Chiara La Morgia

Leber’s Hereditary Optic Neuropathy

Opinion statementLeber’s hereditary optic neuropathy (LHON) is a maternally inherited blinding disease with variable penetrance. Three primary mitochondrial DNA mutations, affecting the respiratory complex I, are necessary but not sufficient to cause blindness. Reduced efficiency of ATP synthesis and increased oxidative stress are believed to sensitize the retinal ganglion cells to apoptosis. Different therapeutic strategies are considered to counteract this pathogenic mechanism. However, potential treatments for the visual loss are complicated by the fact that patients are unlikely to benefit after optic atrophy occurs. There is no proven therapy to prevent or reverse the optic neuropathy in LHON. Results from a recent trial with idebenone hold promise to limit neurodegeneration and improve final outcome, promoting recovery of visual acuity. Other therapeutic options are under scrutiny, including gene therapy, agents increasing mitochondrial biogenesis, and anti-apoptotic drugs.

Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background.

Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.

Idebenone Treatment In Leber's Hereditary Optic Neuropathy

Sir, We have read with great interest the results presented by Klopstock et al. (2011) concerning the RHODOS study on a clinical trial with idebenone in Lebers hereditary optic neuropathy (LHON) and we would like to share our own experience of idebenone therapy in LHON. Idebenone has been an approved drug (Mnesis®, Takeda Italia Farmaceutici) in Italy since the early 1990s and, after the initial report by Mashima et al . (1992) on its possible efficacy in LHON, we offered this therapeutic option to all of our new consecutive patients with LHON, almost all of whom accepted treatment. Idebenone was given after informed consent following the regulation for ‘off-label’ drug administration and was provided for free by the National Health Service, under the legislation for certified rare disorders. Patients were initially treated with 270 mg/day (Cortelli et al ., 1997; Carelli et al ., 1998 a , b ), but following the reports on idebenone treatment in Friedreich ataxia, the dosages were increased to 540–675 mg/day (Rustin et al ., 1999; Kearney et al ., 2009). To evaluate retrospectively the efficacy of idebenone therapy, we reviewed all of our patients with LHON, idebenone treated and untreated, after approval of the institutional Internal Review Board. Inclusion criteria for treated patients were the initiation of therapy within 1 year after visual loss in the second eye, and for all patients (treated and untreated) age at onset of at least 10 years and a follow-up of at least 5 years. We included only patients treated within 1 year after onset because this is the time frame to reach the nadir of the visual loss and the probability of spontaneous recovery of vision is highest in the following 5 years (Nikoskelainen et al ., 1983; Barboni et al ., 2005, 2010; …

Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies

Mitochondrial optic neuropathies, that is, Leber hereditary optic neuropathy and dominant optic atrophy, selectively affect retinal ganglion cells, causing visual loss with relatively preserved pupillary light reflex. The mammalian eye contains a light detection system based on a subset of retinal ganglion cells containing the photopigment melanopsin. These cells give origin to the retinohypothalamic tract and support the non-image-forming visual functions of the eye, which include the photoentrainment of circadian rhythms, light-induced suppression of melatonin secretion and pupillary light reflex. We studied the integrity of the retinohypothalamic tract in five patients with Leber hereditary optic neuropathy, in four with dominant optic atrophy and in nine controls by testing the light-induced suppression of nocturnal melatonin secretion. This response was maintained in optic neuropathy subjects as in controls, indicating that the retinohypothalamic tract is sufficiently preserved to drive light information detected by melanopsin retinal ganglion cells. We then investigated the histology of post-mortem eyes from two patients with Leber hereditary optic neuropathy and one case with dominant optic atrophy, compared with three age-matched controls. On these retinas, melanopsin retinal ganglion cells were characterized by immunohistochemistry and their number and distribution evaluated by a new protocol. In control retinas, we show that melanopsin retinal ganglion cells are lost with age and are more represented in the parafoveal region. In patients, we demonstrate a relative sparing of these cells compared with the massive loss of total retinal ganglion cells, even in the most affected areas of the retina. Our results demonstrate that melanopsin retinal ganglion cells resist neurodegeneration due to mitochondrial dysfunction and maintain non-image-forming functions of the eye in these visually impaired patients. We also show that in normal human retinas, these cells are more concentrated around the fovea and are lost with ageing. The current results provide a plausible explanation for the preservation of pupillary light reaction despite profound visual loss in patients with mitochondrial optic neuropathy, revealing the robustness of melanopsin retinal ganglion cells to a metabolic insult and opening the question of mechanisms that might protect these cells.

Augmentation of restless legs syndrome with long‐term tramadol treatment

Restless legs syndrome (RLS) augmentation, defined as a kind of suppression of the circadian rhythm of the disease in which sensory and motor symptoms appear earlier during the day (and over previously unaffected body parts), with a progressive phase advance until, backwards, the symptoms may cover the entire day, has been described only after treatment with dopaminergic drugs. We report clinical and polysomnographic accounts of a patient developing RLS augmentation after long‐term treatment with tramadol, an opioid agonist with selectivity for μ‐receptor and added norepinephrine and serotonin reuptake inhibition properties. Polysomnographic measures showed an improvement of RLS and a disappearance of diurnal sensory and motor RLS symptoms after tramadol was stopped. Our case confirms a recent retrospective report of augmentation of RLS after treatment with tramadol, and begs the question whether augmentation is truly restricted to dopaminergic drugs.

Melanopsin retinal ganglion cell loss in Alzheimer disease

Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction.

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

Mounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.

Melanopsin-expressing retinal ganglion cells: implications for human diseases

In the last decade, there was the seminal discovery of melanopsin-expressing retinal ganglion cells (mRGCs) as a new class of photoreceptors that subserve the photoentrainment of circadian rhythms and other non-image forming functions of the eye. Since then, there has been a growing research interest on these cells, mainly focused on animal models. Only recently, a few studies have started to address the relevance of the mRGC system in humans and related diseases. We recently discovered that mRGCs resist neurodegeneration in two inherited mitochondrial disorders that cause blindness, i.e. Leber hereditary optic neuropathy and dominant optic atrophy. The mechanism leading to mRGCs sparing in these blinding disorders, characterized by extensive and selective loss of RGCs, is currently unknown and under investigation. Other studies reported on mRGCs in glaucoma, on genetic variation of the melanopsin gene (OPN4) in seasonal affective disorder and on the role of mRGCs in migraineous photophobia. Our own data and studies from others have shown a significant reduction of mRGCs with aging. We anticipate that these studies will lead to many other investigations addressing the role of mRGCs and circadian photoreception in the pathogenesis of circadian and sleep abnormalities in neurodegenerative disorders.

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.

The optic nerve: a "mito-window" on mitochondrial neurodegeneration.

Retinal ganglion cells (RGCs) project their long axons, composing the optic nerve, to the brain, transmitting the visual information gathered by the retina, ultimately leading to formed vision in the visual cortex. The RGC cellular system, representing the anterior part of the visual pathway, is vulnerable to mitochondrial dysfunction and optic atrophy is a very frequent feature of mitochondrial and neurodegenerative diseases. The start of the molecular era of mitochondrial medicine, the year 1988, was marked by the identification of a maternally inherited form of optic atrophy, Lebers hereditary optic neuropathy, as the first disease due to mitochondrial DNA point mutations. The field of mitochondrial medicine has expanded enormously over the last two decades and many neurodegenerative diseases are now known to have a primary mitochondrial etiology or mitochondrial dysfunction plays a relevant role in their pathogenic mechanism. Recent technical advancements in neuro-ophthalmology, such as optical coherence tomography, prompted a still ongoing systematic re-investigation of retinal and optic nerve involvement in neurodegenerative disorders. In addition to inherited optic neuropathies, such as Lebers hereditary optic neuropathy and dominant optic atrophy, and in addition to the syndromic mitochondrial encephalomyopathies or mitochondrial neurodegenerative disorders such as some spinocerebellar ataxias or familial spastic paraparesis and other disorders, we draw attention to the involvement of the optic nerve in classic age-related neurodegenerative disorders such as Parkinson and Alzheimer disease. We here provide an overview of optic nerve pathology in these different clinical settings, and we review the possible mechanisms involved in the pathogenesis of optic atrophy. This may be a model of general value for the field of neurodegeneration. This article is part of a Special Issue entitled ‘Mitochondrial function and dysfunction in neurodegeneration’.