Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 718
Filtrar
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
3.
Klin Monbl Augenheilkd ; 236(11): 1271-1282, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31639883

RESUMO

Leber's hereditary optic neuropathy (LHON) typically affects young adults with a higher prevalence in men, but can ultimately occur at any age and also in women. LHON is caused by point mutations in the mitochondrial DNA, which lead to a defect in complex I of the mitochondrial respiratory chain. This in turn causes dysfunction and later degeneration of retinal ganglion cells, followed by ascending optic atrophy. Classically, LHON presents as a subacute unilateral loss of visual acuity, dyschromatopsia in the red-green axis and a central or centrocecal scotoma. The partner eye usually develops similar symptoms within 3 - 6 months of onset of the disease. In 25% of cases, however, the disease begins bilaterally. In the natural course of the disease, the majority of patients remain with a visual acuity less than 0.1, even though a small proportion may experience a spontaneous improvement in visual acuity. In 2015, the ubiquinone analogue Idebenone was approved by the European Medicines Agency for the treatment of LHON. The decisive factors for therapeutic success are an early start and an appropriate treatment duration. It should also be noted that a proportion of patients may experience a delayed response to therapy. However, a complete recovery of visual acuity is rare even under therapy. Since patients affected by LHON are mostly young adults of working age, who go largely blind more or less acutely, immediate support with magnifying vision aids and advice on social and vocational rehabilitation is essential. Alternative therapeutic approaches such as gene therapy, neuroprotection or stem cell-based aspects are currently the subject of clinical studies and offer hope for further perspectives for those affected. Although with Idebenone a causal therapy has already been approved for LHON, many questions regarding the pathogenesis of the disease have not yet been completely clarified. This particularly concerns gender prevalence and possible additional triggers or protective factors. In this overview, the clinical course of LHON, diagnostics and current therapy recommendations as well as the special features and current explanatory approaches to incomplete penetrance and symptoms of LHON are explained.


Assuntos
Terapia Genética , Atrofia Óptica Hereditária de Leber , DNA Mitocondrial , Feminino , Humanos , Masculino , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/terapia , Células Ganglionares da Retina , Acuidade Visual , Adulto Jovem
8.
Orphanet J Rare Dis ; 14(1): 150, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31226990

RESUMO

BACKGROUND: The vision loss in Leber hereditary optic neuropathy patients is due to mitochondrial DNA mutations. No treatment has shown a clear-cut benefit on a clinically meaningful end-point. However, clinical evidences suggest two therapeutic approaches: the reduction of the mutation load in heteroplasmic patients or the elevation of mitochondrial DNA amount in homoplasmic patients. RESULTS: Here we show that ketogenic treatment, in cybrid cell lines, reduces the percentage of the m.13094 T > C heteroplasmic mutation and also increases the mitochondrial DNA levels of the m.11778G > A mitochondrial genotype. CONCLUSIONS: These results suggest that ketogenic diet could be a therapeutic strategy for Leber hereditary optic neuropathy.


Assuntos
DNA Mitocondrial/genética , Mutação/genética , Atrofia Óptica Hereditária de Leber/genética , Dieta Cetogênica , Feminino , Humanos , Masculino , Mutação Puntual/genética
9.
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
10.
BMJ Case Rep ; 12(3)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30936345

RESUMO

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disorder characterised by bilateral, painless visual loss which leads to severe optic atrophy. It can be associated with other conditions including multiple sclerosis (MS), movement disorders, epilepsy and cardiac arrhythmias. The association of LHON with an MS-like illness is often referred to as Harding's disease (or Harding's syndrome). We report two siblings, who both harbour the 11 778 mitochondrial DNA (mtDNA) mutation, but who manifest markedly different clinical phenotypes; a male with classical LHON and a female with an MS-like illness. LHON affects males four to five times more often than females. By contrast, Harding's disease is seen predominantly in females, in a pattern comparable to that seen in MS. The pathogenic basis behind the variation in penetrance and phenotype between genders and individual family members remains unclear.


Assuntos
Esclerose Múltipla/fisiopatologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Mutação Puntual/genética , Transtornos da Visão/etiologia , DNA Mitocondrial/genética , Família , Feminino , Transtornos Neurológicos da Marcha/genética , Transtornos Neurológicos da Marcha/fisiopatologia , Aconselhamento Genético , Humanos , Imunoterapia , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/genética , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Encaminhamento e Consulta , Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Resultado do Tratamento , Transtornos da Visão/genética , Transtornos da Visão/fisiopatologia
11.
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
12.
Klin Monbl Augenheilkd ; 236(4): 451-461, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30831606

RESUMO

BACKGROUND: Inherited optic neuropathies (IONs) cover a spectrum of clinically and genetically heterogenic conditions. Genetic evaluation of patients with IONs may enable their better clinico-diagnostic assessment and management of the disease. The aim of the present study was to determine the genetic condition related to the phenotype in patients with diverse inherited optic neuropathies. PATIENTS AND METHODS: A retrospective study was performed in 12 adults and 8 children of 8 non-related families. Clinical phenotyping, supported by color fundus, FAF, and OCT imaging, was performed. Genetic testing was obtained for all family members suspected for ION. RESULTS: Identification of pathogenic mutations in eight non-related families helped to confirm the diagnosis of ION. Affected from ION were ten patients (eight adults and two children; four women and six men). Bilateral Leber's hereditary optic neuropathy (LHON) was linked to the m.11778G>A mutation in two families (two affected and five carriers). Secondary homoplasmic LHON mutations in MT-ND1 (m.4216T>C) and MT-CO3 genes (m.9804G>A) were confirmed in two families (each one subject, three eyes affected), without detection of a primary LHON mutation. One member presented a picture of right-sited optic neuropathy associated with a c.220C>G mutation in the ACO2 gene and a heterozygous c.185C>T mutation in the LDLR gene. Autosomal dominant optic atrophy was confirmed in three non-related families (five subjects with bilateral ION), where molecular genetic analyses confirmed four different heterozygous mutations in OPA1: c.1847+1G>T; c.2497-1G>A, 297A>G and c.(2983+1_2984-1)_(c.*3211) (2 splicing mutations, 1 missense mutation, and 1 gross deletion encompassing exons 30 and 31). CONCLUSIONS: Combining clinics and molecular genetics when evaluating patients with IONs helps in characterizing disease and, therefore, is strongly recommended for such patients.


Assuntos
Atrofia Óptica Autossômica Dominante , Atrofia Óptica Hereditária de Leber , Adulto , Criança , DNA Mitocondrial , Feminino , Humanos , Masculino , Mutação , Atrofia Óptica Autossômica Dominante/genética , Atrofia Óptica Hereditária de Leber/genética , Linhagem , Estudos Retrospectivos
13.
Nervenarzt ; 90(2): 121-130, 2019 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-30643957

RESUMO

Mitochondrial diseases (MD) are caused by mutations in the mitochondrial DNA or nuclear DNA. The clinical manifestation is often most severe in tissues with high energy demands. The most common MDs are Leber's hereditary optic neuropathy (LHON), chronic progressive external ophthalmoplegia (CPEO) and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). Therapeutic approaches for MD include bridging of respiratory chain defects, pharmacological stimulation of mitochondrial metabolism, supplementation of deficient factors and symptomatic treatment. Initial gene therapeutic approaches for causal treatment have already reached the clinical development stage. This article provides an introduction to MD, a summary of the most important syndromes and an overview over established and innovative therapeutic approaches.


Assuntos
Doenças Mitocondriais , DNA Mitocondrial/genética , Terapia Genética , Humanos , Doenças Mitocondriais/genética , Doenças Mitocondriais/terapia , Encefalomiopatias Mitocondriais/genética , Encefalomiopatias Mitocondriais/terapia , Mutação , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/terapia
15.
Hum Mol Genet ; 28(9): 1515-1529, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597069

RESUMO

Mitochondrial DNA (mtDNA) mutations have been associated with Leber's hereditary optic neuropathy (LHON) and their pathophysiology remains poorly understood. In this study, we investigated the pathophysiology of a LHON susceptibility allele (m.3394T>C, p.30Y>H) in the Mitochondrial (MT)-ND1 gene. The incidence of m.3394T>C mutation was 2.7% in the cohort of 1741 probands with LHON. Extremely low penetrances of LHON were observed in 26 pedigrees carrying only m.3394T>C mutation, while 21 families bearing m.3394T>C, together with m.11778G>A or m.14484T>C mutation, exhibited higher penetrance of LHON than those in families carrying single mtDNA mutation(s). The m.3394T>C mutation disrupted the specific electrostatic interactions between Y30 of p.MT-ND1 with the sidechain of E4 and backbone carbonyl group of M1 of NDUFA1 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 1) of complex I, thereby altering the structure and function of complex I. We demonstrated that these cybrids bearing only m.3394T>C mutation caused mild mitochondrial dysfunctions and those harboring both m.3394T>C and m.11778G>A mutations exhibited greater mitochondrial dysfunctions than cybrids carrying only m.11778G>A mutation. In particular, the m.3394T>C mutation altered the stability of p.MT-ND1 and complex I assembly. Furthermore, the m.3394T>C mutation decreased the activities of mitochondrial complexes I, diminished mitochondrial ATP levels and membrane potential and increased the production of reactive oxygen species in the cybrids. These m.3394T>C mutation-induced alterations aggravated mitochondrial dysfunctions associated with the m.11778G>A mutation. These resultant biochemical defects contributed to higher penetrance of LHON in these families carrying both mtDNA mutations. Our findings provide new insights into the pathophysiology of LHON arising from the synergy between mitochondrial ND1 and ND4 mutations.


Assuntos
Alelos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , NADH Desidrogenase/genética , Atrofia Óptica Hereditária de Leber/diagnóstico , Atrofia Óptica Hereditária de Leber/genética , Fenótipo , Sequência de Aminoácidos , Animais , Axônios/metabolismo , Linhagem Celular , Genes Mitocondriais , Estudos de Associação Genética , Predisposição Genética para Doença , Camundongos , NADH Desidrogenase/química , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fosforilação , Transmissão Sináptica , Vesículas Sinápticas/metabolismo
16.
Hum Mol Genet ; 28(3): 422-433, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30304398

RESUMO

Leber's hereditary optic neuropathy (LHON) is a classical mitochondrial disease caused by mutations in the mitochondrial DNA encoding complex I subunits. Oxidative stress associated with complex I defect has been implicated in developing LHON phenotype such as retinal ganglion cell (RGC) death and loss of vision. However, the mechanism of LHON pathogenesis is still not very clear and thus no effective therapies are available to date. Using cybrid models for LHON, we show that autophagy is significantly compromised in cells carrying LHON-specific mtDNA mutations, which results in reduced clearance of dysfunctional mitochondria contributing to cell death. We further show that pharmacological activation of autophagy selectively clears the damaged mitochondria and thus repairs mitochondrial defects and improves overall cell survival in LHON cell models. Our results suggest that compromised autophagy is the missing link from oxidative stress to LHON pathogenesis. Activation of mitophagy ameliorates mitochondrial defects and exerts a protective role by improving cell survival in cells carrying LHON mutations that could be utilized as a potential therapeutic target for LHON treatment.


Assuntos
Mitofagia/fisiologia , Atrofia Óptica Hereditária de Leber/genética , Atrofia Óptica Hereditária de Leber/fisiopatologia , Apoptose/genética , Morte Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , DNA Mitocondrial/genética , Humanos , Mitocôndrias/fisiologia , Mutação , Estresse Oxidativo/fisiologia
18.
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
20.
Curr Opin Neurol ; 32(1): 99-104, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30516647

RESUMO

PURPOSE OF REVIEW: Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder in the population and it carries a poor visual prognosis. In this article, we review the development of treatment strategies for LHON, the evidence base and the areas of unmet clinical need. RECENT FINDINGS: There is accumulating evidence that increasing mitochondrial biogenesis could be an effective strategy for protecting retinal ganglion cells in LHON. A number of clinical trials are currently investigating the efficacy of viral-based gene therapy for patients harbouring the m.11778G>A mtDNA mutation. For female LHON carriers of childbearing age, mitochondrial replacement therapy is being offered to prevent the maternal transmission of pathogenic mtDNA mutations. SUMMARY: Although disease-modifying treatment options remain limited, a better understanding of the underlying disease mechanisms in LHON is paving the way for complementary neuroprotective and gene therapeutic strategies for this mitochondrial optic nerve disorder.


Assuntos
DNA Mitocondrial/genética , Mutação , Atrofia Óptica Hereditária de Leber/terapia , Terapia Genética , Humanos , Atrofia Óptica Hereditária de Leber/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA