Publications by authors named "Michele Carbonelli"

61 Publications

Brain functional MRI responses to blue light stimulation in Leber's hereditary optic neuropathy.

Biochem Pharmacol 2021 Feb 27:114488. Epub 2021 Feb 27.

Unità di RM Funzionale, Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neuroimmagini Funzionali e Molecolari, Bologna, Italy.

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive photoreceptors contributing both to image and non-image-forming (NIF) functions of the eye. They convey light signal to the brain to modulate circadian entrainment, sleep, alertness, cognition, brightness perception and coarse vision. Given that rods and cones also contribute to all these impacts of light, isolating mRGC visual and NIF roles in humans is challenging so that mRGC functions remains to be fully characterized. Here, we evaluated light-driven visual and cognitive brain responses in Leber's Hereditary Optic Neuropathy (LHON), an inherited optic neuropathy that is characterized by a selective relative sparing of the melanopsin-expressing retinal ganglion cells (mRGCs). Twelve patients and twelve matched healthy controls (HC) were enrolled in a functional brain magnetic resonance imaging (fMRI) protocol including visual and visual-cognitive paradigms under blue (480 nm) and red (620 nm) light exposures. Primary visual cortex activation was detected in LHON patients; in particular higher occipital activation was found in response to sustained blue vs. red stimulation in LHON vs. HC. Similarly, brain responses to the executive task were larger under blue vs. red light in LHON over lateral prefrontal cortex. These findings are in line with the relative mRGC sparing demonstrated in LHON and support the mRGC contribution to both non-visual and visual brain functions, with potential implication for visual rehabilitation in hereditary optic neuropathy patients.
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http://dx.doi.org/10.1016/j.bcp.2021.114488DOI Listing
February 2021

Impaired complex I repair causes recessive Leber's hereditary optic neuropathy.

J Clin Invest 2021 Mar;131(6)

Institute of Human Genetics, School of Medicine, Technische Universität München, Munich, Germany.

Leber's hereditary optic neuropathy (LHON) is the most frequent mitochondrial disease and was the first to be genetically defined by a point mutation in mitochondrial DNA (mtDNA). A molecular diagnosis is achieved in up to 95% of cases, the vast majority of which are accounted for by 3 mutations within mitochondrial complex I subunit-encoding genes in the mtDNA (mtLHON). Here, we resolve the enigma of LHON in the absence of pathogenic mtDNA mutations. We describe biallelic mutations in a nuclear encoded gene, DNAJC30, in 33 unsolved patients from 29 families and establish an autosomal recessive mode of inheritance for LHON (arLHON), which to date has been a prime example of a maternally inherited disorder. Remarkably, all hallmarks of mtLHON were recapitulated, including incomplete penetrance, male predominance, and significant idebenone responsivity. Moreover, by tracking protein turnover in patient-derived cell lines and a DNAJC30-knockout cellular model, we measured reduced turnover of specific complex I N-module subunits and a resultant impairment of complex I function. These results demonstrate that DNAJC30 is a chaperone protein needed for the efficient exchange of complex I subunits exposed to reactive oxygen species and integral to a mitochondrial complex I repair mechanism, thereby providing the first example to our knowledge of a disease resulting from impaired exchange of assembled respiratory chain subunits.
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http://dx.doi.org/10.1172/JCI138267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954600PMC
March 2021

Therapeutic Options in Hereditary Optic Neuropathies.

Drugs 2021 Jan;81(1):57-86

IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy.

Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be  developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.
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http://dx.doi.org/10.1007/s40265-020-01428-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843467PMC
January 2021

Chromatic Pupillometry Findings in Alzheimer's Disease.

Front Neurosci 2020 11;14:780. Epub 2020 Aug 11.

IRCCS Istituto Delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna, Italy.

Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.
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http://dx.doi.org/10.3389/fnins.2020.00780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431959PMC
August 2020

Idebenone increases chance of stabilization/recovery of visual acuity in OPA1-dominant optic atrophy.

Ann Clin Transl Neurol 2020 04 3;7(4):590-594. Epub 2020 Apr 3.

IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna, Italy.

We previously documented that idebenone treatment in OPA1-Dominant Optic Atrophy (OPA1-DOA) led to some degrees of visual improvement in seven patients. We here present the results of a cohort study, which investigated the effect of off-label idebenone administration in a larger OPA1-DOA group compared with untreated patients. Inclusion criteria were: OPA1-DOA clinical and molecular diagnosis, baseline visual acuity (VA) greater than/equal to counting fingers and treatment duration greater than 7 months. We found a significant difference between the last visit and baseline VA in favor of stabilization/recovery in idebenone-treated as compared to untreated patients. This effect was retained after controlling for confounders.
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http://dx.doi.org/10.1002/acn3.51026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187718PMC
April 2020

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy.

Ann Neurol 2020 07 21;88(1):18-32. Epub 2020 Apr 21.

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Objective: Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed.

Methods: We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient-derived fibroblasts.

Results: Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype-modifier variants. All the DOA-associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28-associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA-associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28-associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission-inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells.

Interpretation: This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18-32.
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http://dx.doi.org/10.1002/ana.25723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383914PMC
July 2020

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.

Sci Rep 2020 03 16;10(1):4785. Epub 2020 Mar 16.

IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy.

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria.
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http://dx.doi.org/10.1038/s41598-020-61735-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075867PMC
March 2020

SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder.

J Clin Invest 2020 01;130(1):108-125

Unit of Neurology, Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.

Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.
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http://dx.doi.org/10.1172/JCI128514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934201PMC
January 2020

First missense mutation in an Italian proband with optic atrophy and deafness.

Neurol Genet 2019 Jun 8;5(3):e329. Epub 2019 Apr 8.

IRCCS Istituto delle Scienze Neurologiche di Bologna (C.L.M., L.C., F.T., F.P., M.C., R.L., V.C.), UOC Clinica Neurologica; Dipartimento di Scienze Biomediche e Neuromotorie (C.L.M., R.L., V.C.), Università di Bologna; and Studio Oculistico d'Azeglio (P.B.), Bologna, Italy.

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http://dx.doi.org/10.1212/NXG.0000000000000329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499220PMC
June 2019

Melanopsin Retinal Ganglion Cells and Pupil: Clinical Implications for Neuro-Ophthalmology.

Front Neurol 2018 7;9:1047. Epub 2018 Dec 7.

Unità Operativa Complessa Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Bologna, Italy.

Melanopsin retinal ganglion cells (mRGCs) are intrinsically photosensitive RGCs that mediate many relevant non-image forming functions of the eye, including the pupillary light reflex, through the projections to the olivary pretectal nucleus. In particular, the post-illumination pupil response (PIPR), as evaluated by chromatic pupillometry, can be used as a reliable marker of mRGC function . In the last years, pupillometry has become a promising tool to assess mRGC dysfunction in various neurological and neuro-ophthalmological conditions. In this review we will present the most relevant findings of pupillometric studies in glaucoma, hereditary optic neuropathies, ischemic optic neuropathies, idiopathic intracranial hypertension, multiple sclerosis, Parkinson's disease, and mood disorders. The use of PIPR as a marker for mRGC function is also proposed for other neurodegenerative disorders in which circadian dysfunction is documented.
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http://dx.doi.org/10.3389/fneur.2018.01047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292931PMC
December 2018

Peculiar combinations of individually non-pathogenic missense mitochondrial DNA variants cause low penetrance Leber's hereditary optic neuropathy.

PLoS Genet 2018 02 14;14(2):e1007210. Epub 2018 Feb 14.

Neurology Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy.

We here report on the existence of Leber's hereditary optic neuropathy (LHON) associated with peculiar combinations of individually non-pathogenic missense mitochondrial DNA (mtDNA) variants, affecting the MT-ND4, MT-ND4L and MT-ND6 subunit genes of Complex I. The pathogenic potential of these mtDNA haplotypes is supported by multiple evidences: first, the LHON phenotype is strictly inherited along the maternal line in one very large family; second, the combinations of mtDNA variants are unique to the two maternal lineages that are characterized by recurrence of LHON; third, the Complex I-dependent respiratory and oxidative phosphorylation defect is co-transferred from the proband's fibroblasts into the cybrid cell model. Finally, all but one of these missense mtDNA variants cluster along the same predicted fourth E-channel deputed to proton translocation within the transmembrane domain of Complex I, involving the ND1, ND4L and ND6 subunits. Hence, the definition of the pathogenic role of a specific mtDNA mutation becomes blurrier than ever and only an accurate evaluation of mitogenome sequence variation data from the general population, combined with functional analyses using the cybrid cell model, may lead to final validation. Our study conclusively shows that even in the absence of a clearly established LHON primary mutation, unprecedented combinations of missense mtDNA variants, individually known as polymorphisms, may lead to reduced OXPHOS efficiency sufficient to trigger LHON. In this context, we introduce a new diagnostic perspective that implies the complete sequence analysis of mitogenomes in LHON as mandatory gold standard diagnostic approach.
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http://dx.doi.org/10.1371/journal.pgen.1007210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828459PMC
February 2018

Patterns of Retinal Ganglion Cell Damage in Neurodegenerative Disorders: Parvocellular vs Magnocellular Degeneration in Optical Coherence Tomography Studies.

Front Neurol 2017 22;8:710. Epub 2017 Dec 22.

IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.

Many neurodegenerative disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD), are characterized by loss of retinal ganglion cells (RGCs) as part of the neurodegenerative process. Optical coherence tomography (OCT) studies demonstrated variable degree of optic atrophy in these diseases. However, the pattern of degenerative changes affecting the optic nerve (ON) can be different. In particular, neurodegeneration is more evident for magnocellular RGCs in AD and multiple system atrophy with a pattern resembling glaucoma. Conversely, in PD and Huntington's disease, the parvocellular RGCs are more vulnerable. This latter pattern closely resembles that of mitochondrial optic neuropathies, possibly pointing to similar pathogenic mechanisms. In this review, the currently available evidences on OCT findings in these neurodegenerative disorders are summarized with particular emphasis on the different pattern of RGC loss. The ON degeneration could become a validated biomarker of the disease, which may turn useful to follow natural history and possibly assess therapeutic efficacy.
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http://dx.doi.org/10.3389/fneur.2017.00710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744067PMC
December 2017

International Consensus Statement on the Clinical and Therapeutic Management of Leber Hereditary Optic Neuropathy.

J Neuroophthalmol 2017 12;37(4):371-381

IRCCS Institute of Neurological Sciences of Bologna (VC, MC, CLM), Bellaria Hospital, Bologna, Italy; Unit of Neurology (VC, CLM), Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy; Department of Neurology (IFdC), Erasmus Medical Center, Rotterdam, the Netherlands; Neuro-Ophthalmology Unit (AK), University of Lausanne, Jules Gonin Eye Hospital, Lausanne, Switzerland; Department of Neurology (TK), Friedreich-Baur-Institute, Ludwing-Maximilians-University, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy) (TK), Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) (TK), Munich, Germany; Eye Center (WAL), Medical Center, Faculty of Medicine, University of Freiburg, Breisgau, Germany; Departments of Ophthalmology, Neurology and Neurological Surgery (NJN), Emory University School of Medicine, Atlanta, Georgia; Department of Ophthalmology (CO); Referral Center for Rare Diseases OPHTARA, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France; Department of Ophthalmology (JWRP), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Doheny Eye Institute (AAS), Los Angeles, California; Department of Ophthalmology (AAS), David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Neuro-ophthalmology (JvE), The Rotterdam Eye Hospital, Rotterdam, the Netherlands; Rotterdam Ophthalmic Institute (ROI) (JvE), Rotterdam, the Netherlands; Fondation Ophtalmologique Adolphe de Rothschild (CV-C), Paris, France; School of Optometry and Vision Sciences (MV), Cardiff University, and Cardiff Eye Clinic, University Hospital of Wales, Cardiff, United Kingdom; Wellcome Trust Center for Mitochondrial Research (PY-W-M), Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom; Newcastle Eye Center (PY-W-M), Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom; NIHR Biomedical Research Center at Moorfields Eye Hospital and UCL Institute of Ophthalmology (PY-W-M), London, United Kingdom; Department of Clinical Neurosciences (PY-W-M), School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; Department of Ophthalmology (PB), San Raffaele Scientific Institute, Milan, Italy; and Studio Oculistico d'Azeglio (PB), Bologna, Italy.

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 European Medicine Agency, under exceptional circumstances because of the rarity and severity of the disease. However, what remains unclear includes the optimal target population, timing, dose, and frequency of administration of idebenone in LHON due to lack of accepted definitions, criteria, and general guidelines for the clinical management of LHON. To address these issues, a consensus conference with a panel of experts from Europe and North America was held in Milan, Italy, in 2016. The intent was to provide expert consensus statements for the clinical and therapeutic management of LHON based on the currently available evidence. We report the conclusions of this conference, providing the guidelines for clinical and therapeutic management of LHON.
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http://dx.doi.org/10.1097/WNO.0000000000000570DOI Listing
December 2017

Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy.

Br J Ophthalmol 2016 09 27;100(9):1232-7. Epub 2015 Nov 27.

Studio Oculistico d'Azeglio, Bologna, Italy Scientific Institute San Raffaele, Milan, Italy.

Aims: To evaluate longitudinal retinal ganglion cell inner plexiform layer (GC-IPL) and macular retinal nerve fibre layer (mRNFL) thickness changes in acute Leber's hereditary optic neuropathy (LHON).

Methods: Six eyes of four patients with LHON underwent SD-OCT (optical coherence tomography) at month 1, 3, 6 and 12 after visual loss. In two eyes, the examination was carried out in the presymptomatic stage. The relationship and curves for area under the receiver operator characteristic (AUROC) were generated to assess the ability of each parameter to detect ganglion cell loss.

Results: Significant longitudinal thinning of GC-IPL and mRNFL was detected in LHON. GC-IPL thinning was detectable in the deviation map during the presymptomatic stage in the inner ring of the nasal sector and then it progressively extended following a centrifugal and spiral pattern. Similarly, mRNFL thinning began in the inferonasal sector and it progressively extended. No further statistically significant changes were detected after month 3. The highest level of AUROC values at 1 month were detected in the nasal sectors and inferonasal mRNFL thickness reached AUROC value=1. All the parameters were equally able to detect ganglion cell loss from month 2 to 12.

Conclusions: The natural history of GC-IPL thinning follows a specific pattern of reduction, reflecting the anatomical course of papillomacular fibres. Month 6 represents the end of GC-IPL loss. GC-IPL and mRNFL thinning is detectable before onset of visual loss. These observations can help future therapeutic approaches for both LHON carriers at high risk of conversion and patients with acute early LHON.
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http://dx.doi.org/10.1136/bjophthalmol-2015-307326DOI Listing
September 2016

Intraocular lens power calculation after myopic excimer laser surgery: Selecting the best method using available clinical data.

J Cataract Refract Surg 2015 Sep;41(9):1880-8

From the G.B. Bietti Foundation-IRCCS (Savini, Ducoli), Rome, the Studio Oculistico d'Azeglio (Barboni, Carbonelli), Bologna, and the Scientific Institute San Raffaele (Barboni), Milan, Italy; the Jules Stein Eye Institute (Hoffer), University of California, Los Angeles, and St. Mary's Eye Center (Hoffer), Santa Monica, California, USA.

Purpose: To compare the results of methods to calculate intraocular lens (IOL) power after myopic excimer laser surgery.

Setting: G.B. Bietti Foundation-IRCCS, Rome, Italy.

Design: Prospective interventional case series.

Methods: Eyes were classified into 4 groups: Group 1 (preoperative keratometry available, refractive change known), Group 2 (preoperative keratometry available, refractive change uncertain), Group 3 (preoperative keratometry unavailable, refractive change known), and Group 4 (preoperative keratometry unavailable, refractive change unknown). The IOL power was calculated by 19 methods. The median absolute error in refraction prediction and the percentage of eyes with a refraction prediction error within ±0.50 diopter (D) were calculated.

Results: In Group 1 (n = 30), the Savini, Seitz/Speicher/Savini, and Masket methods provided the lowest median absolute error (0.29 D, 0.35 D, and 0.34 D, respectively), with more than 70% of eyes within ±0.50 D of the predicted refraction. In Group 2 (n = 16), the Seitz/Speicher method achieved the best result (median absolute error 0.37 D), with 75% of eyes within ±0.50 D of the predicted refraction. In Group 3 (n = 18), the Masket method provided the lowest median absolute error (0.24 D), with 72.2% of eyes within ±0.50 D of the predicted refraction. In Group 4 (n = 6), the Shammas no-history method had the lowest median absolute error (0.31 D), with 83% of eyes within ±0.50 D of the predicted refraction.

Conclusion: Intraocular lens power can be accurately calculated in post-laser surgery eyes when the preoperative corneal power and refractive change are known and when they are not.

Financial Disclosure: Dr. Hoffer receives book royalties for IOL Power and formula royalties from all manufacturers using the Hoffer Q formula to ensure it is programmed correctly. No other author has a financial or proprietary interest in any material or method mentioned.
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http://dx.doi.org/10.1016/j.jcrs.2015.10.026DOI Listing
September 2015

Melanopsin retinal ganglion cell loss in Alzheimer disease.

Ann Neurol 2016 Jan 18;79(1):90-109. Epub 2015 Dec 18.

IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.

Objective: 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.

Methods: We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls.

Results: We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs.

Interpretation: We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.
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http://dx.doi.org/10.1002/ana.24548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737313PMC
January 2016

Macular Microcysts in Mitochondrial Optic Neuropathies: Prevalence and Retinal Layer Thickness Measurements.

PLoS One 2015 5;10(6):e0127906. Epub 2015 Jun 5.

San Raffaele Scientific Institute, Milan, Italy; Studio Oculistico d'Azeglio, Bologna, Italy.

Purpose: To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON).

Methods: All patients with molecularly confirmed MON, i.e. Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections.

Results: MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7μm vs 122.3±9μm in MM patients (p<0.01) and 128.5±8μm vs. 122.3±9μm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mμ) compared to patients without MM [77.5±8mμ (p<0.001)] and controls [78.4±7mμ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls.

Conclusion: The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127906PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457906PMC
March 2016

Syndromic parkinsonism and dementia associated with OPA1 missense mutations.

Ann Neurol 2015 Jul 10;78(1):21-38. Epub 2015 Jun 10.

Mitochondrial Biology Unit, Medical Research Council, Cambridge, United Kingdom.

Objective: 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.

Methods: Patients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.

Results: Affected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase-negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.

Interpretation: The association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism.
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http://dx.doi.org/10.1002/ana.24410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008165PMC
July 2015

Medical management of hereditary optic neuropathies.

Front Neurol 2014 31;5:141. Epub 2014 Jul 31.

UOC Clinica Neurologica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria , Bologna , Italy ; Unità di Neurologia, Dipartimento di Scienze Biomediche e NeuroMotorie (DIBINEM), Università di Bologna , Bologna , Italy.

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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http://dx.doi.org/10.3389/fneur.2014.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117178PMC
August 2014

A novel in-frame 18-bp microdeletion in MT-CYB causes a multisystem disorder with prominent exercise intolerance.

Hum Mutat 2014 Aug 28;35(8):954-8. Epub 2014 Jun 28.

Dipartimento di Biologia e Biotecnologie "L. Spallanzani", Università di Pavia, Pavia, Italy.

A novel heteroplasmic mitochondrial DNA (mtDNA) microdeletion affecting the cytochrome b gene (MT-CYB) was identified in an Italian female patient with a multisystem disease characterized by sensorineural deafness, cataracts, retinal pigmentary dystrophy, dysphagia, postural and gait instability, and myopathy with prominent exercise intolerance. The deletion is 18-base pair long and encompasses nucleotide positions 15,649-15,666, causing the loss of six amino acids (Ile-Leu-Ala-Met-Ile-Pro) in the protein, but leaving the remaining of the MT-CYB sequence in frame. The defective complex III function was cotransferred with mutant mtDNA in cybrids, thus unequivocally establishing its pathogenic role. Maternal relatives failed to show detectable levels of the deletion in blood and urinary epithelium, suggesting a de novo mutational event. This is the second report of an in-frame intragenic deletion in MT-CYB, which most likely occurred in early stages of embryonic development, associated with a severe multisystem disorder with prominent exercise intolerance.
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http://dx.doi.org/10.1002/humu.22596DOI Listing
August 2014

Influence of axial length and corneal power on the astigmatic power of toric intraocular lenses.

J Cataract Refract Surg 2013 Dec;39(12):1900-3

Purpose: To assess the influence of the anterior chamber depth (ACD), predicted by corneal power (keratometry [K]), and axial length (AL) on the astigmatic power of toric intraocular lenses (IOLs).

Setting: Private practice, Bologna, Italy.

Design: Noninterventional theoretical study.

Methods: Meridional analysis (based on the Hoffer Q formula) was applied to an eye model with K ranging from 38.0 to 48.0 diopters and AL ranging from 20 to 30 mm. For each diopter (D) of K and each millimeter of AL, the ratio between the toricity at the IOL plane and the toricity at the corneal plane was computed. Several simulations with the Acrysof toric IOL were performed.

Results: The ratio between toricity at the IOL plane and toricity at the corneal plane depended on the predicted ACD. The highest value (1.86) was found with the steepest K (48.0 D) and longest AL (30.0 mm) and the lowest value (1.29), with the flattest K (38.0 D) and shortest AL (20.0 mm). When applied to the toric IOL, the results suggest that a low ratio (≤1.41) led to overcorrection of astigmatism relative to the value reported by the manufacturer's online calculator. In contrast, a high ratio (>1.60) led to undercorrection of the astigmatism.

Conclusion: The ACD influenced the ratio between the cylinder power in the IOL plane and the cylinder power in the corneal plane and should be accounted for when selecting a toric IOL in an eye whose K and AL are far from the average values.
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http://dx.doi.org/10.1016/j.jcrs.2013.04.047DOI Listing
December 2013

Scheimpflug analysis of corneal power changes after myopic excimer laser surgery.

J Cataract Refract Surg 2013 Apr 7;39(4):605-10. Epub 2013 Mar 7.

G.B. Bietti Foundation-IRCCS, Rome, Italy.

Purpose: To assess the ability of corneal power measurements by a rotating Scheimpflug camera to measure the refractive change induced by myopic excimer laser surgery.

Setting: G.B. Bietti Foundation-IRCCS, Rome, Italy.

Design: Evaluation of diagnostic test.

Methods: The following corneal power measurements by the Pentacam Scheimpflug camera were analyzed: average keratometry (K), true net power (calculated by Gaussian optics formula), and total corneal refractive power (TCRP) at 2.0 mm, 3.0 mm, and 4.0 mm, calculated by ray tracing on a ring and as the average of the zone inside the ring. The difference between the preoperative and postoperative values was compared with the subjective surgically induced refractive change (SIRC) and with the difference between the preoperative and the postoperative anterior corneal power measured by Placido corneal topography (Keratron).

Results: In 36 consecutive eyes, the average K significantly underestimated the SIRC as determined by subjective refraction (-4.47 diopters [D] ± 1.81 [SD]) and corneal topography (-4.38 ± 1.81 D). The 3.0 mm and 4.0 mm ring total corneal refractive power significantly overestimated the SIRC. The remaining values did not show statistically significant differences with respect to the SIRC. The 3.0 mm zone TCRP and the 2.0 mm ring TCRP provided the lowest median difference compared with the SIRC (-0.07 D and -0.17 D, respectively) and the closest agreement.

Conclusions: The corneal power values provided by the Scheimpflug camera accurately reflected the SIRC after myopic excimer laser surgery. The best options seem to be the 3.0 mm zone TCRP and the 2.0 mm ring TCRP.
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http://dx.doi.org/10.1016/j.jcrs.2012.12.031DOI Listing
April 2013

Comparison of methods to measure corneal power for intraocular lens power calculation using a rotating Scheimpflug camera.

J Cataract Refract Surg 2013 Apr 9;39(4):598-604. Epub 2013 Feb 9.

G.B. Bietti Foundation IRCCS, Rome, Italy.

Purpose: To assess the accuracy of corneal power measurements provided by a Scheimpflug camera (Pentacam HR) for intraocular lens (IOL) power calculation in unoperated eyes and compare the results with those of simulated keratometry (SimK) performed with a Placido-disk corneal topographer (Keratron).

Setting: Private practice.

Design: Evaluation of diagnostic test.

Methods: Eight Scheimpflug camera corneal power measurements were analyzed: (1) average K, (2) true net power calculated using the Gaussian optics formula, (3) total corneal refractive power at 2.0 mm calculated by ray tracing on a ring and (4) as the average of the zone inside the ring, (5) total corneal refractive power at 3.0 mm on a ring and (6) as the average of the zone inside the ring, (7) the equivalent K reading at 3.0 mm and (8) at 4.5 mm. The IOL power was calculated using the Hoffer Q, Holladay 1, and SRK/T formulas.

Results: No statistically significant differences were observed between any corneal power measurements, including simulated K, in 41 consecutive patients. The latter showed slightly lower mean absolute errors with all 3 formulas (range 0.26 to 0.27 diopter [D]). The Scheimpflug camera gave the lowest median absolute errors with all formulas; that is, the 3.0 mm equivalent K reading with the Hoffer Q formula (0.18 D) and Holladay 1 formula (0.17 D) and the 2.0 mm total corneal refractive power ring with the SRK/T formula (0.18 D).

Conclusion: Corneal power measurements provided by the Scheimpflug camera and Placido disk corneal topographer displayed comparable accuracy in IOL power calculation.
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http://dx.doi.org/10.1016/j.jcrs.2012.11.022DOI Listing
April 2013

Anterior chamber and aqueous depth measurement in pseudophakic eyes: agreement between ultrasound biometry and scheimpflug imaging.

J Refract Surg 2013 Feb;29(2):121-5

Bietti Eye Doundation, Rome, Italy.

Purpose: To compare anterior chamber depth (ACD) and aqueous depth (AQD) measurements provided by a Scheimpflug camera combined with corneal topography to those obtained by immersion ultrasound (US) biometry when assessing the distance between the cornea and intraocular lens (IOL) in pseudophakic patients.

Methods: In a sample of 40 consecutive patients, each patient underwent measurements of ACD and AQD by means of the two techniques. Scheimpflug (Sirius; C.S.O., Firenze, Italy) measurements were obtained by manually tracing a line between the anterior surface of the IOL and the central cornea. Results were compared by t test. Agreement was evaluated by Bland-Altman plots with 95% limits of agreement (LoA).

Results: There was no statistically significant difference between the AQD as measured by US (3.95 ± 0.34 mm; range: 3.39 to 4.74 mm) and the AQD as measured by Scheimpflug photography (3.96 ± 0.34 mm; range: 3.41 to 4.77 mm; P = .3187). The statistically (but not clinically) significant difference between the ACD as measured by US (4.54 ± 0.37 mm; range: 3.93 to 5.35 mm) and Scheimpflug photography (4.58 ± 0.34 mm; range: 4.03 to 5.36 mm; P = .0024) disappeared after setting the US speed for ACD at 1,545 m/sec (mean ACD: 4.58 ± 0.37 mm; range: 3.96 to 5.39 mm). The 95% LoA ranged between -0.15 and +0.18 mm for AQD and between -0.12 and +0.21 mm for ACD.

Conclusions: In pseudophakic eyes, the manual ACD and AQD measurements obtained from the Scheimpflug camera combined with corneal topography are not significantly different compared to those provided by US and therefore can be considered interchangeable with the latter.
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http://dx.doi.org/10.3928/1081597X-20130117-07DOI Listing
February 2013

Retinal nerve fiber layer thickness variability in Leber hereditary optic neuropathy carriers.

Eur J Ophthalmol 2012 Nov-Dec;22(6):985-91. Epub 2012 May 4.

2 Dipartimento di Scienze Neurologiche, Università di Bologna, Bologna - Italy.

Purpose: Recent investigations suggested that unaffected carriers of Leber hereditary optic neuropathy (LHON) may show subclinical visual alterations. Structural changes have also been detected by optical coherence tomography (OCT), which revealed a temporal thickening of the retinal nerve fiber layer (RNFL). These changes may reflect compensatory effects such as mitochondria accumulation within the RNFL axons. This study aimed to investigate whether the RNFL of LHON carriers shows greater than expected thickness variations, which may reflect transient subclinical changes, over the course of years.

Methods: Using Stratus OCT, the RNFL thickness was measured yearly from 2005 to 2008 in 24 Brazilian LHON carriers, all with homoplasmic 11778/ND4 mtDNA mutation. An Italian sample of 20 healthy subjects served as a control. Data were compared also to a previously published sample (n=59) of glaucomatous eyes.

Results: The LHON carriers showed test-retest standard deviations that were larger than normal controls in the temporal (p=0.004), superior (p<0.0001), and inferior quadrants (p=0.019). Compared to the glaucoma cases, no statistical differences were observed.

Conclusions: The RNFL thickness in LHON carriers, when measured at different time points, has higher variability than in normal subjects. Transitory RNFL swelling may be caused either by compensatory mechanisms (increased mitochondrial biogenesis) or by axonal stasis preceding decompensation of retinal ganglion cells. In both situations, these changes may represent the origin of the visual alterations previously detected in LHON carriers. Alternatively, increased variability of RNFL thickness may be influenced by the LHON microangiopathy, as retinal blood vessels contribute to the OCT RNFL thickness measurements.
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http://dx.doi.org/10.5301/ejo.5000154DOI Listing
January 2016