ABSTRACT
BACKGROUND: The clinical relevance of promoter mutations and single nucleotide polymorphism rs2853669 of telomerase reverse transcriptase (TERT) and telomere length in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) patients remains unclear. Moreover, some studies speculated that TERT promoter status might influence the prognostic role of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in newly diagnosed GBM. We carried out a large study to investigate their clinical impact and their interaction in newly diagnosed GBM patients. PATIENTS AND METHODS: We included 273 newly diagnosed IDH wild-type GBM patients who started treatment at Veneto Institute of Oncology IOV - IRCCS (Padua, Italy) from December 2016 to January 2020. TERT promoter mutations (-124 C>T and -146 C>T) and SNP rs2853669 (-245 T>C), relative telomere length (RTL) and MGMT methylation status were retrospectively assessed in this prospective cohort of patients. RESULTS: Median overall survival (OS) of 273 newly diagnosed IDH wild-type GBM patients was 15 months. TERT promoter was mutated in 80.2% of patients, and most had the rs2853669 single nucleotide polymorphism as T/T genotype (46.2%). Median RTL was 1.57 (interquartile range 1.13-2.32). MGMT promoter was methylated in 53.4% of cases. At multivariable analysis, RTL and TERT promoter mutations were not associated with OS or progression-free survival (PFS). Notably, patients C carrier of rs2853669 (C/C+C/T genotypes) showed a better PFS compared with those with the T/T genotype (hazard ratio 0.69, P = 0.007). In terms of OS and PFS, all interactions between MGMT, TERT and RTL and between TERT and rs2853669 genotype were not statistically significant. CONCLUSIONS: Our findings suggest the presence of the C variant allele at the rs2853669 of the TERT promoter as an attractive independent prognostic biomarker of disease progression in IDH wild-type GBM patients. RTL and TERT promoter mutational status were not correlated to survival regardless of MGMT methylation status.
Subject(s)
Brain Neoplasms , Glioblastoma , Telomerase , Humans , Prognosis , Glioblastoma/genetics , Isocitrate Dehydrogenase/genetics , Retrospective Studies , Methylation , Prospective Studies , Brain Neoplasms/diagnosis , Telomere , Telomerase/genetics , DNA Modification Methylases/genetics , Tumor Suppressor Proteins/genetics , DNA Repair Enzymes/geneticsSubject(s)
2',5'-Oligoadenylate Synthetase/genetics , Anosmia/etiology , COVID-19/pathology , Spike Glycoprotein, Coronavirus/genetics , Alleles , Alzheimer Disease/genetics , Alzheimer Disease/pathology , COVID-19/complications , COVID-19/virology , Genome-Wide Association Study , Humans , Olfactory Bulb/metabolism , Polymorphism, Genetic , Prognosis , Risk Factors , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Severity of Illness IndexABSTRACT
In this work, the presence of calcium-dependent calcium channels and their receptors (RyR) has been investigated in Paracentrotus lividus eggs and early embryos, from unfertilized egg to four-blastomere stages. Electrophysiological recordings of RyR single-channel current fluctuations showed that RyRs are functional during the first developmental events with a maximum at zygote stage, c. 40 min after fertilization, corresponding to the first cleavage. The nature of vertebrate-like RyRs active at this stage was established by specific activation/blockade experiments.
Subject(s)
Paracentrotus , Zygote , Animals , Blastomeres/metabolism , Calcium/metabolism , Fertilization/physiology , Oocytes/metabolism , Ryanodine Receptor Calcium Release Channel/metabolism , Sea Urchins/metabolism , Zygote/metabolismABSTRACT
Novel species of fungi described in this study include those from various countries as follows: Antartica, Cladosporium austrolitorale from coastal sea sand. Australia, Austroboletus yourkae on soil, Crepidotus innuopurpureus on dead wood, Curvularia stenotaphri from roots and leaves of Stenotaphrum secundatum and Thecaphora stajsicii from capsules of Oxalis radicosa. Belgium, Paraxerochrysium coryli (incl. Paraxerochrysium gen. nov.) from Corylus avellana. Brazil, Calvatia nordestina on soil, Didymella tabebuiicola from leaf spots on Tabebuia aurea, Fusarium subflagellisporum from hypertrophied floral and vegetative branches of Mangifera indica and Microdochium maculosum from living leaves of Digitaria insularis. Canada, Cuphophyllus bondii from a grassland. Croatia, Mollisia inferiseptata from a rotten Laurus nobilis trunk. Cyprus, Amanita exilis on calcareous soil. Czech Republic, Cytospora hippophaicola from wood of symptomatic Vaccinium corymbosum. Denmark, Lasiosphaeria deviata on pieces of wood and herbaceous debris. Dominican Republic, Calocybella goethei among grass on a lawn. France (Corsica), Inocybe corsica on wet ground. France (French Guiana), Trechispora patawaensis on decayed branch of unknown angiosperm tree and Trechispora subregularis on decayed log of unknown angiosperm tree. Germany, Paramicrothecium sambuci (incl. Paramicrothecium gen. nov.) on dead stems of Sambucus nigra. India, Aureobasidium microtermitis from the gut of a Microtermes sp. termite, Laccaria diospyricola on soil and Phylloporia tamilnadensis on branches of Catunaregam spinosa. Iran, Pythium serotinoosporum from soil under Prunus dulcis. Italy, Pluteus brunneovenosus on twigs of broadleaved trees on the ground. Japan, Heterophoma rehmanniae on leaves of Rehmannia glutinosa f. hueichingensis. Kazakhstan, Murispora kazachstanica from healthy roots of Triticum aestivum. Namibia, Caespitomonium euphorbiae (incl. Caespitomonium gen. nov.) from stems of an Euphorbia sp. Netherlands, Alfaria junci, Myrmecridium junci, Myrmecridium juncicola, Myrmecridium juncigenum, Ophioceras junci, Paradinemasporium junci (incl. Paradinemasporium gen. nov.), Phialoseptomonium junci, Sporidesmiella juncicola, Xenopyricularia junci and Zaanenomyces quadripartis (incl. Zaanenomyces gen. nov.), from dead culms of Juncus effusus, Cylindromonium everniae and Rhodoveronaea everniae from Evernia prunastri, Cyphellophora sambuci and Myrmecridium sambuci from Sambucus nigra, Kiflimonium junci, Sarocladium junci, Zaanenomyces moderatricis-academiae and Zaanenomyces versatilis from dead culms of Juncus inflexus, Microcera physciae from Physcia tenella, Myrmecridium dactylidis from dead culms of Dactylis glomerata, Neochalara spiraeae and Sporidesmium spiraeae from leaves of Spiraea japonica, Neofabraea salicina from Salix sp., Paradissoconium narthecii (incl. Paradissoconium gen. nov.) from dead leaves of Narthecium ossifragum, Polyscytalum vaccinii from Vaccinium myrtillus, Pseudosoloacrosporiella cryptomeriae (incl. Pseudosoloacrosporiella gen. nov.) from leaves of Cryptomeria japonica, Ramularia pararhabdospora from Plantago lanceolata, Sporidesmiella pini from needles of Pinus sylvestris and Xenoacrodontium juglandis (incl. Xenoacrodontium gen. nov. and Xenoacrodontiaceae fam. nov.) from Juglans regia. New Zealand, Cryptometrion metrosideri from twigs of Metrosideros sp., Coccomyces pycnophyllocladi from dead leaves of Phyllocladus alpinus, Hypoderma aliforme from fallen leaves Fuscopora solandri and Hypoderma subiculatum from dead leaves Phormium tenax. Norway, Neodevriesia kalakoutskii from permafrost and Variabilispora viridis from driftwood of Picea abies. Portugal, Entomortierella hereditatis from a biofilm covering a deteriorated limestone wall. Russia, Colpoma junipericola from needles of Juniperus sabina, Entoloma cinnamomeum on soil in grasslands, Entoloma verae on soil in grasslands, Hyphodermella pallidostraminea on a dry dead branch of Actinidia sp., Lepiota sayanensis on litter in a mixed forest, Papiliotrema horticola from Malus communis, Paramacroventuria ribis (incl. Paramacroventuria gen. nov.) from leaves of Ribes aureum and Paramyrothecium lathyri from leaves of Lathyrus tuberosus. South Africa, Harzia combreti from leaf litter of Combretum collinum ssp. sulvense, Penicillium xyleborini from Xyleborinus saxesenii, Phaeoisaria dalbergiae from bark of Dalbergia armata, Protocreopsis euphorbiae from leaf litter of Euphorbia ingens and Roigiella syzygii from twigs of Syzygium chordatum. Spain, Genea zamorana on sandy soil, Gymnopus nigrescens on Scleropodium touretii, Hesperomyces parexochomi on Parexochomus quadriplagiatus, Paraphoma variabilis from dung, Phaeococcomyces kinklidomatophilus from a blackened metal railing of an industrial warehouse and Tuber suaveolens in soil under Quercus faginea. Svalbard and Jan Mayen, Inocybe nivea associated with Salix polaris. Thailand, Biscogniauxia whalleyi on corticated wood. UK, Parasitella quercicola from Quercus robur. USA, Aspergillus arizonicus from indoor air in a hospital, Caeliomyces tampanus (incl. Caeliomyces gen. nov.) from office dust, Cippumomyces mortalis (incl. Cippumomyces gen. nov.) from a tombstone, Cylindrium desperesense from air in a store, Tetracoccosporium pseudoaerium from air sample in house, Toxicocladosporium glendoranum from air in a brick room, Toxicocladosporium losalamitosense from air in a classroom, Valsonectria portsmouthensis from air in men's locker room and Varicosporellopsis americana from sludge in a water reservoir. Vietnam, Entoloma kovalenkoi on rotten wood, Fusarium chuoi inside seed of Musa itinerans, Micropsalliota albofelina on soil in tropical evergreen mixed forests and Phytophthora docyniae from soil and roots of Docynia indica. Morphological and culture characteristics are supported by DNA barcodes. Citation: Crous PW, Osieck ER, Jurjevic Z, et al. 2021. Fungal Planet description sheets: 1284-1382. Persoonia 47: 178-374. https://doi.org/10.3767/persoonia.2021.47.06.
ABSTRACT
Novel species of fungi described in this study include those from various countries as follows: Antartica, Cladosporium austrolitorale from coastal sea sand. Australia, Austroboletus yourkae on soil, Crepidotus innuopurpureus on dead wood, Curvularia stenotaphri from roots and leaves of Stenotaphrum secundatum and Thecaphora stajsicii from capsules of Oxalis radicosa. Belgium, Paraxerochrysium coryli (incl. Paraxerochrysium gen. nov.) from Corylus avellana. Brazil, Calvatia nordestina on soil, Didymella tabebuiicola from leaf spots on Tabebuia aurea, Fusarium subflagellisporum from hypertrophied floral and vegetative branches of Mangifera indica and Microdochium maculosum from living leaves of Digitaria insularis. Canada, Cuphophyllus bondii from a grassland. Croatia, Mollisia inferiseptata from a rotten Laurus nobilis trunk. Cyprus, Amanita exilis on calcareous soil. Czech Republic, Cytospora hippophaicola from wood of symptomatic Vaccinium corymbosum. Denmark, Lasiosphaeria deviata on pieces of wood and herbaceous debris. Dominican Republic, Calocybella goethei among grass on a lawn. France (Corsica), Inocybe corsica on wet ground. France (French Guiana), Trechispora patawaensis on decayed branch of unknown angiosperm tree and Trechispora subregularis on decayed log of unknown angiosperm tree. Germany, Paramicrothecium sambuci (incl. Paramicrothecium gen. nov.) on dead stems of Sambucus nigra. India, Aureobasidium microtermitis from the gut of a Microtermes sp. termite, Laccaria diospyricola on soil and Phylloporia tamilnadensis on branches of Catunaregam spinosa. Iran, Pythium serotinoosporum from soil under Prunus dulcis. Italy, Pluteus brunneovenosus on twigs of broadleaved trees on the ground. Japan, Heterophoma rehmanniae on leaves of Rehmannia glutinosa f. hueichingensis. Kazakhstan, Murispora kazachstanica from healthy roots of Triticum aestivum. Namibia, Caespitomonium euphorbiae (incl. Caespitomonium gen. nov.) from stems of an Euphorbia sp. Netherlands, Alfaria junci, Myrmecridium junci, Myrmecridium juncicola, Myrmecridium juncigenum, Ophioceras junci, Paradinemasporium junci (incl. Paradinemasporium gen. nov.), Phialoseptomonium junci, Sporidesmiella juncicola, Xenopyricularia junci and Zaanenomyces quadripartis (incl. Zaanenomyces gen. nov.), from dead culms of Juncus effusus, Cylindromonium everniae and Rhodoveronaea everniae from Evernia prunastri, Cyphellophora sambuci and Myrmecridium sambuci from Sambucus nigra, Kiflimonium junci, Sarocladium junci, Zaanenomyces moderatricis-academiae and Zaanenomyces versatilis from dead culms of Juncus inflexus, Microcera physciae from Physcia tenella, Myrmecridium dactylidis from dead culms of Dactylis glomerata, Neochalara spiraeae and Sporidesmium spiraeae from leaves of Spiraea japonica, Neofabraea salicina from Salix sp., Paradissoconium narthecii (incl. Paradissoconium gen. nov.) from dead leaves of Narthecium ossifragum, Polyscytalum vaccinii from Vaccinium myrtillus, Pseudosoloacrosporiella cryptomeriae (incl. Pseudosoloacrosporiella gen. nov.) from leaves of Cryptomeria japonica, Ramularia pararhabdospora from Plantago lanceolata, Sporidesmiella pini from needles of Pinus sylvestris and Xenoacrodontium juglandis (incl. Xenoacrodontium gen. nov. and Xenoacrodontiaceae fam. nov.) from Juglans regia. New Zealand, Cryptometrion metrosideri from twigs of Metrosideros sp., Coccomyces pycnophyllocladi from dead leaves of Phyllocladus alpinus, Hypoderma aliforme from fallen leaves Fuscopora solandri and Hypoderma subiculatum from dead leaves Phormium tenax. Norway, Neodevriesia kalakoutskii from permafrost and Variabilispora viridis from driftwood of Picea abies. Portugal, Entomortierella hereditatis from a biofilm covering a deteriorated limestone wall. Russia, Colpoma junipericola from needles of Juniperus sabina, Entoloma cinnamomeum on soil in grasslands, Entoloma verae on soil in grasslands, Hyphodermella pallidostraminea on a dry dead branch of Actinidia sp., Lepiota sayanensis on litter in a mixed forest, Papiliotrema horticola from Malus communis, Paramacroventuria ribis (incl. Paramacroventuria gen. nov.) from leaves of Ribes aureum and Paramyrothecium lathyri from leaves of Lathyrus tuberosus. South Africa, Harzia combreti from leaf litter of Combretum collinum ssp. sulvense, Penicillium xyleborini from Xyleborinus saxesenii, Phaeoisaria dalbergiae from bark of Dalbergia armata, Protocreopsis euphorbiae from leaf litter of Euphorbia ingens and Roigiella syzygii from twigs of Syzygium chordatum. Spain, Genea zamorana on sandy soil, Gymnopus nigrescens on Scleropodium touretii, Hesperomyces parexochomi on Parexochomus quadriplagiatus, Paraphoma variabilis from dung, Phaeococcomyces kinklidomatophilus from a blackened metal railing of an industrial warehouse and Tuber suaveolens in soil under Quercus faginea. Svalbard and Jan Mayen, Inocybe nivea associated with Salix polaris. Thailand, Biscogniauxia whalleyi on corticated wood. UK, Parasitella quercicola from Quercus robur. USA, Aspergillus arizonicus from indoor air in a hospital, Caeliomyces tampanus (incl. Caeliomyces gen. nov.) from office dust, Cippumomyces mortalis (incl. Cippumomyces gen. nov.) from a tombstone, Cylindrium desperesense from air in a store, Tetracoccosporium pseudoaerium from air sample in house, Toxicocladosporium glendoranum from air in a brick room, Toxicocladosporium losalamitosense from air in a classroom, Valsonectria portsmouthensis from air in men's locker room and Varicosporellopsis americana from sludge in a water reservoir. Vietnam, Entoloma kovalenkoi on rotten wood, Fusarium chuoi inside seed of Musa itinerans, Micropsalliota albofelina on soil in tropical evergreen mixed forests and Phytophthora docyniae from soil and roots of Docynia indica. Morphological and culture characteristics are supported by DNA barcodes. Citation: Crous PW, Osieck ER, Jurjevic Z, et al. 2021. Fungal Planet description sheets: 1284-1382. Persoonia 47: 178-374. https://doi.org/10.3767/persoonia.2021.47.06.
ABSTRACT
Danon disease is a severe multisystem disorder clinically characterized by hypertrophic cardiomyopathy, skeletal myopathy and mental retardation in male patients, and by a milder phenotype (predominantly involving cardiac muscle) in female patients. The disease is inherited as an X-linked dominant trait. The primary deficiency of lysosome-associated membrane protein-2 (LAMP-2) causes disruption of autophagy, leading to an impaired fusion of lysosomes to autophagosomes and biogenesis of lysosomes. We surveyed over 500 Danon disease patients reported in the literature from the first description to the present, in order to summarize the clinical, pathological and molecular data and treatment perspectives. An early molecular diagnosis is of crucial importance for genetic counselling and for therapeutic interventions: in male patients, the prognosis is poor due to rapid progression towards heart failure, and only heart transplantation modifies the disease course.
Subject(s)
Glycogen Storage Disease Type IIb , Adult , Female , Glycogen Storage Disease Type IIb/diagnosis , Glycogen Storage Disease Type IIb/genetics , Glycogen Storage Disease Type IIb/pathology , Humans , MaleABSTRACT
Novel species of fungi described in this study include those from various countries as follows: Australia, Austroboletus asper on soil, Cylindromonium alloxyli on leaves of Alloxylon pinnatum, Davidhawksworthia quintiniae on leaves of Quintinia sieberi, Exophiala prostantherae on leaves of Prostanthera sp., Lactifluus lactiglaucus on soil, Linteromyces quintiniae (incl. Linteromyces gen. nov.) on leaves of Quintinia sieberi, Lophotrichus medusoides from stem tissue of Citrus garrawayi, Mycena pulchra on soil, Neocalonectria tristaniopsidis (incl. Neocalonectria gen. nov.) and Xyladictyochaeta tristaniopsidis on leaves of Tristaniopsis collina, Parasarocladium tasmanniae on leaves of Tasmannia insipida, Phytophthora aquae-cooljarloo from pond water, Serendipita whamiae as endophyte from roots of Eriochilus cucullatus, Veloboletus limbatus (incl. Veloboletus gen. nov.) on soil. Austria, Cortinarius glaucoelotus on soil. Bulgaria, Suhomyces rilaensis from the gut of Bolitophagus interruptus found on a Polyporus sp. Canada, Cantharellus betularum among leaf litter of Betula, Penicillium saanichii from house dust. Chile, Circinella lampensis on soil, Exophiala embothrii from rhizosphere of Embothrium coccineum. China, Colletotrichum cycadis on leaves of Cycas revoluta. Croatia, Phialocephala melitaea on fallen branch of Pinus halepensis. Czech Republic, Geoglossum jirinae on soil, Pyrenochaetopsis rajhradensis from dead wood of Buxus sempervirens. Dominican Republic, Amanita domingensis on litter of deciduous wood, Melanoleuca dominicana on forest litter. France, Crinipellis nigrolamellata (Martinique) on leaves of Pisonia fragrans, Talaromyces pulveris from bore dust of Xestobium rufovillosum infesting floorboards. French Guiana, Hypoxylon hepaticolor on dead corticated branch. Great Britain, Inocybe ionolepis on soil. India, Cortinarius indopurpurascens among leaf litter of Quercus leucotrichophora. Iran, Pseudopyricularia javanii on infected leaves of Cyperus sp., Xenomonodictys iranica (incl. Xenomonodictys gen. nov.) on wood of Fagus orientalis. Italy, Penicillium vallebormidaense from compost. Namibia, Alternaria mirabibensis on plant litter, Curvularia moringae and Moringomyces phantasmae (incl. Moringomyces gen. nov.) on leaves and flowers of Moringa ovalifolia, Gobabebomyces vachelliae (incl. Gobabebomyces gen. nov.) on leaves of Vachellia erioloba, Preussia procaviae on dung of Procavia capensis. Pakistan, Russula shawarensis from soil on forest floor. Russia, Cyberlindnera dauci from Daucus carota. South Africa, Acremonium behniae on leaves of Behnia reticulata, Dothiora aloidendri and Hantamomyces aloidendri (incl. Hantamomyces gen. nov.) on leaves of Aloidendron dichotomum, Endoconidioma euphorbiae on leaves of Euphorbia mauritanica, Eucasphaeria proteae on leaves of Protea neriifolia, Exophiala mali from inner fruit tissue of Malus sp., Graminopassalora geissorhizae on leaves of Geissorhiza splendidissima, Neocamarosporium leipoldtiae on leaves of Leipoldtia schultzii, Neocladosporium osteospermi on leaf spots of Osteospermum moniliferum, Neometulocladosporiella seifertii on leaves of Combretum caffrum, Paramyrothecium pituitipietianum on stems of Grielum humifusum, Phytopythium paucipapillatum from roots of Vitis sp., Stemphylium carpobroti and Verrucocladosporium carpobroti on leaves of Carpobrotus quadrifolius, Suttonomyces cephalophylli on leaves of Cephalophyllum pilansii. Sweden, Coprinopsis rubra on cow dung, Elaphomyces nemoreus from deciduous woodlands. Spain, Polyscytalum pini-canariensis on needles of Pinus canariensis, Pseudosubramaniomyces septatus from stream sediment, Tuber lusitanicum on soil under Quercus suber. Thailand, Tolypocladium flavonigrum on Elaphomyces sp. USA, Chaetothyrina spondiadis on fruits of Spondias mombin, Gymnascella minnisii from bat guano, Juncomyces patwiniorum on culms of Juncus effusus, Moelleriella puertoricoensis on scale insect, Neodothiora populina (incl. Neodothiora gen. nov.) on stem cankers of Populus tremuloides, Pseudogymnoascus palmeri from cave sediment. Vietnam, Cyphellophora vietnamensis on leaf litter, Tylopilus subotsuensis on soil in montane evergreen broadleaf forest. Morphological and culture characteristics are supported by DNA barcodes.
ABSTRACT
An abnormal structural form of glycogen (with less branching points or amylopectin-like polysaccharide) called polyglucosan (PG) may accumulate in various tissues such as striated and smooth muscles, brain, nerve, liver and skin, and cause a group of nine different genetic disorders manifesting with a variety of clinical phenotypes that affect mainly the nervous system (Lafora disease, adult PG body disease), the heart (glycogen storage disease type XV, hypertrophic cardiomyopathy type 6, PG body myopathy type 1) and the skeletal muscle (glycogen storage disease type IV, glycogen storage disease type VII, PG body myopathy type 2), depending on the organs which are mostly affected by the PG aggregates. The pathological feature of PG storage in tissues is a hallmark of these disorders. Whole-genome sequencing has allowed to obtain a diagnosis in a large number of patients with a previously unrecognized disorder. We describe the clinical, pathological and molecular features of these genetic disorders, for many of which the pathological mechanisms underlying the corresponding mutant gene have been investigated and, at least in part, understood.
Subject(s)
Glucans/metabolism , Glycogen Storage Disease Type IV/metabolism , Glycogen Storage Disease/metabolism , Nervous System Diseases/metabolism , Polysaccharides/metabolism , Animals , Humans , Liver/metabolism , Liver/pathology , Muscle, Skeletal/pathologyABSTRACT
AIMS: Pompe disease is an autosomal recessive lysosomal storage disorder resulting from deficiency of acid α-glucosidase (GAA) enzyme. Histopathological hallmarks in skeletal muscle tissue are fibre vacuolization and autophagy. Since 2006, enzyme replacement therapy (ERT) is the only approved treatment with human recombinant GAA alglucosidase alfa. We designed a study to examine ERT-related skeletal muscle changes in 18 modestly to moderately affected late onset Pompe disease (LOPD) patients along with the relationship between morphological/biochemical changes and clinical outcomes. Treatment duration was short-to-long term. METHODS: We examined muscle biopsies from 18 LOPD patients at both histopathological and biochemical level. All patients underwent two muscle biopsies, before and after ERT administration respectively. The study is partially retrospective because the first biopsies were taken before the study was designed, whereas the second biopsy was always performed after at least 6 months of ERT administration. RESULTS: After ERT, 15 out of 18 patients showed improved 6-min walking test (6MWT; P = 0.0007) and most of them achieved respiratory stabilization. Pretreatment muscle biopsies disclosed marked histopathological variability, ranging from an almost normal pattern to a severe vacuolar myopathy. After treatment, we detected morphological improvement in 15 patients and worsening in three patients. Post-ERT GAA enzymatic activity was mildly increased compared with pretreatment levels in all patients. Protein levels of the mature enzyme increased in 14 of the 18 patients (mean increase = +35%; P < 0.05). Additional studies demonstrated an improved autophagic flux after ERT in some patients. CONCLUSIONS: ERT positively modified skeletal muscle pathology as well as motor and respiratory outcomes in the majority of LOPD patients.
Subject(s)
Glycogen Storage Disease Type II/drug therapy , Glycogen Storage Disease Type II/pathology , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , alpha-Glucosidases/therapeutic use , Adult , Aged , Enzyme Replacement Therapy/methods , Female , Humans , Male , Middle Aged , Recombinant Proteins/therapeutic use , Retrospective StudiesABSTRACT
The monotypic genus Phylloporopsis is described as new to science based on Phylloporus boletinoides. This species occurs widely in eastern North America and Central America. It is reported for the first time from a neotropical montane pine woodland in the Dominican Republic. The confirmation of this newly recognised monophyletic genus is supported and molecularly confirmed by phylogenetic inference based on multiple loci (ITS, 28S, TEF1-α, and RPB1). A detailed morphological description of P. boletinoides from the Dominican Republic and Florida (USA) is provided along with colour images of fresh basidiomata in habitat, line drawings of the main anatomical features, transmitted light microscopic images of anatomical features and scanning electron microscope images of basidiospores. The taxonomic placement, ecological requirements and distribution patterns of P. boletinoides are reviewed and the relationships with phylogenetically related or morphologically similar lamellate and boletoid taxa such as Phylloporus, Phylloboletellus, Phyllobolites and Bothia are discussed.
ABSTRACT
Ocular myopathy, typically manifesting as progressive external ophthalmoplegia (PEO), is among the most common mitochondrial phenotypes. The purpose of this study is to better define the clinical phenotypes associated with ocular myopathy. This is a retrospective study on a large cohort from the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases". We distinguished patients with ocular myopathy as part of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy), and then PEO with isolated ocular myopathy from PEO-plus when PEO was associated with additional features of multisystemic involvement. Ocular myopathy was the most common feature in our cohort of mitochondrial patients. Among the 722 patients with a definite genetic diagnosis, ocular myopathy was observed in 399 subjects (55.3%) and was positively associated with mtDNA single deletions and POLG mutations. Ocular myopathy as manifestation of a multisystem mitochondrial encephalomyopathy (PEO-encephalomyopathy, n = 131) was linked to the m.3243A>G mutation, whereas the other "PEO" patients (n = 268) were associated with mtDNA single deletion and Twinkle mutations. Increased lactate was associated with central neurological involvement. We then defined, among the PEO group, as "pure PEO" the patients with isolated ocular myopathy and "PEO-plus" those with ocular myopathy and other features of neuromuscular and multisystem involvement, excluding central nervous system. The male proportion was significantly lower in pure PEO than PEO-plus. This study reinforces the need for research on the role of gender in mitochondrial diseases. The phenotype definitions here revisited may contribute to a more homogeneous patient categorization, useful in future studies and clinical trials.
Subject(s)
Ophthalmoplegia, Chronic Progressive External/genetics , Ophthalmoplegia, Chronic Progressive External/physiopathology , Adult , Age of Onset , DNA Polymerase gamma/genetics , DNA, Mitochondrial , Female , GTP Phosphohydrolases/genetics , Genetic Association Studies , Humans , Italy , Male , Mutation , Ophthalmoplegia, Chronic Progressive External/diagnosis , Ophthalmoplegia, Chronic Progressive External/epidemiology , Phenotype , Retrospective Studies , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.
Subject(s)
Enzyme Replacement Therapy , Glycogen Storage Disease Type II/drug therapy , Quality of Life , Adult , Consensus , Drug Administration Schedule , Europe , Humans , Practice Guidelines as TopicABSTRACT
Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids. Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G>C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options.
Subject(s)
Fibroblasts/cytology , Lipase/genetics , Lipid Metabolism, Inborn Errors/pathology , Muscular Diseases/pathology , Pluripotent Stem Cells/cytology , Cell Culture Techniques , Cell Differentiation , Fibroblasts/pathology , Humans , Lipid Metabolism, Inborn Errors/genetics , Lipid Metabolism, Inborn Errors/metabolism , Lipolysis , Models, Biological , Muscular Diseases/genetics , Muscular Diseases/metabolism , Mutation , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/pathology , Triglycerides/metabolismABSTRACT
BACKGROUND AND OBJECTIVE: High altitude may be a factor associated with cerebral venous thrombosis (CVT). As our knowledge of CVT at high altitude is limited, it was decided to pool such information from the available case studies to determine whether high altitude can predispose to CVT. METHODS: A systematic review of the literature was performed for cases reporting CVT at high altitude. Searches of the PubMed database (up to July 2016) were performed for publications, using 'cerebral venous thrombosis' and 'high altitude' as keywords. Cross-referencing was also done to complete the search. RESULTS: Ultimately, 13 articles were included in our systematic review. The population consisted of 17 patients, predominately male (14/17), with a mean age of 32 (range: 19-47) years. Altitude range was 3000-8200m. Nine patients stayed at high altitude for>2 weeks; the duration of high altitude stay was unknown for the remainder. A hypercoagulable state was found in nine patients: secondary polycythemia in five; protein C deficiency in one; protein S deficiency in one; and factor V Leiden mutations in two. No comorbidities were found in any of these patients. CONCLUSION: Long-term stays at high altitude in association with a hypercoagulable state - in particular, congenital or acquired thrombophilia - appears to predispose to CVT. The association of CVT with a single exposure to high altitude seems low, but the risk cannot as yet be specifically estimated.
Subject(s)
Altitude , Intracranial Thrombosis/etiology , Venous Thrombosis/etiology , Adult , Blood Coagulation Disorders/etiology , Female , Humans , Intracranial Thrombosis/blood , Intracranial Thrombosis/diagnostic imaging , Male , Middle Aged , Neuroimaging , Venous Thrombosis/blood , Venous Thrombosis/diagnostic imaging , Young AdultABSTRACT
miRNA expression profile and predicted pathways involved in selected limb-girdle muscular dystrophy (LGMD)2A/2B patients were investigated. A total of 187 miRNAs were dysregulated in all patients, with six miRNAs showing opposite regulation in LGMD2A versus LGMD2B patients. Silico analysis evidence: (1) a cluster of the dysregulated miRNAs resulted primarily involved in inflammation and calcium metabolism, and (2) two genes predicted as controlled by calcium-assigned miRNAs (Vitamin D Receptor gene and Guanine Nucleotide Binding protein beta polypeptide 1gene) showed an evident upregulation in LGMD2B patients, in accordance with miRNA levels. Our data support alterations in calcium pathway status in LGMD 2A/B, suggesting myofibre calcium imbalance as a potential therapeutic target. Copyright © 2016 John Wiley & Sons, Ltd.
Subject(s)
Calcium/metabolism , Gene Expression Profiling , MicroRNAs/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Receptors, Calcitriol/genetics , Signal Transduction/genetics , Adolescent , Adult , Child , Child, Preschool , Female , GTP-Binding Protein beta Subunits/genetics , GTP-Binding Protein beta Subunits/metabolism , Gene Expression Regulation , Humans , Male , MicroRNAs/metabolism , Middle Aged , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Receptors, Calcitriol/metabolismABSTRACT
OBJECTIVE: A multicentre observational study was aimed to assess the prevalence of late-onset Pompe disease (LOPD) in a large high-risk population, using the dried blood spot (DBS) as a main screening tool. DESIGN/METHODS: 17 Italian neuromuscular centres were involved in the late-onset Pompe early diagnosis (LOPED) study. Inclusion criteria were: (1) age ≥5â years, (2) persistent hyperCKaemia and (3) muscle weakness at upper and/or lower limbs (limb-girdle muscle weakness, LGMW). Acid α-glucosidase (GAA) activity was measured separately on DBS by fluorometric as well as tandem mass spectrometry methods. A DBS retest was performed in patients resulted positive at first assay. For the final diagnosis, GAA deficiency was confirmed by a biochemical assay in skeletal muscle, whereas genotype was assessed by GAA molecular analysis. RESULTS: In a 14-month period, we studied 1051 cases: 30 positive samples (2.9%) were detected by first DBS screening, whereas, after retesting, 21 samples were still positive. Biochemical and molecular genetic studies finally confirmed LOPD diagnosis in 17 cases (1.6%). The median time from the onset of symptoms/signs to diagnosis was 5â years. Among those patients, 35% showed presymptomatic hyperCKaemia and 59% showed hyperCKaemia+LGMW, whereas 6% manifested with LGMW. CONCLUSIONS: LOPED study suggests that GAA activity should be accurately screened by DBS in all patients referring for isolated hyperCKaemia and/or LGMW. A timely diagnosis was performed in five patients with presymptomatic hyperCKaemia, but two had already manifested with relevant changes on muscle morphology and MRI. Consequently, enzyme replacement therapy was started in 14/17 patients, including the 2 patients still clinically presymptomatic but with a laboratory evidence of disease progression.
Subject(s)
Glycogen Storage Disease Type II/diagnosis , Adult , Age of Onset , Creatine Kinase/blood , Early Diagnosis , Female , Fluorometry , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/therapy , Humans , Male , Middle Aged , Muscle Weakness/etiology , Muscle, Skeletal/pathology , Pathology, Molecular/methods , Reproducibility of Results , Risk , Tandem Mass Spectrometry , alpha-Glucosidases/geneticsABSTRACT
We report a measurement of the time-dependent CP asymmetry of B[over ¯]^{0}âD_{CP}^{(*)}h^{0} decays, where the light neutral hadron h^{0} is a π^{0}, η, or ω meson, and the neutral D meson is reconstructed in the CP eigenstates K^{+}K^{-}, K_{S}^{0}π^{0}, or K_{S}^{0}ω. The measurement is performed combining the final data samples collected at the Ï(4S) resonance by the BABAR and Belle experiments at the asymmetric-energy B factories PEP-II at SLAC and KEKB at KEK, respectively. The data samples contain (471±3)×10^{6} BB[over ¯] pairs recorded by the BABAR detector and (772±11)×10^{6} BB[over ¯] pairs recorded by the Belle detector. We measure the CP asymmetry parameters -η_{f}S=+0.66±0.10(stat)±0.06(syst) and C=-0.02±0.07(stat)±0.03(syst). These results correspond to the first observation of CP violation in B[over ¯]^{0}âD_{CP}^{(*)}h^{0} decays. The hypothesis of no mixing-induced CP violation is excluded in these decays at the level of 5.4 standard deviations.
ABSTRACT
BACKGROUND: Myalgia, defined as any pain perceived in muscle, is very common in the general population and a frequent cause for referral to neurologists, rheumatologists and internists in general. It is however only rarely due to primary muscle disease and often referred from ligaments, joints, bones, the peripheral and central nervous system. A muscle biopsy should only be performed if this is likely to be diagnostically useful. At present no 'guidelines' exist. METHODS: An EFNS panel of muscle specialists was set to review relevant studies from PubMed dating as far back as 1/1/1990. Only Class IV studies were available and therefore the recommendations arrived at are 'best practice recommendations' based on information harvested from the literature search and expert opinion. RESULTS: Muscle cramps should be recognized while drugs, infections, metabolic/ endocrinological and rheumatological causes of myalgia should be identified from the history and examination and pertinent laboratory tests. A muscle biopsy is more likely to be diagnostically useful if myalgia is exertional and if one or more of the following apply: i) there is myoglobinuria, (ii) there is a second wind phenomenon, (iii) there is muscle weakness, (iv) there is muscle hypertrophy /atrophy, (v) there is hyperCKemia (>2-3× normal), and (vi) there is a myopathic EMG. CONCLUSIONS: Patients presenting with myalgia can be recommended to have a biopsy based on careful history and examination and on simple laboratory screening.
Subject(s)
Biopsy/standards , Myalgia/diagnosis , Exercise/physiology , Humans , Myalgia/etiology , Myalgia/physiopathology , Predictive Value of TestsABSTRACT
AIMS: The peculiar clinical features and the pathogenic mechanism related to calpain-3 deficiency (impaired sarcomere remodelling) suggest that the ubiquitin-proteasome degradation pathway may have a crucial role in Limb Girdle Muscular Dystrophy 2A (LGMD2A). We therefore investigated muscle atrophy and the role of the ubiquitin-proteasome and lysosomal-autophagic degradation pathways. METHODS: We selected 25 adult male LGMD2A patients (and seven controls), classified them using clinical severity score, analysed muscle fibre size by morphometry and protein and/or transcriptional expression levels of the most important atrophy- and autophagy-related genes (MuRF1,â atrogin1,â LC3,â p62,â Bnip3). RESULTS: Muscle fibre size was significantly lower in LGMD2A than in controls and it was significantly correlated with patients' clinical disability score recorded at the time of biopsy, suggesting that functional and structural muscle impairment are dependent. The large majority of atrophic fibres originate from a mechanism different from regeneration, as assessed by neonatal myosin immunolabelling. As compared with controls, LGMD2A muscles have higher MuRF1 (but not atrogin1) protein and MuRF1 gene expression levels, and MuRF1 protein levels significantly correlated with both muscle fibre size and clinical disability score. LGMD2A muscles have slightly increased levels of LC3-II and p62 proteins and a significant up-regulation of p62 and Bnip3 gene expression. CONCLUSIONS: In LGMD2A muscles the activation of the atrophy programme appeared to depend mainly upon induction of the ubiquitin-proteasome system and, to a lesser extent, the autophagic-lysosomal degradation pathway.
Subject(s)
Calpain/metabolism , Muscle Proteins/metabolism , Muscular Atrophy/metabolism , Muscular Dystrophies, Limb-Girdle/metabolism , Adolescent , Adult , Humans , Male , Middle Aged , Proteasome Endopeptidase Complex/metabolism , Regeneration/physiology , Ubiquitin/metabolism , Up-Regulation , Young AdultABSTRACT
Nemaline myopathy (NM) constitutes a heterogeneous group of congenital myopathies. Mutations in the nebulin gene (NEB) are the main cause of recessively inherited NM. NEB is one of the most largest genes in human. To date, 68 NEB mutations, mainly small deletions or point mutations have been published. The only large mutation characterized is the 2.5 kb deletion of exon 55 in the Ashkenazi Jewish population. To investigate any copy number variations in this enormous gene, we designed a novel custom comparative genomic hybridization microarray, NM-CGH, targeted towards the seven known genes causative for NM. During the validation of the NM-CGH array we identified two novel deletions in two different families. The first is the largest deletion characterized in NEB to date, (â¼53 kb) encompassing 24 exons. The second deletion (1 kb) covers two exons. In both families, the copy number change was the second mutation to be characterized and shown to have been inherited from one of the healthy carrier parents. In addition to these novel mutations, copy number variation was identified in four samples in three families in the triplicate region of NEB. We conclude that this method appears promising for the detection of copy number variations in NEB.