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Patrick Yu-wai-man - One of the best experts on this subject based on the ideXlab platform.

  • Retinal vascular geometry and tortuosity changes in patients with Leber hereditary optic neuropathy (LHON)
    Spencer S. Eccles Health Sciences Library University of Utah, 2019
    Co-Authors: Neringa Jurkute, Anna Majander, Andrew Webster, Marcela Votruba, Maged Habib, Bashir Al-diri, Patrick Yu-wai-man
    Abstract:

    LHON is the most common primary Mitochondrial DNA Disorder. In the subacute stage, fundus examination typically reveals hyperaemic optic discs, telangiectactic microangiopathy, swelling of the retinal nerve fiber layer and tortuosity of the central retinal vessels. The purpose of the study was to describe and quantify retinal vascular geometry (RVG) and tortuosity in different stages of the disease

  • Visual and psychological morbidity among patients with autosomal dominant optic atrophy
    Acta ophthalmologica, 2013
    Co-Authors: Maura Bailie, Marcela Votruba, Patrick F. Chinnery, P G Griffiths, Patrick Yu-wai-man
    Abstract:

    Editor, Autosomal dominant optic atrophy (DOA) is the most common inherited optic nerve Disorder seen in neuro-ophthalmological practice (Yu-Wai-Man et al. 2011). The majority of patients with DOA harbour pathogenic mutations within the OPA1 gene, which codes for an inner Mitochondrial membrane protein intricately involved in Mitochondrial biogenesis, Mitochondrial DNA replication and network stability (Amati-Bonneau et al. 2009). The pathological hallmark of this nuclear Mitochondrial Disorder is progressive retinal ganglion cell loss, leading to optic nerve degeneration and bilateral visual failure from early childhood. About 20% of OPA1 mutation carriers will develop a more severe form of the disease (DOA+) characterized by prominent extraocular neurological features including deafness, ataxia, peripheral neuropathy and myopathy (Yu-Wai-Man et al. 2010). The visual and psychological impact of DOA has not yet been reported. The aim of this study was to quantify the functional impact of DOA on patients’ quality of life and to determine, in particular, whether the additional neurological burden that develops in DOA+ further compounds the visual disability in this group of patients. A total of 38 patients harbouring confirmed pathogenic OPA1 mutations were recruited into this study: 30 patients with isolated optic atrophy and eight patients with DOA+ phenotypes. A telephone interview was conducted by a single investigator (MB), who was blinded to the patients’ mutational status and clinical history, using two well-validated questionnaires: the Visual Function Index (VF-14) (Kirkman et al. 2009) and the Hospital Anxiety and Depression Scale (HADS) (Hinz et al. 2010). Visual acuity data were obtained from the patients’ records. This study had the relevant institutional ethical approval and complied with the Declaration of Helsinki. The mean VF-14 score for the entire patient cohort was 37.3 (Standard deviation = 25.6). Patients with DOA+ had significantly worse visual acuities and VF-14 scores compared with those with pure DOA (Fig. 1A). Borderline or definite symptoms of anxiety and depression were present in 19/38 (50.0%) and 7/38 (18.4%) patients, respectively. Compared with the general adult population, the mean HADS scores were significantly increased for both anxiety (p = 0.0490) and depression scales (p = 0.0287) (data not shown). On subgroup analysis, significantly higher depression scores, but not anxiety scores, were found in patients with DOA+ compared with those with pure DOA (Fig. 1B,C). There was a statistically significant correlation between VF-14 score and (i) LogMAR vision, (ii) anxiety score and (iii) depression score (Fig. 1D–F). Fig 1 OPA1 patient cohort analysis. The data have been represented as box plots with the whiskers representing the minimum and maximum values. The ends of the boxes are the upper and lower quartiles, the vertical lengths of the boxes indicate the interquartile ... Patients with DOA experience significant difficulties in their activities of daily living, the severity being comparable to the degree of functional handicap in Leber hereditary optic neuropathy (LHON) – a classical primary Mitochondrial DNA Disorder that typically presents with catastrophic bilateral blindness in early adulthood (Kirkman et al. 2009). Unlike LHON, visual failure in DOA has a more insidious course, but it is invariably progressive, and the VF-14 score clearly indicates the considerable visual morbidity associated with this Disorder. Furthermore, although half of all OPA1 mutation carriers will eventually fulfil the legal requirement for blind registration (LogMAR < 1.30 in the United Kingdom), impaired activities of daily living were also apparent for those with visual acuities below this threshold, and this patient group should not be denied support from social services. Another observation from our study is the significant psychological impact of DOA, with levels of anxiety and depression approaching those seen in patients undergoing cancer treatment (Hinz et al. 2010). Importantly, the psychological distress seemed magnified in patients manifesting DOA+ phenotypes. From a practical perspective, these patients therefore represent a high-risk group that requires greater clinical input and improved access to rehabilitative services to lessen the impact of the neurological complications on the already considerable visual deficits.

  • A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.
    Brain : a journal of neurology, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

  • A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy
    Brain, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Aylin Garip - One of the best experts on this subject based on the ideXlab platform.

  • A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.
    Brain : a journal of neurology, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

  • A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy
    Brain, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Jan-willem Taanman - One of the best experts on this subject based on the ideXlab platform.

  • A nuclear modifier for a Mitochondrial DNA Disorder.
    Trends in genetics : TIG, 2001
    Co-Authors: Jan-willem Taanman
    Abstract:

    Abstract The first human nuclear gene locus that acts as a modifier for a mutation in the Mitochondrial genome was identified recently. The gene determines the clinical penetrance of the 1555A→G mutation in the Mitochondrial 12S rRNA gene, a mutation that can cause hearing loss. A mouse model indicates that the modifier gene might not encode a Mitochondrial protein, but could instead be involved in an energy-requiring process specific to the inner ear.

Maura Bailie - One of the best experts on this subject based on the ideXlab platform.

  • Visual and psychological morbidity among patients with autosomal dominant optic atrophy
    Acta ophthalmologica, 2013
    Co-Authors: Maura Bailie, Marcela Votruba, Patrick F. Chinnery, P G Griffiths, Patrick Yu-wai-man
    Abstract:

    Editor, Autosomal dominant optic atrophy (DOA) is the most common inherited optic nerve Disorder seen in neuro-ophthalmological practice (Yu-Wai-Man et al. 2011). The majority of patients with DOA harbour pathogenic mutations within the OPA1 gene, which codes for an inner Mitochondrial membrane protein intricately involved in Mitochondrial biogenesis, Mitochondrial DNA replication and network stability (Amati-Bonneau et al. 2009). The pathological hallmark of this nuclear Mitochondrial Disorder is progressive retinal ganglion cell loss, leading to optic nerve degeneration and bilateral visual failure from early childhood. About 20% of OPA1 mutation carriers will develop a more severe form of the disease (DOA+) characterized by prominent extraocular neurological features including deafness, ataxia, peripheral neuropathy and myopathy (Yu-Wai-Man et al. 2010). The visual and psychological impact of DOA has not yet been reported. The aim of this study was to quantify the functional impact of DOA on patients’ quality of life and to determine, in particular, whether the additional neurological burden that develops in DOA+ further compounds the visual disability in this group of patients. A total of 38 patients harbouring confirmed pathogenic OPA1 mutations were recruited into this study: 30 patients with isolated optic atrophy and eight patients with DOA+ phenotypes. A telephone interview was conducted by a single investigator (MB), who was blinded to the patients’ mutational status and clinical history, using two well-validated questionnaires: the Visual Function Index (VF-14) (Kirkman et al. 2009) and the Hospital Anxiety and Depression Scale (HADS) (Hinz et al. 2010). Visual acuity data were obtained from the patients’ records. This study had the relevant institutional ethical approval and complied with the Declaration of Helsinki. The mean VF-14 score for the entire patient cohort was 37.3 (Standard deviation = 25.6). Patients with DOA+ had significantly worse visual acuities and VF-14 scores compared with those with pure DOA (Fig. 1A). Borderline or definite symptoms of anxiety and depression were present in 19/38 (50.0%) and 7/38 (18.4%) patients, respectively. Compared with the general adult population, the mean HADS scores were significantly increased for both anxiety (p = 0.0490) and depression scales (p = 0.0287) (data not shown). On subgroup analysis, significantly higher depression scores, but not anxiety scores, were found in patients with DOA+ compared with those with pure DOA (Fig. 1B,C). There was a statistically significant correlation between VF-14 score and (i) LogMAR vision, (ii) anxiety score and (iii) depression score (Fig. 1D–F). Fig 1 OPA1 patient cohort analysis. The data have been represented as box plots with the whiskers representing the minimum and maximum values. The ends of the boxes are the upper and lower quartiles, the vertical lengths of the boxes indicate the interquartile ... Patients with DOA experience significant difficulties in their activities of daily living, the severity being comparable to the degree of functional handicap in Leber hereditary optic neuropathy (LHON) – a classical primary Mitochondrial DNA Disorder that typically presents with catastrophic bilateral blindness in early adulthood (Kirkman et al. 2009). Unlike LHON, visual failure in DOA has a more insidious course, but it is invariably progressive, and the VF-14 score clearly indicates the considerable visual morbidity associated with this Disorder. Furthermore, although half of all OPA1 mutation carriers will eventually fulfil the legal requirement for blind registration (LogMAR < 1.30 in the United Kingdom), impaired activities of daily living were also apparent for those with visual acuities below this threshold, and this patient group should not be denied support from social services. Another observation from our study is the significant psychological impact of DOA, with levels of anxiety and depression approaching those seen in patients undergoing cancer treatment (Hinz et al. 2010). Importantly, the psychological distress seemed magnified in patients manifesting DOA+ phenotypes. From a practical perspective, these patients therefore represent a high-risk group that requires greater clinical input and improved access to rehabilitative services to lessen the impact of the neurological complications on the already considerable visual deficits.

  • A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.
    Brain : a journal of neurology, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

  • A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy
    Brain, 2011
    Co-Authors: Thomas Klopstock, Patrick Yu-wai-man, Konstantinos Dimitriadis, Jacinthe Rouleau, Suzette Heck, Maura Bailie, Alaa Atawan, Sandip Chattopadhyay, Marion Schubert, Aylin Garip
    Abstract:

    Major advances in understanding the pathogenesis of inherited metabolic disease caused by Mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber’s hereditary optic neuropathy is the most common Mitochondrial DNA Disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber’s hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber’s hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or Mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the Mitochondrial Disorder, Leber’s hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Rita Horvath - One of the best experts on this subject based on the ideXlab platform.

  • Adult-onset spinocerebellar ataxia syndromes due to MTATP6 mutations
    Journal of neurology neurosurgery and psychiatry, 2012
    Co-Authors: Gerald Pfeffer, Rita Horvath, Robert W. Taylor, Emma L. Blakely, Charlotte L. Alston, Adam Hassani, Mike Boggild, David C. Samuels, Patrick F. Chinnery
    Abstract:

    Background Spinocerebellar ataxia syndromes presenting in adulthood have a broad range of causes, and despite extensive investigation remain undiagnosed in up to ∼50% cases. Mutations in the Mitochondrially encoded MTATP6 gene typically cause infantile-onset Leigh syndrome and, occasionally, have onset later in childhood. The authors report two families with onset of ataxia in adulthood (with pyramidal dysfunction and/or peripheral neuropathy variably present), who are clinically indistinguishable from other spinocerebellar ataxia patients. Methods Genetic screening study of the MTATP6 gene in 64 pedigrees with unexplained ataxia, and case series of two families who had MTATP6 mutations. Results Three pedigrees had mutations in MTATP6 , two of which have not been reported previously and are detailed in this report. These families had the m.9185T>C and m.9035T>C mutations, respectively, which have not previously been associated with adult-onset cerebellar syndromes. Other investigations including muscle biopsy and respiratory chain enzyme activity were non-specific or normal. Conclusions MTATP6 sequencing should be considered in the workup of undiagnosed ataxia, even if other investigations do not suggest a Mitochondrial DNA Disorder.

  • Identification of an X-Chromosomal Locus and Haplotype Modulating the Phenotype of a Mitochondrial DNA Disorder
    American journal of human genetics, 2005
    Co-Authors: Gavin Hudson, Sharon Keers, Patrick Yu Wai Man, Philip G. Griffiths, Kirsi Huoponen, Marja-liisa Savontaus, Eeva Nikoskelainen, Massimo Zeviani, Franco Carrara, Rita Horvath
    Abstract:

    Mitochondrial DNA (mtDNA) mutations are a major cause of human disease. A large number of different molecular defects ultimately compromise oxidative phosphorylation, but it is not clear why the same biochemical defect can cause diverse clinical phenotypes. There is emerging evidence that nuclear genes modulate the phenotype of primary mtDNA Disorders. Here, we define an X-chromosomal haplotype that interacts with specific MTND mutations to cause visual failure in the most common mtDNA disease, Leber hereditary optic neuropathy. This effect is independent of the mtDNA genetic background and explains the variable penetrance and sex bias that characterizes this Disorder.