Marcela Votruba

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• MA BM BCh FRCOphth PhD FLSW
• Professor at Cardiff University

Purpose To investigate the impact of central serous chorioretinopathy on sleep and mood in patients with acute and chronic central serous chorioretinopathy. Methods This cross-sectional study compared sleep and mood differences between central serous chorioretinopathy and control patients recruited from Ophthalmology clinics at the John Radcliffe...

The International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy was published in 2017 based on data available in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. It provided the guidelines f...

Aims/Purpose: Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder resulting in severe bilateral vision loss. Age at symptom onset and estrogen levels are thought to influence disease progression. The Case Record Survey‐2 (CRS‐2; NCT02796274) was conducted to establish the natural history of LHON in idebenone‐naïve patients. He...

A compromised capacity to maintain NAD pools is recognized as a key underlying pathophysiological feature of neurodegenerative diseases. NAD acts as a substrate in major cell functions including mitochondrial homeostasis, cell signalling, axonal transport, axon/Wallerian degeneration, and neuronal energy supply. Dendritic degeneration is an early m...

Objective: To describe the current status of clinical trials of genetic eye diseases with identified molecular targets for future areas of research. Method: Data analysis of the clinical trials database on clinicaltrials.gov with keywords for eight common, genetically tractable inherited eye diseases and their common molecular targets was perfor...

Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTri...

Fostering an international network of women scientists and clinicians, encouraging open dialogue, and inspiring future women scientists in Ophthalmology and Vision Science. How to encourage women scientists and clinicians to go after their dreams Be a listening ear. … Stay open‐minded. … Help her set attainable goals. … Take action. … Encourage her...

WOMEN in EVER is supporting women researchers, clinicians and academic staff in their career development with a goal to prepare them for leadership roles in the scientific community. Globally, only 33 per cent of researchers are women. Women and girls represent half of the world's population and, therefore, also half of its potential. Gender equali...

Aims/Purpose: Inherited retinal dystrophies (IRD) are a group of predominantly monogenic disorders which have genetically heterogeneous origins and display wide clinical phenotypic heterogeneity. The current study aims to describe the clinical diagnoses, demographics, and genetic aetiology of patients in an adult cohort of Welsh patients to provide...

Mitochondrial disease is among the most common form of inherited neurological disorder, with a minimum prevalence of 1:5000 and few if any effective treatments or cures. Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution...

Aims/Purpose: To assess the real‐world effectiveness of idebenone in a heterogenous group of patients with LHON treated with idebenone in Wales. This provides insight into the national outcomes of. Methods: Patients were identified from the ophthalmic genetics service based at Cardiff Eye Unit. Clinical notes were reviewed and details were collated...

We would like to especially recognize the creativity, energy, and substantive contributions from all women in ophthalmology and vision science! You have brought a fresh and much needed perspective to EVER. What Are the Biggest Problems Women Face Today? The lack of women in positions of power. … Patriarchy. … Not enough women at the table. … Sexism...

It is our joint task to translate into reality a more equal and connected world for women scientists in all their diversity. Our round table will foster discussion among delegates on the following topics: Share your clinical experience… Share your research experience…. Discuss your ambitions…. Facilitate an informal exchange with the wider EVER co...

This WOMEN in EVER session is connecting early‐career and leading women scientists from all over Europe, to tackle the under‐representation of women in science by increasing visibility. Distinguished women scientists and clinicians will meet here to connect and to inspire young women scientist about how successful careers in Ophthalmology and Visio...

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, affecting approximately 1 in 25 000 people. DOA has an insidious onset in early childhood. It presents typically with bilateral central painless vision loss, dyschromatopsia, and optic disc pallor due to gradual retinal ganglion cell (RGC) loss and optic nerve deg...

Purpose: To report three older male individuals, all homoplasmic for m.14484 T > C mutation in the ND6 gene, presenting onset of vision loss weeks-months after covid vaccination. None reported a history of covid-19 infection. Methods: All clinical data was extracted and reported here as a Case Series. Results: A 68 years old man (A) had a 3rd dose...

Purpose: Diabetic Macular Œdema (DME) and Age-related Macular Degeneration (nAMD) are the leading causes of vision loss in developed nations. Anti-Vascular Endothelial Growth Factor (aVEGF) has revolutionized the treatment of both conditions, but access is limited by costs. Biosimilars of aVEGF can cut costs, but prescriber concerns over the lack o...

Retinal involvement in mitochondrial disease is a variable feature of mitochondrial dysfunction. The retinal pigment epithelium and photoreceptor layers can both be affected. It manifests with signs ranging from asymptomatic peripheral salt-and-pepper retinopathy to classic bone-spicule pigmentary changes. The consequences can be progressive mild o...

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease‐modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively‐funded research designed by academics meets core needs of people with mitochondrial...

Purpose Global spending on retinal biologic medicines is expected to reach $28M USD by 2025. The first biosimilars (BioSim) of anti-vascular endothelial growth factors (anti-VEGF) are expected to launch in Europe in 2022; cutting costs and improving access to treatment. Physician surveys show concerns over Biosimilars – due to abbreviated regulator...

Purpose Recent increased understanding of molecular and genetic causes of many inherited eye diseases opens the way to novel therapeutic interventions. The key to drug discovery is in delivering precision targets for treatment that open a therapeutic index over toxicity. We set out to define what type of treatments are emerging, against what target...

Retinal ganglion cells (RGCs) undergo dendritic pruning in a variety of neurodegenerative diseases, including glaucoma and autosomal dominant optic atrophy (ADOA). Axotomising RGCs by severing the optic nerve generates an acute model of RGC dendropathy, which can be utilized to assess the therapeutic potential of treatments for RGC degeneration. Ph...

Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber’s hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thi...

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions...

This study investigates whether reduced optic atrophy 1 (Opa1) level promotes apoptosis and retinal vascular lesions associated with diabetic retinopathy (DR). Four groups of mice: wild type (WT) control mice, streptozotocin (STZ)-induced diabetic mice, Opa1+/− mice, and diabetic Opa1+/− mice were used in this study. 16 weeks after diabetes onset,...

Autosomal Dominant Optic Atrophy (ADOA) is an ophthalmological condition associated primarily with mutations in the OPA1 gene. It has variable onset, sometimes juvenile, but in other patients, the disease does not manifest until adult middle age despite the presence of a pathological mutation. Thus, individuals carrying mutations are considered hea...

Purpose The primary mitochondrial disorders encompass a wide‐reaching number of clinical presentations and a spectrum of severity. It is therefore vital to know that research that is designed by academics and competitively funded, meets the core needs of people with mitochondrial disorders and their clinicians. Methods The Priority Setting Partner...

BACKGROUND Leber hereditary optic neuropathy (LHON) leads to bilateral central vision loss. In a clinical trial setting, idebenone has been shown to be safe and to provide a trend toward improved visual acuity, but long-term evidence of effectiveness in real-world clinical practice is sparse. METHODS Open-label, multicenter, retrospective, noncontr...

Leber's hereditary optic neuropathy (LHON) is a rare genetic mitochondrial disease and the primary cause of chronic visual impairment for at least 1 in 10 000 individuals in the U.K. Treatment options remain limited, with only a few drug candidates and therapeutic approaches, either approved or in development. Recently, idebenone has been investiga...

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse...

Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegener...

A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerat...

Mitochondria are known to play an essential role in photoreceptor function and survival that enables normal vision. Within photoreceptors, mitochondria are elongated and extend most of the inner-segment length, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment, as well as acting as a calcium sto...

Purpose: Retinal ganglion cells (RGCs) are susceptible to mitochondrial deficits and also the major cell type affected in patients with mutations in the OPA1 gene in autosomal dominant optic atrophy (ADOA). Here, we characterized mitochondria in RGCs in vitro from a heterozygous B6; C3-Opa1Q285STOP (Opa1+/-) mouse model to investigate mitochondria...

Objective To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. Methods Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. Results We...

Idebenone has recently been investigated as a drug therapy for Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. Although several studies have shown that idebenone can promote vision recovery in patients with LHON, the evidence for the efficacy of idebenone is s...

Objective: Autosomal dominant optic atrophy (ADOA) starts in early childhood with loss of visual acuity and color vision deficits. OPA1 mutations are responsible for the majority of cases, but in a proportion of patients with a clinical diagnosis of ADOA, the cause remains unknown. This study aimed to identify novel ADOA-associated genes and explo...

Mitochondria are known to play an essential role in photoreceptor function and wellbeing that enables normal healthy vision. Within photoreceptors they are elongated and extend most of the length inner segment, where they supply energy for protein synthesis and the phototransduction machinery in the outer segment as well as acting as a calcium stor...

Purpose: To assess the topographic relationship between the photopic negative response (PhNR) and retinal ganglion cell distribution in healthy individuals. Method: Data was recorded from 16 healthy participants. The amplitude of PhNRs obtained in response to focal long duration (250 ms) and brief flash (5 ms), red (660 nm) on blue (469 nm) stim...

Purpose In this prospective observational comparative case series, we aimed to study the peripapillary capillary network with spectral‐domain optical coherence tomography angiography (OCT‐A) in Leber hereditary optic neuropathy (LHON). Methods Twelve eyes of six individuals, of these three males (five eyes) after clinical onset of visual impairmen...

Background: Autosomal dominant optic atrophy (ADOA) is usually caused by mutations in the essential gene, OPA1. This encodes a ubiquitous protein involved in mitochondrial dynamics, hence tissue specificity is not understood. Dysregulated mitophagy (mitochondria recycling) is implicated in ADOA, being increased in OPA1 patient fibroblasts. Furtherm...

Mapping of the mRFP transgene. The insertion of the mRFP transgene was investigated by paired-end sequencing. The insert is located in the 3rd exon of the pkn1 gene, which has been confirmed by PCR using a common forward primer (green) and two different reverse primers; one (red) 1,500 bp from the forward primer in the wild type genome (blue) and o...

Analysis of OPA1 expression in the MEFs used. Protein extracts were prepared from wt, RedMIT-GFP-LC3 and RedMIT-GFP-LC3-OPA1Q285STOP MEFs and analyzed on a 8% acrylamide gel. The OPA1 signal was detected using a rabbit anti-OPA1 antibody (abcam ab42364) and revealed using a polyclonal goat anti-rabbit secondary antibody (Dako P0448) coupled to an E...

mRFP and GFP transgenes do not affect mice reproductive success.

Images from sections of brain and spleen from control, RedMIT/GFP-LC3, and OPA1Q285STOP/RedMIT/GFP-LC3. Brain (Bottom) and spleen (Top) from non-fluorescent (control), RedMIT/GFP-LC3 and OPA1Q285STOP/RedMIT/GFP-LC3 mice were sectioned (10 μm) and imaged on a Zeiss LSM 700 inverted confocal microscope with a plan-Apo 63x NA 1.4 oil-immersion objecti...

Movie of the RedMIT-GFP-LC3 MEFs. Live RedMIT-GFP-LC3 MEFs have been imaged using a custom Olympus IX81 inverted microscope equipped with temperature control (Solent scientific) every 30 s for 8 h. This can be used to quantify the early stages of mitophagy in real time.

Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of senile dementia. It impairs the quality of life of a person and their family, posing a serious economic and social threat in developed countries. The fact that the diagnosis can only be definitively made post-mortem, or when the disease is fairly advanced, presents...

Leber hereditary optic neuropathy (LHON) is currently estimated as the most frequent mitochondrial disease (1 in 27,000-45,000). Its molecular pathogenesis and natural history is now fairly well understood. LHON also is the first mitochondrial disease for which a treatment has been approved (idebenone-Raxone, Santhera Pharmaceuticals) by the Europe...

Purpose With the context of the Ophthalmic Genetic Clinics, this presentation aims to explore the level of understanding of photoreceptor degeneration, the leading cause of inherited blindness, which presents with extreme genetic heterogeneity, making the molecular diagnosis a challenge. The promising future for inherited retinal dystrophies with t...

Purpose Alzheimer's disease is a neurodegenerative disease and the most common cause of senile dementia. The fact that the diagnosis can only be definitively made postmortem, or when the disease is fairly advanced, presents a serious problem if novel therapeutic interventions are to be devised and used early in the course of the disease. Therefore...

Purpose Mutations in OPA1 are the leading cause of dominant optic atrophy, a disease in which a progressive loss of retinal ganglion cells (RGCs) leads to blindness. In the B6;C3‐Opa1Q285STOP mouse, an Opa1 mutation causes a decrease in ATP production and a progressive loss in visual acuity, which coincides with pruning of the predominantly ON‐cent...

Results of the macular and optic nerve head optical coherence tomography imaging.

S-cone critical flicker fusion variables.

L-cone critical flicker fusion variables.

Leber inherited optic neuropathy (LHON) is characterized by subacute bilateral loss of central vision due to dysfunction and loss of retinal ganglion cells (RGCs). Comprehensive visual electrophysiological investigations (including pattern reversal visual evoked potentials, pattern electroretinography and the photopic negative response) performed o...

Absorption of photon energy by neuronal mitochondria leads to numerous downstream neuroprotective effects. Red and near infrared (NIR) light are associated with significantly less safety concerns than light of shorter wavelengths and they are therefore, the optimal choice for irradiating the retina. Potent neuroprotective effects have been demonstr...

Background The onset of Leber hereditary optic neuropathy (LHON) is relatively rare in childhood. This study describes the clinical and molecular genetic features observed in this specific LHON subgroup. Methods Our retrospective study consisted of a UK paediatric LHON cohort of 27 patients and 69 additional cases identified from a systematic revi...

Purpose: Progressive retinal ganglion cell (RGC) loss is the pathological hallmark of autosomal dominant optic atrophy (DOA) caused by pathogenic OPA1 mutations. The aim of this study was to conduct an in-depth psychophysical study of the visual losses in DOA and to infer any selective vulnerability of visual pathways subserved by different RGC su...

OBJECTIVE: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. METHODS: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of...

Objective: To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Methods: Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss...

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical comp...

Purpose: To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. Methods: OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 82 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were...

Purpose To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. Methods OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 44 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were ass...

Primary inherited optic neuropathies are a group of blinding genetic disorders in which optic atrophy secondary to loss of retinal ganglion cells is a key clinical feature. The commonest causes world-wide are mutation in mitochondrial DNA (causing Leber's Hereditary Optic Neuropathy) and mutation in the nuclear gene, OPA1 (causing Autosomal Dominan...

Mutations in the opa1 (optic atrophy 1) gene lead to autosomal dominant optic atrophy (ADOA), a hereditary eye disease. This gene encodes the Opa1 protein, a mitochondrial dynamin-related GTPase required for mitochondrial fusion and the maintenance of normal crista structure. The majority of opa1 mutations encode truncated forms of the protein, lac...

Red light has been shown to provide neuroprotective effects. Axotomising the optic nerve initiates retinal ganglion cell (RGC) degeneration, and an early marker of this is dendritic pruning. We hypothesised that 670 nm light can delay axotomy induced dendritic pruning in the retinal explant. To test this hypothesis, we monitored the effects of 670...

Mitochondrial dysfunction connects metabolic disturbance with numerous pathologies, but the significance of mitochondrial activity in bone remains unclear. We have, therefore, characterized the skeletal phenotype in the Opa3(L122P) mouse model for Costeff syndrome, in which a missense mutation of the mitochondrial membrane protein, Opa3, impairs mi...

Dominant optic atrophy (DOA) arises from mutations in the OPA1 gene that promotes fusion of the inner mitochondrial membrane and plays a role in maintaining ATP levels. Patients display optic disc pallor, retinal ganglion cell (RGC) loss and bilaterally reduced vision. We report a randomized, placebo-controlled trial of idebenone at 2000 mg/kg/day...

Purpose To explore the level of understanding and perceptions of inherited eye diseases and attitudes to genetic testing and gene therapy in a primary eye care setting. Methods This study was undertaken as a part of an EVER foundation fellowship at the School of Optometry and Vision Sciences, Cardiff University, UK in 2014. Participant groups were...

Purpose: To assess the effect of autosomal dominant optic atrophy (ADOA) on ON and OFF retinal ganglion cell (RGC) function by evaluating the ON and OFF components of the photopic negative response (PhNR). Methods: Twelve participants from six families with OPA1 ADOA and 16 age-matched controls were recruited. Electrophysiological assessment inv...

Autosomal dominant optic atrophy (DOA) caused by OPA1 gene mutations leads to retinal ganglion cell (RGC) loss, but the pattern and chronology of loss remain poorly understood. Our aim was to characterise psychophysically the visual losses caused by DOA, and to infer any selective or progressive losses in the distinct visual pathways subserved by d...

Background: Genetic eye pathology represents a significant percentage of the causes of blindness in industrialized countries. This study explores the level of understanding and perceptions of genetics and inherited eye diseases and the attitudes to genetic testing and gene therapy. Methods: The study was conducted in two parts. Participant group...

Aim: The retinal origin of the N95 component of the PERG and the PhNR of the flash ERG is thought to be the retinal ganglion cells. If these components share a common retinal origin, then it may be expected that they would show a similar spatial distribution in the retina. This study aimed to investigate this by comparing the PERG and focal PhNR fr...

Purpose To assess the affect of the missense mutation p.L122P in a mouse model of 3‐methylglutaconic aciduria (MGA‐III), a neuro‐metabolic syndrome which presents with retinal and optic atrophy and neurological impairment. Methods Visual acuity was quantified in an optokinetic nystagmus drum by increasing the spatial frequency of the grating until...

Leber hereditary optic neuropathy and autosomal dominant optic atrophy are the two most common inherited optic neuropathies. The latter has been associated with mutations in the OPA1 and OPA3 genes. To date, only six families with OPA3-associated dominant optic atrophy have been reported. In order to identify additional families, we performed Sange...

Objectives The Sight Loss and Vision Priority Setting Partnership aimed to identify research priorities relating to sight loss and vision through consultation with patients, carers and clinicians. These priorities can be used to inform funding bodies’ decisions and enhance the case for additional research funding. Design Prospective survey with sup...

Inherited optic neuropathies are diseases of retinal ganglion cell dysfunction or loss which lead to optic atrophy. This group of conditions share many common clinical features, which comprise bilateral, symmetrical, painless reduced visual acuity; colour vision defects; central or centro-caecal visual field loss; and pallor of the optic disc. They...

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial...

Purpose The SLV‐PSP process aims to identify research priorities that can be used to inform decisions of funding bodies and enhance the case for additional research funding. Methods People were asked to submit questions about prevention, diagnosis and treatment of sight loss and eye conditions that are most important to them. The survey was availab...