Retinal Function and Neural Conduction Along the Visual Pathways in Affected and Unaffected Carriers With Leber's Hereditary Optic Neuropathy

Ziccardi, Lucia; Sadun, Federico; Negri, Anna M aria De; Barboni, Piero; Savini, Giacomo; Borrelli, Enrico; Morgia, Chiara La; Carelli, Valerio; Parisi, Vincenzo

doi:10.1167/iovs.13-12894

Cited by 38 publications

(53 citation statements)

References 48 publications

(60 reference statements)

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“…Optical coherence test (OCT) scan showed bilateral reduction of macular thickness, due to selective depletion of ganglionic cells and reduction of retinal fiber layers thickness, more severe over the temporal sectors. Pattern electroretinography (PERG) and visual evoked potentials (VEPs) showed a dysfunction of retinal ganglion cells associated with a delay in neural conduction along both large and small optic nerve axons [7]. Direct gene testing of the OPA1 gene (MIM 165500), whole mitochondrial DNA sequencing in blood as well as direct testing for the mtDNA mutations associated with Leber Hereditary Optic Neuropathy (LHON, MIM 535000) were all normal.…”

Section: Case Reportmentioning

confidence: 99%

Acute optic neuropathy associated with a novel MFN2 mutation

Leonardi¹,

Marcotulli²,

Storti

et al. 2015

J Neurol

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Mutations in the mitofusin 2 (MFN2) gene cause CMT2A the most common form of autosomal dominant axonal Charcot-Marie-Tooth (CMT). In addition, mutations in MFN2 have been shown to be responsible for Hereditary Motor Sensory Neuropathy type VI (HSMN VI), a rare early-onset axonal CMT associated with optic neuropathy. Most reports of HMSN VI presented with a sub-acute form of optic neuropathy. Herein, we report a CMT2A patient, who developed very rapidly progressing severe optic neuropathy. A 40-year-old Caucasian man was evaluated for gait disturbance and lower limbs weakness, slowly progressed over the last 2 years. Due to clinical data and family history, a diagnosis of CMT2 was made. The novel heterozygous c.775C > T (p.Arg259Cys) mutation in MFN2 was detected in the patient and his clinical affected mother. Interestingly, the patient developed a severe sudden bilateral visual deterioration few years early, with clinical and instrumental picture suggestive of acute bilateral optic neuropathy. Our report expands the spectrum of MFN2-related manifestation because it indicates that visual symptoms of HMSN VI may enter in the differential with acquired or hereditary acute optic neuropathies, and that severe optic neuropathy is not invariably an early manifestation of the disease but may occur as disease progressed. This report could have an impact on clinicians who evaluate patients with otherwise unexplainable bilateral acute-onset optic neuropathy, especially if associated with a motor and sensory axonal neuropathy.

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Section: Case Reportmentioning

confidence: 99%

Acute optic neuropathy associated with a novel MFN2 mutation

Leonardi¹,

Marcotulli²,

Storti

et al. 2015

J Neurol

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“…Clinical studies demonstrated the maintenance of the pupil responses in LHON patients (31, 32). The diagnostic workup in LHON also may include other neurophysiologic tests such as visual evoked potentials (VEPs) that reveal delayed latency and reduced amplitude of cortical responses and pattern electroretinograms (PERGs), which demonstrate reduced amplitude and delayed latency of responses (33). …”

Section: Clinical Presentation Of Lhon/doa and Clinical Workupmentioning

confidence: 99%

“…Asymptomatic carriers of LHON mutation may also have swollen retinal nerve fibers that can be seen on fundus examination and by OCT (45, 46) (Figure 1B), abnormalities in color vision (47), and in neural conduction along the visual pathways (33, 48). …”

Section: Clinical Presentation Of Lhon/doa and Clinical Workupmentioning

confidence: 99%

Medical Management of Hereditary Optic Neuropathies

Morgia

Carbonelli²,

Barboni

et al. 2014

Front. Neurol.

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Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber’s hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.

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“…6,7 Functionally, in patients with LHON and carriers, it is possible to track the main dysfunction of retinal ganglion cells (RGCs) and of the optic nerve by electrophysiologic methods. In particular, the dysfunction of the RGCs and relative nerve fibers can be studied by using pattern electroretinogram (PERG) recordings, [8][9][10] and abnormal PERG responses in patients with LHON 11,12 and in asymptomatic carriers 12,13 have been found. To verify the extent of the functional impairment along the axons forming the optic nerve, visual evoked potentials (VEP) recordings in response to pattern 14 or multifocal stimuli 15 can be used.…”

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confidence: 99%

“…16 In carriers, instead, the finding of normal VEP suggested a functional integrity of the optic nerve. 12 However, all of these cited studies [11][12][13]16,17 were performed exclusively in the disease "chronic phase" with various degrees of optic atrophy and with no follow-up. 6 Actually, there is a lack of exhaustive information in the literature about the possible functional changes in RGCs (evaluated by PERG) and in visual pathways (evaluated by VEP recordings) that may occur during the "chronic phase" in a wide cohort of patients with LHON.…”

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confidence: 99%

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber’s Hereditary Optic Neuropathy during One Year of Follow-up

Parisi

Ziccardi

Sadun³

et al. 2019

Ophthalmology

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Purpose: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase.Design: Retrospective case series. Participants: Twenty-two patients with LHON (mean age, 36.3AE9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five agesimilar healthy participants, providing 25 eyes, served as controls.Methods: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60ʹ and 15ʹ checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of testeretest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA.Main Outcome Measures: Changes of individual and mean absolute values of 60ʹ and 15ʹ PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group.Results: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values.Conclusions: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.

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Retinal Function and Neural Conduction Along the Visual Pathways in Affected and Unaffected Carriers With Leber's Hereditary Optic Neuropathy

Cited by 38 publications

References 48 publications

Acute optic neuropathy associated with a novel MFN2 mutation

Acute optic neuropathy associated with a novel MFN2 mutation

Medical Management of Hereditary Optic Neuropathies

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber’s Hereditary Optic Neuropathy during One Year of Follow-up

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