Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies

Manners, David Neil; Rizzo, Giovanni; Morgia, Chiara La; Tonon, Caterina; Testa, Claudia; Barboni, Piero; Malucelli, Emil; Valentino, Maria Lucia; Caporali, Leonardo; Strobbe, Daniela; Carelli, Valerio; Lodi, Raffaele

doi:10.3174/ajnr.a4272

Cited by 30 publications

(44 citation statements)

References 38 publications

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“…MRI tractography studies indicate that the loss of RGCs in the anterior visual pathway could result in transsynaptic degeneration that extends from the lateral geniculate nucleus to the optic radiations, as reported previously in other optic neuropathies such as demyelinating optic neuritis and glaucoma [22, 89]. More widespread microstructural white matter changes in mitochondrial optic neuropathies have also become more clearly apparent with the application of high-resolution MRI scanners and diffusion tensor (DT) imaging protocols to study cohorts of patients with LHON and OPA1-related DOA, which is consistent with the known white matter sensitivity to mitochondrial respiratory chain dysfunction [89, 94, 112, 114].…”

Section: Neurodegeneration: In Vivo Imagingsupporting

confidence: 58%

“…More widespread microstructural white matter changes in mitochondrial optic neuropathies have also become more clearly apparent with the application of high-resolution MRI scanners and diffusion tensor (DT) imaging protocols to study cohorts of patients with LHON and OPA1-related DOA, which is consistent with the known white matter sensitivity to mitochondrial respiratory chain dysfunction [89, 94, 112, 114]. Furthermore, the pattern of DT MRI abnormalities and the lowered diffusivity in the white matter skeleton of the cerebellum, brainstem, thalamus and fronto-occipital-temporal lobes could reflect increased fragmentation of the mitochondrial network and altered neuronal dendritic arborization [112].…”

Section: Neurodegeneration: In Vivo Imagingmentioning

confidence: 94%

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A neurodegenerative perspective on mitochondrial optic neuropathies

et al. 2016

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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 component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1625-2) contains supplementary material, which is available to authorized users.

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Section: Neurodegeneration: In Vivo Imagingsupporting

confidence: 58%

Section: Neurodegeneration: In Vivo Imagingmentioning

confidence: 94%

A neurodegenerative perspective on mitochondrial optic neuropathies

et al. 2016

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“…However, to our knowledge only few studies have investigated this and with conflicting results. [22][23][24] Our study did not find an increased risk of deafness for LHON patients.…”

Section: Discussionmentioning

confidence: 51%

Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study

Vestergaard

Rosenberg

Torp‐Pedersen

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients.METHODS. This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population.RESULTS. Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders.CONCLUSIONS. The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.

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“…However, unlike the well‐recognized link between LHON mtDNA mutations and demyelination, the link between OPA1 mutations and MS is not well established. To date, an MS‐like illness has only been described in one patient with an OPA1 mutation, although another patient had coincidental MRI findings consistent with MS, and several case series have described abnormal white matter high signal changes in OPA1 mutation carriers . In this report, we describe three additional unrelated white Caucasian patients who presented to our tertiary neuro‐ophthalmological center with a clinically definite spinal cord MS phenotype, and who were eventually found to harbor pathogenic OPA1 mutations.…”

Section: Introductionmentioning

confidence: 87%

A multiple sclerosis‐like disorder in patients with OPA1 mutations

Yu‐Wai‐Man

Spyropoulos

Duncan

et al. 2016

Ann Clin Transl Neurol

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We describe three unrelated patients presenting with a spinal cord syndrome and neuroimaging features consistent with multiple sclerosis (MS). All harbored a pathogenic OPA1 mutation. Although the neurological phenotype resembled neuromyelitis optica (NMO), anti‐aquaporin 4 antibodies were not detected and the disorder followed a slow progressive course. The coincidental occurrence of OPA1 mutations and an MS‐like disorder is likely to have modulated the phenotypic manifestations of both disorders, but unlike the previously reported association of Leber hereditary optic neuropathy and MS (Harding disease), the optic neuropathy in patients with OPA1 mutations and an MS‐like disorder can be mild with a good visual prognosis.

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Diffusion Tensor Imaging Mapping of Brain White Matter Pathology in Mitochondrial Optic Neuropathies

Cited by 30 publications

References 38 publications

A neurodegenerative perspective on mitochondrial optic neuropathies

A neurodegenerative perspective on mitochondrial optic neuropathies

Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study

A multiple sclerosis‐like disorder in patients with OPA1 mutations

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