTN4IP1 mutations show early-onset optic neuropathy that can be followed by additional neurological symptoms such as seizures, ataxia, mental retardation, or even severe encephalopathy. Here, we report two siblings from a Chinese family who presented with early-onset optic neuropathy, epilepsy, and mild intellectual disability. Using whole exome sequencing combined with Sanger sequencing, we identified novel compound heterozygous RTN4IP1 mutations (c.646G > A, p.G216R and c.1162C > T, p.R388X) which both co-segregated with the disease phenotype and were predicted to be disease-causing by prediction software. An in vitro functional study in urine cells obtained from one of the patients revealed low expression of the RTN4IP1 protein. Our results identify novel compound heterozygous mutations in RTN4IP1 which are associated with OPA10, highlighting the frequency of RTN4IP1 mutations in human autosomal recessive IONs. To our knowledge, this is the first report of RTN4IP1 carriers from China.


Assuntos
Proteínas de Transporte/genética , Proteínas Mitocondriais/genética , Atrofia Óptica Hereditária de Leber/genética , Proteínas de Transporte/metabolismo , Criança , Feminino , Heterozigoto , Humanos , Proteínas Mitocondriais/metabolismo , Mutação , Atrofia Óptica Hereditária de Leber/patologia , Sequenciamento Completo do Exoma
5.
J Neurol ; 266(6): 1474-1480, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30911824

RESUMO

OBJECTIVE: Subclinical abnormalities, including microangiopathy, swelling of nerve fibers, visual field abnormalities and visual functional impairments had been reported in Leber's hereditary optic neuropathy (LHON) carriers. The purpose of this study was to investigate microstructural changes of brain white matter in asymptomatic LHON carriers using DTI and tract-based spatial statistics (TBSS). METHODS: DTI and neuro-ophthalmologic measurements were acquired in 14 LHON carriers and 15 gender- and age-matched healthy controls, and diffusion metrics, including fractional anisotropy (FA), axial (AD), radial diffusion (RD) and mean diffusion (MD) were calculated. Intergroup differences in diffusion metrics were compared regressing out potential nuisance covariates of age and gender. A correlation analysis was performed to test associations between abnormal neuro-ophthalmologic measures and diffusion metrics while controlling the effects of age and gender. RESULTS: Compared to healthy controls, LHON carriers showed a weak increase of thickness of the retinal nerve fiber layer (RNFL) of the right inferior quadrant (F = 5.22, p = 0.032, before multiple comparison correction). LHON carriers exhibited widespread decreased FA value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, major and minor forceps, bilateral inferior fronto-occipital fasciculi and left superior longitudinal fasciculus), increased RD value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, major and minor forceps, bilateral inferior fronto-occipital fasciculi, bilateral inferior longitudinal fasciculi, bilateral superior longitudinal fasciculi and bilateral uncinate fasciculi) and increased MD value (bilateral anterior thalamic radiations, bilateral corticospinal tracts, minor forceps, bilateral inferior fronto-occipital fasciculi, bilateral inferior longitudinal fasciculi, left superior longitudinal fasciculus and bilateral uncinate fasciculi). Moreover, these changed diffusion metrics were not correlated with age, gender, LHON mutations and retinal measures in LHON carriers. CONCLUSION: Our results show microstructural alterations in brain white matter in asymptomatic LHON carriers, indicating that LHON-related genetic mutations themselves might result in occult white matter alterations in the brain.


Assuntos
Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/patologia , Nervo Óptico/patologia , Retina/patologia , Substância Branca/patologia , Adolescente , Adulto , Criança , Imagem de Tensor de Difusão , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/diagnóstico por imagem , Disco Óptico/diagnóstico por imagem , Disco Óptico/patologia , Nervo Óptico/diagnóstico por imagem , Estudos Prospectivos , Retina/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto Jovem
6.
J Fr Ophtalmol ; 42(3): 269-275, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30712826

RESUMO

INTRODUCTION: Leber's Hereditary Optic Neuropathy (LHON) causes a rapid and severe decrease in visual acuity. Raxone® (Idebenone, Santhera) is the only drug to have a European Marketing Authorization for the treatment of this optic neuropathy. It can be proposed in the first months after the onset of this optic neuropathy, according to an international consensus meeting. PATIENTS AND METHODS: Retrospective study of the efficacy of Raxone® on the visual acuity of patients with genetically confirmed LHON who were followed in four Parisian hospitals. The primary endpoint is the best recovery of LogMar visual acuity between baseline and the end of follow-up. The secondary endpoints are the evolution of LogMar visual acuity of the best eye at baseline and change in LogMar visual acuity for each eye considered separately. RESULTS: Seventeen patients, three women and 14 men, mean age 34.2 years, naive to treatment with Raxone® were included in this study. The mean duration of treatment was 11.0±6.6 months. A mitochondrial DNA mutation was found in all patients. Only 2 had the 14484 mutation. A recovery of better LogMar visual acuity was found at the end of the treatment for 4 eyes (23.5 %), and a deterioration was observed for 8 (47.0 %). Only 2 eyes (11.7 %) with the best visual acuity at baseline improved. On the other hand, 17.6 % of the eyes considered separately had an improvement in their LogMar visual acuity at the end of the treatment. CONCLUSION: The results confirm the trend of Raxone® treatment to improve patients' visual acuity. Given the recommendations of a consensus conference, this treatment should be started early after the onset of LHON. It is therefore important to look for this diagnosis in the presence of any hereditary optic neuropathy, in order to be able to initiate this treatment.


Assuntos
Atrofia Óptica Hereditária de Leber/tratamento farmacológico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/patologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Paris , Estudos Retrospectivos , Resultado do Tratamento , Ubiquinona/uso terapêutico , Acuidade Visual/efeitos dos fármacos , Adulto Jovem
7.
Mitochondrion ; 46: 187-194, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29890302

RESUMO

Little is known about the molecular mechanism of the rare coexistence of Leber's Hereditary Optic Neuropathy (LHON) and multiple sclerosis (MS), also known as the Harding's syndrome. In this study, we provide novel evidence that the m.11778A > G variant causes a defective metabolic interplay between mitochondrial oxidative phosphorylation and glycolysis. We used dermal fibroblasts derived from a female proband exhibiting clinical symptoms compatible with LHON-MS due to the presence of the pathogenic m.11778A > G variant at near homoplasmic levels. Our mitochondrial morphometric analysis reveals abnormal cristae architecture. Live-cell respiratory studies show stunted metabolic potential and spare respiratory capacity, vital for cell survival upon a sudden energy demand. The m.11778 A > G variant also alters glycolytic activities with a diminished compensatory glycolysis, thereby preventing an efficient metabolic reprogramming during a mitochondrial ATP crisis. Our collective results provide evidence of limited bioenergetic flexibility in the presence of the m.11778 A > G variant. Our study sheds light on the potential pathophysiologic mechanism of the m.11778 A > G variant leading to energy crisis in this patient with the LHON-MS disease.


Assuntos
DNA Mitocondrial/genética , Glicólise , Mitocôndrias/metabolismo , Esclerose Múltipla/patologia , Atrofia Óptica Hereditária de Leber/patologia , Fosforilação Oxidativa , Mutação Puntual , Adulto , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Mitocôndrias/patologia , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , Atrofia Óptica Hereditária de Leber/complicações , Atrofia Óptica Hereditária de Leber/genética
8.
Mitochondrion ; 46: 270-277, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30081212

RESUMO

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by acute bilateral vision loss. The pathophysiology involves reactive oxygen species (ROS), which can be affected by medications. This article reviews the evidence for medications with demonstrated and theoretical effects on mitochondrial function, specifically in relation to increased ROS production. The data reviewed provides guidance when selecting medications for individuals with LHON mutations (carriers) and are susceptible to conversion to affected. However, as with all medications, the proven benefits of these therapies must be weighed against, in some cases, purely theoretical risks for this unique patient population.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Atrofia Óptica Hereditária de Leber/patologia , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/toxicidade , Humanos
9.
Retin Cases Brief Rep ; 13(3): 232-237, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28291071

RESUMO

PURPOSE: To report cases that showed partition-like, dark areas in the cone mosaic on adaptive optics scanning laser ophthalmoscopy (AO-SLO) images in eyes with inner nuclear layer (INL) microcystic changes. METHODS: Eyes with INL microcystic changes were imaged by prototype AO-SLO. RESULTS: An eye with Leber hereditary optic neuropathy, an eye with traumatic optic neuropathy, and an eye with retinitis pigmentosa that showed microcystic lesions in the INL were imaged by AO-SLO. The images revealed characteristic, dark, partition-like lesions in the cone mosaic of all the eyes in areas where microcystic changes in the INL were shown by spectral domain optical coherence tomography. The AO-SLO findings in eyes with optic neuropathy were quite similar in shape and size to those seen in eyes with retinitis pigmentosa. CONCLUSION: We report cases that manifest dark, partition-like areas in the cone mosaic on AO-SLO images. Microcystic lesions in the INL may affect the images of the cone mosaic.


Assuntos
Oftalmoscopia/métodos , Atrofia Óptica/patologia , Retinite Pigmentosa/patologia , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia Óptica Hereditária de Leber/patologia , Adulto Jovem
10.
BMC Res Notes ; 11(1): 911, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572950

RESUMO

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON penetrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations. DATA DESCRIPTION: We collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/genética , Penetrância , Feminino , Heterozigoto , Humanos , Itália , Masculino , Mutação , Atrofia Óptica Hereditária de Leber/patologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Linhagem , Espanha
11.
Am J Ophthalmol ; 192: 217-228, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29885298

RESUMO

PURPOSE: To study the macular microvascular networks in patients affected by chronic Leber hereditary optic neuropathy (LHON) using optical coherence tomography angiography (OCTA), and to quantify these changes in different macular sectors. DESIGN: Prospective cross-sectional study. METHODS: Patients with a clinical and molecularly confirmed diagnosis of LHON (affected patients in the chronic stage) were enrolled from the neuro-ophthalmology clinic at the Doheny-UCLA. Patients and controls underwent a complete ophthalmologic evaluation, including imaging with OCTA. RESULTS: Twenty-nine eyes from 15 LHON patients (14 male) and 20 eyes from 20 healthy subjects (13 male) were included in the analysis. Mean age was 32.0 ± 14.2 years (range 16-49 years) in the LHON group and 34.2 ± 10.1 years (range 23-48 years) in the control group (P = .552). In the parafoveal region, the vessel length density was lower in LHON patients, at both the SCP (9.1% ± 0.5% and 9.3% ± 0.4%, P = .041) and DCP (9.4% ± 0.5% and 9.8% ± 0.3%, P = .008) levels. In the sectorial analysis, vascular changes remained significant only in the parafoveal nasal and inferior regions. Univariate linear regression analysis demonstrated that the strongest associations with visual acuity were with parafoveal SCP perfusion density (R2 = .276, P = .045) and parafoveal SCP vessel length density (R2 = .277, P = .044). CONCLUSIONS: LHON eyes have SCP and DCP changes that are mainly confined to the nasal and inferior parafoveal sectors that correspond to the papillomacular bundle. Furthermore, visual loss is associated with the SCP flow impairment, but not with the OCT-detectable structural damage.


Assuntos
Atrofia Óptica Hereditária de Leber/patologia , Vasos Retinianos/patologia , Adolescente , Adulto , Estudos Transversais , Feminino , Angiofluoresceinografia , Humanos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Regressão , Tomografia de Coerência Óptica , Acuidade Visual , Adulto Jovem
12.
Neural Plast ; 2018: 7108948, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29853847

RESUMO

The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber's congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber's hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.


Assuntos
Terapia Genética , Glaucoma/terapia , Atrofia Óptica Hereditária de Leber/terapia , Células Ganglionares da Retina/patologia , Animais , Glaucoma/patologia , Humanos , Atrofia Óptica Hereditária de Leber/patologia
13.
Sci Rep ; 8(1): 5587, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615737

RESUMO

In many human disorders mitochondrial dysfunction is central to degeneration of retinal ganglion cells. As these cells do not regenerate, vision is irreversibly lost. Here we show reversal of visual dysfunction by a mitochondrially targeted adeno associated virus in transgenic mice harboring a G11778A mutation in the ND4 subunit of complex I persists longterm and it is associated with reduced loss of RGCs and their axons, improved oxidative phosphorylation, persistence of transferred ND4 DNA and transcription of ND4 mRNA.


Assuntos
Técnicas de Transferência de Genes , Genes Mitocondriais/genética , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/fisiopatologia , Visão Ocular/genética , Animais , Contagem de Células , Modelos Animais de Doenças , Camundongos , Mutação , Neurônios/patologia , Atrofia Óptica Hereditária de Leber/patologia , Nervo Óptico/patologia , Células Ganglionares da Retina/patologia
15.
Curr Opin Ophthalmol ; 29(3): 234-238, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29538182

RESUMO

PURPOSE OF REVIEW: Highlight some of the recent advances in gene therapy and gene modification for optic nerve disease to promote axon regeneration, neuroprotection, and increased visual functioning. RECENT FINDINGS: Visual loss secondary to optic nerve damage occurs in numerous ophthalmologic and neurologic conditions. Damaged retinal ganglion cells (RGCs) do not regenerate once they undergo apoptosis after injury. Gene therapy has been studied to replace gene mutations in disorders affecting the optic nerve as well as to alter genes responsible for suppressing or activating pathways of optic nerve growth and regeneration. Recent clinical trials for Leber's Hereditary Optic Neuropathy have demonstrated safety and feasibility as potential future treatment. Animal studies utilizing gene therapy for optic nerve regeneration have shown various degrees of RGC axon regrowth and target reinnervation. Some studies have also successfully demonstrated a state of neuroprotection in RGCs allowing them to survive in greater numbers following injury. SUMMARY: Additional studies will have to evaluate long-term efficacy and safety of these potential treatments, as well as the consequences of manipulating tumor suppressor genes and oncogenes.


Assuntos
Terapia Genética/métodos , Regeneração Nervosa/fisiologia , Doenças do Nervo Óptico/terapia , Células Ganglionares da Retina/fisiologia , Animais , Axônios/fisiologia , Humanos , Neuroproteção/fisiologia , Atrofia Óptica Hereditária de Leber/patologia , Nervo Óptico/fisiologia , Traumatismos do Nervo Óptico/terapia
16.
Hum Mol Genet ; 27(11): 1999-2011, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29579248

RESUMO

Mutations in mitochondrial DNA (mtDNA) have been associated with Leber's hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we demonstrated that a missense mutation (m.12338T>C, p.1M>T) in the ND5 gene contributed to the pathogenesis of LHON. The m.12338T>C mutation affected the first methionine (Met1) with a threonine and shortened two amino acids of ND5. We therefore hypothesized that the mutated ND5 perturbed the structure and function of complex I. Using the cybrid cell models, generated by fusing mtDNA-less (ρ°) cells with enucleated cells from LHON patients carrying the m.12338T>C mutation and a control subject belonging to the same mtDNA haplogroup, we demonstrated that the m.12338T>C mutation caused the reduction of ND5 polypeptide, perturbed assemble and activity of complex I. Furthermore, the m.12338T>C mutation caused respiratory deficiency, diminished mitochondrial adenosine triphosphate levels and membrane potential and increased the production of reactive oxygen species. The m.12338T>C mutation promoted apoptosis, evidenced by elevated release of cytochrome c into cytosol and increased levels of apoptosis-activated proteins: caspases 9, 3, 7 and Poly ADP ribose polymerase in the cybrids carrying the m.12338T>C mutation, as compared with control cybrids. Moreover, we also document the involvement of m.12338T>C mutation in decreased mitophagy, as showed by reduced levels of autophagy protein light chain 3 and accumulation of autophagic substrate p62 in the in mutant cybrids as compared with control cybrids. These data demonstrated the direct link between mitochondrial dysfunction caused by complex I mutation and apoptosis or mitophagy. Our findings may provide new insights into the pathophysiology of LHON.


Assuntos
Complexo I de Transporte de Elétrons/genética , Proteínas Mitocondriais/genética , Atrofia Óptica Hereditária de Leber/genética , Relação Estrutura-Atividade , Apoptose/genética , DNA Mitocondrial/genética , Humanos , Células Híbridas , Mitofagia/genética , Mutação de Sentido Incorreto/genética , Atrofia Óptica Hereditária de Leber/metabolismo , Atrofia Óptica Hereditária de Leber/patologia
17.
Stem Cell Res ; 28: 56-60, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29427840

RESUMO

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease caused by homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. In this report, we generated an induced pluripotent stem cell (iPSCs) line, TVGH-iPSC-010-09, from the peripheral blood mononuclear cells of a female patient with Leber's hereditary optic neuropathy (LHON) by using the Sendai-virus delivery system. The resulting iPSCs retained the disease-causing mitochondrial DNA mutation, expressed pluripotent markers and could differentiate into the three germ layers. We believe LHON patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease.


Assuntos
Técnicas de Cultura de Células/métodos , Células-Tronco Pluripotentes Induzidas/citologia , Atrofia Óptica Hereditária de Leber/patologia , Animais , Diferenciação Celular , DNA Mitocondrial/genética , Feminino , Humanos , Cariotipagem , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Taxa de Mutação
18.
Am J Med Genet A ; 173(11): 3093-3097, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944608

RESUMO

Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other-skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.


Assuntos
Genoma Mitocondrial/genética , Ictiose/genética , Queratina-10/genética , Atrofia Óptica Hereditária de Leber/genética , Adolescente , Predisposição Genética para Doença , Humanos , Ictiose/patologia , Recém-Nascido , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Mutação , Atrofia Óptica Hereditária de Leber/patologia , Fenótipo
19.
Invest Ophthalmol Vis Sci ; 58(10): 3923-3930, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28768321

RESUMO

Purpose: Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation. Methods: Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations. Results: A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected. Conclusions: The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial/genética , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/genética , Mutação Puntual , Adulto , Análise Mutacional de DNA , Família , Feminino , Haplótipos/genética , Humanos , Índia/epidemiologia , Masculino , Mitocôndrias/genética , Atrofia Óptica Hereditária de Leber/epidemiologia , Atrofia Óptica Hereditária de Leber/patologia , Linhagem , Adulto Jovem
20.
Eur J Radiol ; 93: 24-29, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28668421

RESUMO

PURPOSE: To quantitatively analyze the optic nerve alterations in chronic Leber's hereditary optic neuropathy (LHON) using reduced field-of-view diffusion tensor imaging (rFOV-DTI) and evaluate the correlation of diffusion parameters with visual functional and peripapillary retinal nerve fiber layer (RNFL) thickness. METHODS: Twenty-five patients (50 affected optic nerves) with chronic LHON and 28 healthy controls (56 normal optic nerves) were enrolled. The rFOV-DTI was performed in the bilateral optic nerves for all the subjects. The fractional anisotropy (FA), mean diffusivity (MD), principal eigenvalue (λ//), and orthogonal eigenvalue (λ⊥) were calculated for quantitative analysis. Visual field (VF) and visual acuity (VA) were measured in all subjects. The peripapillary RNFL thickness was assessed using optical coherence tomography (OCT). The correlation of DTI diffusion parameters with visual function and peripapillary RNFL thickness was evaluated. RESULTS: Compared with optic nerves in the control group, the mean FA was significant decreased (P<0.005), and the mean MD, λ//and λ⊥ significant increased (P<0.005). The average and temporal peripapillary RNFL thickness were significantly thinned in LHON patients. There was a significant correlation between optic nerve FA and VA, mean deviation of visual field (MDVF) (P<0.005). Also, optic nerve FA correlated significantly with average RNFL thickness (P<0.05) but not with MD, λ//and λ⊥ (P>0.05). However, none of the DTI parameters correlated with age and disease duration (P>0.05). CONCLUSIONS: Our study has demonstrated that rFOV-DTI could provide information of optic nerve damage in chronic LHON, and can serve as technique for detecting and evaluating pathological changes in the optic nerve in LHON.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Tensor de Difusão/métodos , Atrofia Óptica Hereditária de Leber/diagnóstico por imagem , Atrofia Óptica Hereditária de Leber/patologia , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/patologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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