Publications by authors named "Pascal Reynier"

194 Publications

Dominant Optic Atrophy: How to Determine the Pathogenicity of Novel Variants?

J Neuroophthalmol 2021 Sep 30. Epub 2021 Sep 30.

Baylor College of Medicine (JZ), Houston, Texas, US; Department of Ophthalmology (SR, PWM, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; MITOVASC Institute (MF, PR, DM), CNRS 6015, INSERM U1083, University of Angers, France; Singapore National Eye Center (DM), Singapore, Singapore; Singapore Eye Research Institute (DM), Singapore, Singapore; Duke-NUS Medical School (DM), Singapore, Singapore; Copenhagen University Hospital Denmark (DM), Copenhagen, Denmark; Departments of Ophthalmology (AGL), Neurology, and Neurosurgery, Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), The University of Iowa Hospitals and Clinics, Iowa City, Iowa.

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http://dx.doi.org/10.1097/WNO.0000000000001352DOI Listing
September 2021

Achieving Expert-Level Interpretation of Serum Protein Electrophoresis through Deep Learning Driven by Human Reasoning.

Clin Chem 2021 Oct;67(10):1406-1414

Laboratoire de Biochimie et Biologie Moléculaire, Centre Hospitalier Universitaire d'Angers, Angers, France.

Background: Serum protein electrophoresis (SPE) is a common clinical laboratory test, mainly indicated for the diagnosis and follow-up of monoclonal gammopathies. A time-consuming and potentially subjective human expertise is required for SPE analysis to detect possible pitfalls and to provide a clinically relevant interpretation.

Methods: An expert-annotated SPE dataset of 159 969 entries was used to develop SPECTR (serum protein electrophoresis computer-assisted recognition), a deep learning-based artificial intelligence, which analyzes and interprets raw SPE curves produced by an analytical system into text comments that can be used by practitioners. It was designed following academic recommendations for SPE interpretation, using a transparent architecture avoiding the "black box" effect. SPECTR was validated on an external, independent cohort of 70 362 SPEs and challenged by a panel of 9 independent experts from other hospital centers.

Results: SPECTR was able to identify accurately both quantitative abnormalities (r ≥ 0.98 for fractions quantification) and qualitative abnormalities [receiver operating characteristic-area under curve (ROC-AUC) ≥ 0.90 for M-spikes, restricted heterogeneity of immunoglobulins, and beta-gamma bridging]. Furthermore, it showed highly accurate at both detecting (ROC-AUC ≥ 0.99) and quantifying (r = 0.99) M-spikes. It proved highly reproducible and resilient to minor variations and its agreement with human experts was higher (κ = 0.632) than experts between each other (κ = 0.624).

Conclusions: SPECTR is an algorithm based on artificial intelligence suitable to high-throughput SPEs analyses and interpretation. It aims at improving SPE reproducibility and reliability. It is freely available in open access through an online tool providing fully editable validation assistance for SPE.
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http://dx.doi.org/10.1093/clinchem/hvab133DOI Listing
October 2021

ACO2 clinicobiological dataset with extensive phenotype ontology annotation.

Sci Data 2021 08 5;8(1):205. Epub 2021 Aug 5.

Unité Mixte de Recherche MITOVASC, CNRS 6015/INSERM 1083, Université d'Angers, Angers, France.

Pathogenic variants of the aconitase 2 gene (ACO2) are responsible for a broad clinical spectrum involving optic nerve degeneration, ranging from isolated optic neuropathy with recessive or dominant inheritance, to complex neurodegenerative syndromes with recessive transmission. We created the first public locus-specific database (LSDB) dedicated to ACO2 within the "Global Variome shared LOVD" using exclusively the Human Phenotype Ontology (HPO), a standard vocabulary for describing phenotypic abnormalities. All the variants and clinical cases listed in the literature were incorporated into the database, from which we produced a dataset. We followed a rational and comprehensive approach based on the HPO thesaurus, demonstrating that ACO2 patients should not be classified separately between isolated and syndromic cases. Our data highlight that certain syndromic patients do not have optic neuropathy and provide support for the classification of the recurrent pathogenic variants c.220C>G and c.336C>G as likely pathogenic. Overall, our data records demonstrate that the clinical spectrum of ACO2 should be considered as a continuum of symptoms and refines the classification of some common variants.
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http://dx.doi.org/10.1038/s41597-021-00984-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342444PMC
August 2021

Tear metabolomics highlights new potential biomarkers for differentiating between Sjögren's syndrome and other causes of dry eye.

Ocul Surf 2021 Jul 28;22:110-116. Epub 2021 Jul 28.

Mitolab, MitoVasc Institute, CNRS, 6015, INSERM U1083, University of Angers, France; Department of Biochemistry and Molecular Biology, University Hospital, Angers, France.

Purpose: The lacrimal exocrinopathy of primary Sjögren's syndrome (pSS) is one of the main causes of severe dry eye syndrome and a burden for patients. Early recognition and treatment could prevent irreversible damage to lacrimal glands. The aim of this study was to find biomarkers in tears, using metabolomics and data mining approaches, in patients with newly-diagnosed pSS compared to other causes of dry eye syndrome.

Methods: A prospective cohort of 40 pSS and 40 non-pSS Sicca patients with dryness was explored through a standardized targeted metabolomic approach using liquid chromatography coupled with mass spectrometry. A metabolomic signature predictive of the pSS status was sought out using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the studied population into training, validation and test sets.

Results: Among the 104 metabolites accurately measured in tears, we identified a discriminant signature composed of nine metabolites (two amino acids: serine, aspartate; one biogenic amine: dopamine; six lipids: Lysophosphatidylcholine C16:1, C18:1, C18:2, sphingomyelin C16:0 and C22:3, and the phoshatidylcholine diacyl PCaa C42:4), with robust performances (ROC-AUC = 0.83) for predicting the pSS status. Adjustment for age, sex and anti-SSA antibodies did not disrupt the link between the metabolomic signature and the pSS status. The non-lipidic components also remained specific for pSS regardless of the dryness severity.

Conclusion: Our results reveal a metabolomic signature for tears that distinguishes pSS from other dry eye syndromes and further highlight nine key metabolites of potential interest for early diagnosis and therapeutics of pSS.
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http://dx.doi.org/10.1016/j.jtos.2021.07.006DOI Listing
July 2021

Towards personalized medicine for amyotrophic lateral sclerosis.

Trends Endocrinol Metab 2021 Nov 26;32(11):839-841. Epub 2021 Jul 26.

University of Angers, Institut National de la Santé et de la Recherche Médicale (INSERM) and Centre National de la Recherche Scientifique (CNRS) Mitochondrial and Cardiovascular Physiopathology (MitoVasc) Institute, Angers, France; Department of Biochemistry and Molecular Biology, University Hospital, Angers, France.

Mohassel et al. provide unprecedented dichotomy of consequences on sphingolipid biosynthesis between pathogenic variants in the SPTLC1 gene, responsible for either amyotrophic lateral sclerosis (ALS) or hereditary sensory and autonomic neuropathy type 1 (HSAN1). Normalization of sphingolipid levels by siRNA selectively targeting the ALS mutant allele mRNA sheds light on new therapeutic approaches.
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http://dx.doi.org/10.1016/j.tem.2021.07.002DOI Listing
November 2021

Protective role of the mitochondrial fusion protein OPA1 in hypertension.

FASEB J 2021 07;35(7):e21678

MITOVASC Institute and CARFI Facility, University of Angers, Angers, France.

Hypertension is associated with excessive reactive oxygen species (ROS) production in vascular cells. Mitochondria undergo fusion and fission, a process playing a role in mitochondrial function. OPA1 is essential for mitochondrial fusion. Loss of OPA1 is associated with ROS production and cell dysfunction. We hypothesized that mitochondria fusion could reduce oxidative stress that defect in fusion would exacerbate hypertension. Using (a) Opa1 haploinsufficiency in isolated resistance arteries from Opa1 mice, (b) primary vascular cells from Opa1 mice, and (c) RNA interference experiments with siRNA against Opa1 in vascular cells, we investigated the role of mitochondria fusion in hypertension. In hypertension, Opa1 haploinsufficiency induced altered mitochondrial cristae structure both in vascular smooth muscle and endothelial cells but did not modify protein level of long and short forms of OPA1. In addition, we demonstrated an increase of mitochondrial ROS production, associated with a decrease of superoxide dismutase 1 protein expression. We also observed an increase of apoptosis in vascular cells and a decreased VSMCs proliferation. Blood pressure, vascular contractility, as well as endothelium-dependent and -independent relaxation were similar in Opa1 , WT, L-NAME-treated Opa1 and WT mice. Nevertheless, chronic NO-synthase inhibition with L-NAME induced a greater hypertension in Opa1 than in WT mice without compensatory arterial wall hypertrophy. This was associated with a stronger reduction in endothelium-dependent relaxation due to excessive ROS production. Our results highlight the protective role of mitochondria fusion in the vasculature during hypertension by limiting mitochondria ROS production.
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http://dx.doi.org/10.1096/fj.202000238RRRDOI Listing
July 2021

Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns.

J Clin Med 2021 May 28;10(11). Epub 2021 May 28.

Pathogenesis and Control of Chronic and Emerging Infections, INSERM, Etablissement Français du Sang, University of Montpellier, University of the Antilles, 34393 Montpellier, France.

Worldwide, one million HIV-exposed uninfected (HEU) children are born yearly, and chronic health impairments have been reported in these children. Mitochondrial DNA (mtDNA) instability and altered mtDNA content have been evidenced in these children, but an exhaustive characterization of altered mitochondrial genomes has never been reported. We applied deep mtDNA sequencing coupled to the deletion identification algorithm eKLIPse to the blood of HEU neonates ( = 32), which was compared with healthy controls ( = 15). Dried blood spots (DBS) from African HEU children were collected seven days after birth between November 2009 and May 2012. DBS from French healthy controls were collected at birth (or <3 days of life) in 2012 and in 2019. In contrast to the absence of mtDNA instability observed at the nucleotide level, we identified significant amounts of heteroplasmic mtDNA deletions in 75% of HEU children and in none of controls. The heteroplasmy rate of the 62 mtDNA deletions identified varied from 0.01% to up to 50%, the highest rates being broadly compatible with bioenergetic defect and clinical expression. mtDNA integrity is commonly affected in HEU neonates. The nature of the deletions suggests a mechanism related to aging or tumor-associated mtDNA instability. This child population may be at risk of additional mtDNA genetic alterations considering that they will be exposed to other mitotoxic drugs including antiretroviral or anti-tuberculosis treatment.
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http://dx.doi.org/10.3390/jcm10112399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197798PMC
May 2021

Mitochondrial Dysfunction in Mitochondrial Medicine: Current Limitations, Pitfalls, and Tomorrow.

Methods Mol Biol 2021 ;2276:1-29

Université de Paris, INSERM U1016, Institut Cochin, CNRS UMR8104, Paris, France.

Until recently restricted to hereditary mitochondrial diseases, mitochondrial dysfunction is now recognized as a key player and strategic factor in the pathophysiological of many human diseases, ranging from the metabolism, vascular, cardiac, and neurodegenerative diseases to cancer. Because of their participation in a myriad of cellular functions and signaling pathways, precisely identifying the cause of mitochondrial "dysfunctions" can be challenging and requires robust and controlled techniques. Initially limited to the analysis of the respiratory chain functioning, these analytical techniques now enlarge to the analyses of mitochondrial and cellular metabolism, based on metabolomic approaches.Here, we address the methods used to assay mitochondrial dysfunction, with a highlight on the techniques used in diagnosis on tissues and cells derived from patients, the information they provide, and their strength and weakness.Targeting mitochondrial dysfunction by various strategies is a huge challenge, requires robust methods of evaluation, and should be able to take into consideration the mitochondria dynamics and localization. The future of mitochondrial medicine is strongly related to a perfect comprehension of its dysfunction.
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http://dx.doi.org/10.1007/978-1-0716-1266-8_1DOI Listing
June 2021

Dominant mutations are a frequent cause of isolated optic atrophy.

Brain Commun 2021 7;3(2):fcab063. Epub 2021 Apr 7.

Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.

Biallelic mutations in , encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in , among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. analyses of variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all fibroblasts. Overall, our data position as the third most frequently mutated gene in autosomal inherited optic neuropathies, after and , and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells.
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http://dx.doi.org/10.1093/braincomms/fcab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152918PMC
April 2021

Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders.

Genet Med 2021 09 26;23(9):1769-1778. Epub 2021 May 26.

MitoLab, UMR CNRS 6015, INSERM U1083, Institut MitoVasc, Université d'Angers, Angers, France.

Purpose: Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, interfering with those resulting from mitochondrial disorders.

Methods: Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model.

Results: Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects.

Conclusion: Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability.
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http://dx.doi.org/10.1038/s41436-021-01206-wDOI Listing
September 2021

Optic neuropathy linked to ACAD9 pathogenic variants: A potentially riboflavin-responsive disorder?

Mitochondrion 2021 07 20;59:169-174. Epub 2021 May 20.

CHU Montpellier, Département de Neuropédiatrie, Montpellier, France; INM, University Montpellier, INSERM, Montpellier, France; National Center in Rare Diseases, Genetics of Sensory Diseases, University Hospital, Montpellier, France. Electronic address:

Mitochondrial complex I (CI) deficiencies (OMIM 252010) are the commonest inherited mitochondrial disorders in children. Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoenzyme involved chiefly in CI assembly and possibly in fatty acid oxidation. Biallelic pathogenic variants result in CI dysfunction, with a phenotype ranging from early onset and sometimes fatal mitochondrial encephalopathy with lactic acidosis to late-onset exercise intolerance. Cardiomyopathy is often associated. We report a patient with childhood-onset optic and peripheral neuropathy without cardiac involvement, related to CI deficiency. Genetic analysis revealed compound heterozygous pathogenic variants in ACAD9, expanding the clinical spectrum associated to ACAD9 mutations. Importantly, riboflavin treatment (15 mg/kg/day) improved long-distance visual acuity and demonstrated significant rescue of CI activity in vitro.
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http://dx.doi.org/10.1016/j.mito.2021.05.002DOI Listing
July 2021

High-throughput screening identifies suppressors of mitochondrial fragmentation in OPA1 fibroblasts.

EMBO Mol Med 2021 Jun 20;13(6):e13579. Epub 2021 May 20.

Mitochondrial Biology Group, Institut Pasteur, CNRS UMR 3691, Paris, France.

Mutations in OPA1 cause autosomal dominant optic atrophy (DOA) as well as DOA+, a phenotype characterized by more severe neurological deficits. OPA1 deficiency causes mitochondrial fragmentation and also disrupts cristae, respiration, mitochondrial DNA (mtDNA) maintenance, and cell viability. It has not yet been established whether phenotypic severity can be modulated by genetic modifiers of OPA1. We screened the entire known mitochondrial proteome (1,531 genes) to identify genes that control mitochondrial morphology using a first-in-kind imaging pipeline. We identified 145 known and novel candidate genes whose depletion promoted elongation or fragmentation of the mitochondrial network in control fibroblasts and 91 in DOA+ patient fibroblasts that prevented mitochondrial fragmentation, including phosphatidyl glycerophosphate synthase (PGS1). PGS1 depletion reduces CL content in mitochondria and rebalances mitochondrial dynamics in OPA1-deficient fibroblasts by inhibiting mitochondrial fission, which improves defective respiration, but does not rescue mtDNA depletion, cristae dysmorphology, or apoptotic sensitivity. Our data reveal that the multifaceted roles of OPA1 in mitochondria can be functionally uncoupled by modulating mitochondrial lipid metabolism, providing novel insights into the cellular relevance of mitochondrial fragmentation.
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http://dx.doi.org/10.15252/emmm.202013579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185549PMC
June 2021

Metabolomic Sexual Dimorphism of the Mouse Brain is Predominantly Abolished by Gonadectomy with a Higher Impact on Females.

J Proteome Res 2021 05 14;20(5):2772-2779. Epub 2021 Apr 14.

Département de Biochimie et Génétique, Centre Hospitalier Universitaire, 49933 Angers, France.

The importance of sexual dimorphism of the mouse brain metabolome was recently highlighted, in addition to a high regional specificity found between the frontal cortex, the cerebellum, and the brain stem. To address the origin of this dimorphism, we performed gonadectomy on both sexes, followed by a metabolomic study targeting 188 metabolites in the three brain regions. While sham controls, which underwent the same surgical procedure without gonadectomy, reproduced the regional sexual dimorphism of the metabolome previously identified, no sex difference was identifiable after gonadectomy, through both univariate and multivariate analyses. These experiments also made it possible to identify which sex was responsible for the dimorphism for 35 metabolites. The female sex contributed to the difference for more than 80% of them. Our results show that gonads are the main contributors to the brain sexual dimorphism previously observed, especially in females.
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http://dx.doi.org/10.1021/acs.jproteome.1c00045DOI Listing
May 2021

Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy.

Front Neurol 2021 25;12:602979. Epub 2021 Mar 25.

University Angers, MitoLab team, UMR CNRS 6015-INSERM U1083, Unité MitoVasc, SFR ICAT, Angers, France.

Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that variants are responsible for the majority of dominant IONs, whereas and variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells.
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http://dx.doi.org/10.3389/fneur.2021.602979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027346PMC
March 2021

Ocular growth and metabolomics are dependent upon the spectral content of ambient white light.

Sci Rep 2021 04 7;11(1):7586. Epub 2021 Apr 7.

Singapore Eye Research Institute, Singapore, Singapore.

Myopia results from an excessive axial growth of the eye, causing abnormal projection of remote images in front of the retina. Without adequate interventions, myopia is forecasted to affect 50% of the world population by 2050. Exposure to outdoor light plays a critical role in preventing myopia in children, possibly through the brightness and blue-shifted spectral composition of sunlight, which lacks in artificial indoor lighting. Here, we evaluated the impact of moderate levels of ambient standard white (SW: 233.1 lux, 3900 K) and blue-enriched white (BEW: 223.8 lux, 9700 K) lights on ocular growth and metabolomics in a chicken-model of form-deprivation myopia. Compared to SW light, BEW light decreased aberrant ocular axial elongation and accelerated recovery from form-deprivation. Furthermore, the metabolomic profiles in the vitreous and retinas of recovering form-deprived eyes were distinct from control eyes and were dependent on the spectral content of ambient light. For instance, exposure to BEW light was associated with deep lipid remodeling and metabolic changes related to energy production, cell proliferation, collagen turnover and nitric oxide metabolism. This study provides new insight on light-dependent modulations in ocular growth and metabolomics. If replicable in humans, our findings open new potential avenues for spectrally-tailored light-therapy strategies for myopia.
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http://dx.doi.org/10.1038/s41598-021-87201-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026599PMC
April 2021

Preliminary Metabolomic Profiling of the Vitreous Humor from Hypothermia Fatalities.

J Proteome Res 2021 05 5;20(5):2390-2396. Epub 2021 Apr 5.

Centre Universitaire Romand de Médecine Légale, Hôpital Universitaire de Lausanne, 1000 Lausanne 25, Switzerland.

The postmortem diagnosis of hypothermia fatalities is often complex due to the absence of pathognomonic lesions and biomarkers. In this study, potential novel biomarkers of hypothermia fatalities were searched in the vitreous humor of known cases of hypothermia fatalities ( = 20) compared to control cases ( = 16), using a targeted metabolomics approach allowing quantitative detection of 188 metabolites. A robust discriminant model with good predictivity was obtained with the supervised OPLS-DA multivariate analysis, showing a distinct separation between the hypothermia and control groups. This signature was characterized by the decreased concentrations of five metabolites (methionine sulfoxide, tryptophan, phenylalanine, alanine, and ornithine) and the increased concentration of 28 metabolites (21 phosphatidylcholines, 3 sphingomyelins, spermine, citrulline, acetylcarnitine, and hydroxybutyrylcarnitine) in hypothermia fatalities compared to controls. The signature shows similarities with already identified features in serum such as the altered concentrations of tryptophan, acylcarnitines, and unsaturated phosphatidylcholines, revealing a highly significant increased activity of methionine sulfoxide reductase, attested by a low methionine sulfoxide-to-methionine ratio. Our results show a preliminary metabolomics signature of hypothermia fatalities in the vitreous humor, highlighting an increased methionine sulfoxide reductase activity.
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http://dx.doi.org/10.1021/acs.jproteome.0c00901DOI Listing
May 2021

Iron Deficiency without Anemia Decreases Physical Endurance and Mitochondrial Complex I Activity of Oxidative Skeletal Muscle in the Mouse.

Nutrients 2021 Mar 24;13(4). Epub 2021 Mar 24.

MitoVasc Institut, UMR CNRS 6015-INSERM 1083, University of Angers, 49100 Angers, France.

Iron deficiency (ID), with or without anemia, is responsible for physical fatigue. This effect may be linked to an alteration of mitochondrial metabolism. Our aim was to assess the impact of ID on skeletal striated muscle mitochondrial metabolism. Iron-deficient non-anemic mice, obtained using a bloodletting followed by a low-iron diet for three weeks, were compared to control mice. Endurance was assessed using a one-hour submaximal exercise on a Rotarod device and activities of mitochondrial complexes I and IV were measured by spectrophotometry on two types of skeletal striated muscles, the soleus and the quadriceps. As expected, ID mice displayed hematologic markers of ID and reduced iron stores, although none of them were anemic. In ID mice, endurance was significantly reduced and activity of the respiratory chain complex I, normalized to citrate synthase activity, was significantly reduced in the soleus muscle but not in the quadriceps. Complex IV activities were not significantly different, neither in the soleus nor in the quadriceps. We conclude that ID without anemia is responsible for impaired mitochondrial complex I activity in skeletal muscles with predominant oxidative metabolism. These results bring pathophysiological support to explain the improved physical activity observed when correcting ID in human. Further studies are needed to explore the mechanisms underlying this decrease in complex I activity and to assess the role of iron therapy on muscle mitochondrial metabolism.
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http://dx.doi.org/10.3390/nu13041056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064065PMC
March 2021

DRP1 haploinsufficiency attenuates cardiac ischemia/reperfusion injuries.

PLoS One 2021 25;16(3):e0248554. Epub 2021 Mar 25.

Institut MITOVASC, CNRS UMR 6015 INSERM U1083, Université d'Angers, Angers, France.

Mitochondrial dynamics is a possible modulator of myocardial ischemia/reperfusion injuries (IRI). We previously reported that mice partially deficient in the fusion protein OPA1 exhibited higher IRI. Therefore, we investigated whether deficiency in the fission protein DRP1 encoded by Dnm1l gene would affect IRI in Dnm1l+/- mouse. After baseline characterization of the Dnm1l+/- mice heart, using echocardiography, electron microscopy, and oxygraphy, 3-month-old Dnm1l+/- and wild type (WT) mice were exposed to myocardial ischemia/reperfusion (I/R). The ischemic area-at-risk (AAR) and area of necrosis (AN) were delimited, and the infarct size was expressed by AN/AAR. Proteins involved in mitochondrial dynamics and autophagy were analyzed before and after I/R. Mitochondrial permeability transition pore (mPTP) opening sensitivity was assessed after I/R. Heart weight and left ventricular function were not significantly different in 3-, 6- and 12-month-old Dnm1l+/- mice than in WT. The cardiac DRP1 protein expression levels were 60% lower, whereas mitochondrial area and lipid degradation were significantly higher in Dnm1l+/- mice than in WT, though mitochondrial respiratory parameters and mPTP opening did not significantly differ. Following I/R, the infarct size was significantly smaller in Dnm1l+/- mice than in WT (34.6±3.1% vs. 44.5±3.3%, respectively; p<0.05) and the autophagic markers, LC3 II and P62 were significantly increased compared to baseline condition in Dnm1l+/- mice only. Altogether, data indicates that increasing fusion by means of Dnm1l deficiency was associated with protection against IRI, without alteration in cardiac or mitochondrial functions at basal conditions. This protection mechanism due to DRP1 haploinsufficiency increases the expression of autophagic markers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248554PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993837PMC
October 2021

Deep learning shows no morphological abnormalities in neutrophils in Alzheimer's disease.

Alzheimers Dement (Amst) 2021 20;13(1):e12146. Epub 2021 Feb 20.

Département de Biochimie et Biologie Moléculaire Centre Hospitalier Universitaire d'Angers Angers France.

Introduction: Several studies have provided evidence of the key role of neutrophils in the pathophysiology of Alzheimer's disease (AD). Yet, no study to date has investigated the potential link between AD and morphologically abnormal neutrophils on blood smears.

Methods: Due to the complexity and subjectivity of the task by human analysis, deep learning models were trained to predict AD from neutrophil images. Control models were trained for a known feasible task (leukocyte subtype classification) and for detecting potential biases of overfitting (patient prediction).

Results: Deep learning models achieved state-of-the-art results for leukocyte subtype classification but could not accurately predict AD.

Discussion: We found no evidence of morphological abnormalities of neutrophils in AD. Our results show that a solid deep learning pipeline with positive and bias control models with visualization techniques are helpful to support deep learning model results.
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http://dx.doi.org/10.1002/dad2.12146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896639PMC
February 2021

Dominant mutations in MIEF1 affect mitochondrial dynamics and cause a singular late onset optic neuropathy.

Mol Neurodegener 2021 02 25;16(1):12. Epub 2021 Feb 25.

Université d'Angers, MitoLab team, UMR CNRS 6015 - INSERM U1083, Unité MitoVasc, Angers, France.

Inherited optic neuropathies are the most common mitochondrial diseases, leading to neurodegeneration involving the irreversible loss of retinal ganglion cells, optic nerve degeneration and central visual loss. Importantly, properly regulated mitochondrial dynamics are critical for maintaining cellular homeostasis, and are further regulated by MIEF1 (mitochondrial elongation factor 1) which encodes for MID51 (mitochondrial dynamics protein 51), an outer mitochondrial membrane protein that acts as an adaptor protein to regulate mitochondrial fission. However, dominant mutations in MIEF1 have not been previously linked to any human disease. Using targeted sequencing of genes involved in mitochondrial dynamics, we report the first heterozygous variants in MIEF1 linked to disease, which cause an unusual form of late-onset progressive optic neuropathy characterized by the initial loss of peripheral visual fields. Pathogenic MIEF1 variants linked to optic neuropathy do not disrupt MID51's localization to the outer mitochondrial membrane or its oligomerization, but rather, significantly disrupt mitochondrial network dynamics compared to wild-type MID51 in high spatial and temporal resolution confocal microscopy live imaging studies. Together, our study identifies dominant MIEF1 mutations as a cause for optic neuropathy and further highlights the important role of properly regulated mitochondrial dynamics in neurodegeneration.
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http://dx.doi.org/10.1186/s13024-021-00431-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905578PMC
February 2021

Mitochondria: their role in spermatozoa and in male infertility.

Hum Reprod Update 2021 Jun;27(4):697-719

MITOVASC Institute, CNRS 6015, INSERM U1083, Angers University, Angers 49000, France.

Background: The best-known role of spermatozoa is to fertilize the oocyte and to transmit the paternal genome to offspring. These highly specialized cells have a unique structure consisting of all the elements absolutely necessary to each stage of fertilization and to embryonic development. Mature spermatozoa are made up of a head with the nucleus, a neck, and a flagellum that allows motility and that contains a midpiece with a mitochondrial helix. Mitochondria are central to cellular energy production but they also have various other functions. Although mitochondria are recognized as essential to spermatozoa, their exact pathophysiological role and their functioning are complex. Available literature relative to mitochondria in spermatozoa is dense and contradictory in some cases. Furthermore, mitochondria are only indirectly involved in cytoplasmic heredity as their DNA, the paternal mitochondrial DNA, is not transmitted to descendants.

Objective And Rational: This review aims to summarize available literature on mitochondria in spermatozoa, and, in particular, that with respect to humans, with the perspective of better understanding the anomalies that could be implicated in male infertility.

Search Methods: PubMed was used to search the MEDLINE database for peer-reviewed original articles and reviews pertaining to human spermatozoa and mitochondria. Searches were performed using keywords belonging to three groups: 'mitochondria' or 'mitochondrial DNA', 'spermatozoa' or 'sperm' and 'reactive oxygen species' or 'calcium' or 'apoptosis' or signaling pathways'. These keywords were combined with other relevant search phrases. References from these articles were used to obtain additional articles.

Outcomes: Mitochondria are central to the metabolism of spermatozoa and they are implicated in energy production, redox equilibrium and calcium regulation, as well as apoptotic pathways, all of which are necessary for flagellar motility, capacitation, acrosome reaction and gametic fusion. In numerous cases, alterations in one of the aforementioned functions could be linked to a decline in sperm quality and/or infertility. The link between the mitochondrial genome and the quality of spermatozoa appears to be more complex. Although the quantity of mtDNA, and the existence of large-scale deletions therein, are inversely correlated to sperm quality, the effects of mutations seem to be heterogeneous and particularly related to their pathogenicity.

Wider Implications: The importance of the role of mitochondria in reproduction, and particularly in gamete quality, has recently emerged following numerous publications. Better understanding of male infertility is of great interest in the current context where a significant decline in sperm quality has been observed.
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http://dx.doi.org/10.1093/humupd/dmab001DOI Listing
June 2021

Embryo and Its Mitochondria.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

MITOVASC, Angers University, INSERM 1083-CNRS 6015, IBS-CHU, 49000 Angers, France.

The mitochondria, present in almost all eukaryotic cells, produce energy but also contribute to many other essential cellular functions. One of the unique characteristics of the mitochondria is that they have their own genome, which is only maternally transmitted via highly specific mechanisms that occur during gametogenesis and embryogenesis. The mature oocyte has the highest mitochondrial DNA copy number of any cell. This high mitochondrial mass is directly correlated to the capacity of the oocyte to support the early stages of embryo development in many species. Indeed, the subtle energetic and metabolic modifications that are necessary for each of the key steps of early embryonic development rely heavily on the oocyte's mitochondrial load and activity. For example, epigenetic reprogramming depends on the metabolic cofactors produced by the mitochondrial metabolism, and the reactive oxygen species derived from the mitochondrial respiratory chain are essential for the regulation of cell signaling in the embryo. All these elements have also led scientists to consider the mitochondria as a potential biomarker of oocyte competence and embryo viability, as well as a key target for future potential therapies. However, more studies are needed to confirm these findings. This review article summarizes the past two decades of research that have led to the current understanding of mitochondrial functions in reproduction.
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http://dx.doi.org/10.3390/antiox10020139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908991PMC
January 2021

Secondary coenzyme Q deficiency in neurological disorders.

Free Radic Biol Med 2021 03 12;165:203-218. Epub 2021 Jan 12.

Unité Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, University of Angers, 49933, Angers, France; Neuromuscular Reference Center, Department of Neurology, CHU Angers, 49933, Angers, France. Electronic address:

Coenzyme Q (CoQ) is a ubiquitous lipid serving essential cellular functions. It is the only component of the mitochondrial respiratory chain that can be exogenously absorbed. Here, we provide an overview of current knowledge, controversies, and open questions about CoQ intracellular and tissue distribution, in particular in brain and skeletal muscle. We discuss human neurological diseases and mouse models associated with secondary CoQ deficiency in these tissues and highlight pharmacokinetic and anatomical challenges in exogenous CoQ biodistribution, recent improvements in CoQ formulations and imaging, as well as alternative therapeutical strategies to CoQ supplementation. The last section proposes possible mechanisms underlying secondary CoQ deficiency in human diseases with emphasis on neurological and neuromuscular disorders.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.017DOI Listing
March 2021

A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies.

Hum Mol Genet 2021 03;30(1):21-29

Unité Mixte de Recherche (UMR) MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Université d'Angers, 49933 Angers, France.

Leber's hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e-05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.
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http://dx.doi.org/10.1093/hmg/ddab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033144PMC
March 2021

Dominant optic atrophy: Culprit mitochondria in the optic nerve.

Prog Retin Eye Res 2021 07 17;83:100935. Epub 2020 Dec 17.

Molecular Genetics Laboratory, Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany. Electronic address:

Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.
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http://dx.doi.org/10.1016/j.preteyeres.2020.100935DOI Listing
July 2021

Mitochondrial DNA Parameters in Blood of Infants Receiving Lopinavir/Ritonavir or Lamivudine Prophylaxis to Prevent Breastfeeding Transmission of HIV-1.

J Clin Med 2020 Sep 14;9(9). Epub 2020 Sep 14.

Pathogenèse et Contrôle des Infections Chroniques, INSERM U1058, Université Montpellier, Etablissement Français du Sang, 34934 Montpellier, France.

Children who are human immunodeficiency virus (HIV)-exposed but uninfected (CHEU) accumulate maternal HIV and antiretroviral exposures through pregnancy, postnatal prophylaxis, and breastfeeding. Here, we compared the dynamics of mitochondrial DNA (mtDNA) parameters in African breastfed CHEU receiving lopinavir/ritonavir (LPV/r) or lamivudine (3TC) pre-exposure prophylaxis during the first year of life. The number of mtDNA copies per cell (MCN) and the proportion of deleted mtDNA (MDD) were assessed at day 7 and at week 50 post-delivery (PrEP group). mtDNA depletion was defined as a 50% or more decrease from the initial value, and mtDNA deletions was the detection of mtDNA molecules with large DNA fragment loss. We also performed a sub-analysis with CHEU who did not receive a prophylactic treatment in South Africa (control group). From day seven to week 50, MCN decreased with a median of 41.7% (interquartile range, IQR: 12.1; 64.4) in the PrEP group. The proportion of children with mtDNA depletion was not significantly different between the two prophylactic regimens. Poisson regressions showed that LPV/r and 3TC were associated with mtDNA depletion (reference: control group; LPV/r: PR = 1.75 (CI95%: 1.15-2.68), < 0.01; 3TC: PR = 1.54 (CI95%: 1.00-2.37), = 0.05). Moreover, the proportion of children with MDD was unexpectedly high before randomisation in both groups. Long-term health impacts of these mitochondrial DNA parameters should be investigated further for both CHEU and HIV-infected children receiving LPV/r- or 3TC- based regimens.
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http://dx.doi.org/10.3390/jcm9092972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564660PMC
September 2020

Metabolomic signature of the seminal plasma in men with severe oligoasthenospermia.

Andrology 2020 11 31;8(6):1859-1866. Epub 2020 Aug 31.

Unité Mixte de Recherche MITOVASC, Centre National de la Recherche Scientifique (CNRS) 6015, Institut National de la Santé et de la Recherche Médicale (INSERM) U1083, Université d'Angers, Angers, France.

Background: Male factor is incriminated in approximately 50% of cases of infertility. The metabolomic approach has recently been used in the assessment of sperm quality and male fertility.

Materials And Methods: We analyzed the metabolomic signatures of the seminal plasma in 20 men with severe oligoasthenospermia (prewash total motile sperm count < 5.10 ) (SOA) and compared it to 20 men with normal semen parameters, with a standardized approach of targeted and quantitative metabolomics using high-performance liquid chromatography, coupled with tandem mass spectrometry, and the Biocrates Absolute IDQ p180 kit.

Results: Among the 188 metabolites analyzed, 110 were accurately measured in the seminal plasma. A robust model discriminating the two populations (Q = 55.2%) was obtained by OPLS-DA (orthogonal partial least-squares discriminant analysis), based on the drop in concentrations of 37 metabolites with a VIP (variable important for projection) greater than 1. Overall, in men with SOA, there was a significant decrease in: 17 phosphatidylcholines and four sphingomyelins; acylcarnitines, with free L-carnitine being the most discriminating metabolite; polyunsaturated fatty acids; six amino acids (glutamate, aspartate, methionine, tryptophan, proline, and alanine); and four biogenic amines (spermine, spermidine, serotonin, and alpha-aminoadipate).

Discussion: Our signature includes several metabolic changes with different impacts on the sperm quality: a change in phospholipid composition and the saturation of their fatty acids that is potentially linked to the deterioration of sperm membranes; a carnitine deficiency that can negatively impact the energy production via fatty acid oxidation and oxidative phosphorylation; and a decreased level of amino acids and biogenic amines that can lead to dysregulated metabolic and signaling pathways.

Conclusion: We provide a global overview of the metabolic defects contributing to the structural and functional alteration of spermatozoa in severe oligoasthenospermia. These findings offer new insights into the pathophysiology of male factor infertility that could help to develop future specific treatments.
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http://dx.doi.org/10.1111/andr.12882DOI Listing
November 2020

Endometriosis Lowers the Cumulative Live Birth Rates in IVF by Decreasing the Number of Embryos but Not Their Quality.

J Clin Med 2020 Aug 1;9(8). Epub 2020 Aug 1.

Reproductive Biology Unit, Angers University Hospital, 49000 Angers, France.

Endometriosis and infertility are closely linked, but the underlying mechanisms are still poorly understood. This study aimed to evaluate the impact of endometriosis on in vitro fertilization (IVF) parameters, especially on embryo quality and IVF outcomes. A total of 1124 cycles with intracytoplasmic sperm injection were retrospectively evaluated, including 155 cycles with endometriosis and 969 cycles without endometriosis. Women with endometriosis had significantly lower ovarian reserve markers (AMH and AFC), regardless of previous ovarian surgery. Despite receiving significantly higher doses of exogenous gonadotropins, they had significantly fewer oocytes, mature oocytes, embryos, and top-quality embryos than women in the control group. Multivariate analysis did not reveal any association between endometriosis and the proportion of top-quality embryo (OR = 0.87; 95% CI [0.66-1.12]; = 0.3). The implantation rate and the live birth rate per cycle were comparable between the two groups ( = 0.05), but the cumulative live births rate was significantly lower in in the endometriosis group (32.1% versus 50.7%, = 0.001), as a consequence of the lower number of frozen embryos. In conclusion, endometriosis lowers the cumulative live birth rates by decreasing the number of embryos available to transfer, but not their quality.
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http://dx.doi.org/10.3390/jcm9082478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464781PMC
August 2020

Familial Dysalbuminemic Hyperthyroxinemia: An Underdiagnosed Entity.

J Clin Med 2020 Jul 3;9(7). Epub 2020 Jul 3.

Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, 4 rue Larrey, CEDEX 9, 49933 Angers, France.

Resistance to thyroid hormone (RTH) is a syndrome characterized by impaired sensitivity of tissues to thyroid hormone (TH). The alteration of TH-binding proteins, such as in Familial Dysalbuminemic Hyperthyroxinemia (FDH), can mimic the abnormal serum thyroid tests typical of RTH. We aimed to characterize a population referred to our center with suspected RTH and estimate the proportion of patients with FDH. For 303 different families, we collected clinical and hormonal data and sequenced the thyroid hormone receptor β gene () and exon 7 of the albumin gene (). We found 56 variants (i.e., 38% of the 303 index cases, called RTHβ group). Among the samples screened for FDH variants, 18% had the variant R218H in (FDH group); in addition, 71% of the cases had neither variant (non-FDH/RTHβ group). Patients with FDH had significantly lower free T3 (fT3) and free T4 (fT4) levels and more often an isolated elevation of fT4 than RTHβ patients. Clinically, patients with FDH had fewer symptoms than patients with RTHβ. Our study suggests that FDH should be systematically considered when examining patients suspected of having RTH. In most cases, they present no clinical symptoms, and their biochemical alterations show an elevation of fT4 levels, while fT3 levels are 1.11 times below the upper limit of the assay.
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http://dx.doi.org/10.3390/jcm9072105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408830PMC
July 2020

Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

Neurol Genet 2020 Jun 20;6(3):e428. Epub 2020 May 20.

MitoLab Team (M.C., A.C., C.B., D.G., V.D.-D., S.L., V.P., P.R., D.B., P.A.-B., G.L.), UMR CNRS 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital; Genetics and immuno-cell therapy Team (M.C.), Mohammed First University, Oujda, Morocco; Departments of Biochemistry and Genetics (C.B., D.G., V.D.-D., E.C., V.P., P.R., D.B., P.A.-B.), University Hospital Angers; Department of Ophthalmology (A.M.), Centre Hospitalier Universitaire Saint-Pierre, Brussels, Belgium; Neuroophthalmology Department (C.V.), Rothschild Ophthalmologic Foundation, Paris; Exploration of Visual Function and Neuro-Ophthalmology Department (V.S., S.D.-D., I.D.B.), Lille University Hospital, Rue Emilie Laine, Lille Cedex; CHU Bordeaux (C.G.), Service de Génétique Médicale, Centre de Référence « Neurogénétique » and Université de Bordeaux, INSERM U 1211, Laboratoire Maladies Rares, Génétique et Métabolisme (MRGM) Bordeaux; School of Optometry and Vision Sciences (M.V.), Cardiff University and Cardiff Eye Unit, University Hospital of Wales; NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology (N.J., P.Y.-W.-M.), London; Department of Clinical Neurosciences (P.Y.-W.-M.), Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit, University of Cambridge; Cambridge Eye Unit (P.Y.-W.-M.), Addenbrooke's Hospital, Cambridge University Hospitals, UK; IRCCS Istituto Delle Scienze Neurologiche di Bologna (F.T., L.C., C.L.M., V.C.), Bellaria Hospital; Unit of Neurology (C.L.M., V.C.), Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, Italy; Centre de Compétence Maladies Rares (X.Z.), Clinique Pluridisciplinaire Jules Verne, Nantes; and National Centre in Rare Diseases (I.M.), Genetics of Sensory Diseases, University Hospital, Montpellier, France.

Objective: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Methods: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

Results: We identified 7 and 8 new heterozygous pathogenic variants in and . Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Conclusions: Our results position and as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.
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http://dx.doi.org/10.1212/NXG.0000000000000428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251510PMC
June 2020
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