52 results on '"Paola Origone"'
Search Results
2. A case of Huntington disease‐like 2 in a patient of African ancestry: the everlasting support of clinical examination in the molecular era
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Federica Ruscitti, Paola Origone, Giulia Rosti, Lucia Trevisan, Roberta Marchese, Andrea Brugnolo, Federico Massa, Paola Castellini, and Paola Mandich
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General Medicine - Published
- 2022
3. The role of anterior prefrontal cortex in prospective memory: an exploratory FDG-PET study in early Alzheimer's disease
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Stefano Grisanti, Marco Pagani, Matteo Pardini, Fabrizio De Carli, Matteo Bauckneht, Elisa Doglione, Paola Origone, Federico Massa, Andrea Brugnolo, Dario Arnaldi, Silvia Morbelli, Beatrice Orso, Laura Filippi, Flavio Nobili, and Nicola Girtler
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Male ,0301 basic medicine ,Aging ,medicine.medical_specialty ,Memory, Episodic ,prospective memory ,Prefrontal Cortex ,Disease ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Fluorodeoxyglucose F18 ,Internal medicine ,Healthy control ,Healthy volunteers ,Prospective memory ,medicine ,Humans ,FDG-PET ,Cognitive impairment ,Prefrontal cortex ,Aged ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,General Neuroscience ,Alzheimer's disease ,MCI ,Early Diagnosis ,030104 developmental biology ,Positron emission tomography ,Positron-Emission Tomography ,Correlation analysis ,Cardiology ,Female ,Neurology (clinical) ,Radiopharmaceuticals ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Introduction. Prospective memory (PM) is the ability of forming and maintaining an intention in memory over time while performing another task. From previous studies in healthy volunteers the prefrontal regions are deeply involved in PM, although little is known in early Alzheimer's disease (AD). Hence, we investigated the functional neural basis of PM in patients with mild cognitive impairment due to AD (MCI-AD) by assessing brain metabolism (18F-FDG PET). Methods. Eighteen patients (10 males, age:74±4.9; MMSE score:27.7±1.6) with intermediate or high likelihood of MCI-AD and a control group (HC) of 23 healthy subjects (11 males, age:71.5±5.7) underwent FDG-PET, neuropsychological evaluation and the PM-specific Shum and Ungvari paradigm test. Brain metabolism was correlated with the PM score in the two groups separately to find those brain areas correlated with PM performance ('PM cluster'), which were then used as central hub for the subsequent interregional metabolic connectivity analyses (IRCA). Results. In MCI-AD patients PM score positively correlated with metabolic levels in the right anterior prefrontal cortex (aPFC, middle and inferior frontal gyri); no correlation was found in HC. The IRCA showed in MCI-AD patients a loss of the interhemispheric connectivity of the PM cluster. Conclusion. The functioning of the right aPFC and its metabolic interhemispheric connectivity is crucial in early AD to sustain PM performance which deteriorates along with progressive metabolic failure in these regions.
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- 2020
4. An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia
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Tiziana Mongini, Monica Traverso, Federico Zara, Elena Scarsi, Claudio Bruno, Barbara Carlini, Lucia Trevisan, Rosa Iodice, Marina Grandis, Eugenia Rota, Valeria Prada, Livia Pisciotta, Lucia Ruggiero, Salvatore Gallone, Carlo Minetti, Sabrina Fabbri, Angelo Schenone, Paola Mandich, Serena Patrone, Paola Origone, Chiara Fiorillo, Chiara Gemelli, Gemelli, Chiara, Traverso, Monica, Trevisan, Lucia, Fabbri, Sabrina, Scarsi, Elena, Carlini, Barbara, Prada, Valeria, Mongini, Tiziana, Ruggiero, Lucia, Patrone, Serena, Gallone, Salvatore, Iodice, Rosa, Pisciotta, Livia, Zara, Federico, Origone, Paola, Rota, Eugenia, Minetti, Carlo, Bruno, Claudio, Schenone, Angelo, Mandich, Paola, Fiorillo, Chiara, and Grandis, Marina
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medicine.medical_specialty ,creatine kinase ,diagnostic workflow ,hyperCKemia ,muscle disease ,next-generation sequencing ,Creatine Kinase ,DNA Copy Number Variations ,Electromyography ,Humans ,Glycogen Storage Disease Type II ,Muscular Diseases ,Physiology ,Neurological examination ,Disease ,Asymptomatic ,Myotonic dystrophy ,Cellular and Molecular Neuroscience ,Physiology (medical) ,Internal medicine ,medicine ,In patient ,medicine.diagnostic_test ,business.industry ,Integrated approach ,medicine.disease ,Neurology (clinical) ,medicine.symptom ,Nerve conduction ,business - Abstract
INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields. This article is protected by copyright. All rights reserved.
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- 2022
5. A novel mutation in COL3A1 associates to vascular Ehlers–Danlos syndrome with predominant musculoskeletal involvement
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Paola Origone, Federica Ruscitti, Giulia Rosti, Annalia Cianflone, Paola Mandich, Anna Pichiecchio, Simona Viglio, Maria Iascone, Fabio Gotta, Lucia Trevisan, and Alessandro Geroldi
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Adult ,Male ,Pathology ,medicine.medical_specialty ,COL3A1 ,QH426-470 ,Clinical Reports ,Genetics ,medicine ,Humans ,Heritable connective tissue disorder ,Muscle, Skeletal ,Molecular Biology ,Genetics (clinical) ,Mitral regurgitation ,Clinical Report ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Pathogenicity ,vEDS ,Collagen Type III ,Phenotype ,Increased risk ,medicine.anatomical_structure ,Ehlers–Danlos syndrome ,NGS ,Mutation ,Skin biopsy ,Ehlers-Danlos Syndrome ,business ,Novel mutation ,musculoskeletal involvement ,Artery - Abstract
Background Vascular Ehlers–Danlos syndrome (vEDS) is a heritable connective tissue disorder caused by defects in the type III collagen protein. It is generally considered the most severe form of Ehlers–Danlos syndrome (EDS) due to an increased risk of spontaneous artery or organ rupture. vEDS has an extremely heterogeneous presentation and muscle rupture is considered a minor diagnostic criterium. Methods A patient with a long history of inconclusive examinations and investigations was referred to our unit. The clinical picture was mainly characterized by muscle ruptures, whereas the cardiovascular involvement was limited to mitral regurgitation. We performed a panel analysis of genes associated with inheritable heart diseases using the TruSight Cardio kit (Illumina). A skin biopsy was then performed for functional studies to analyze the different forms of collagen molecules produced in vitro by cutaneous fibroblasts. Results The patient presented the novel variant c.3478A>G (p.Ile1160Val) in COL3A1 (NM_000090.3), whose pathogenicity was supported by biochemical analysis of type III collagen. Conclusion In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, broadening the clinical scenario of the syndrome., In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, enlarging the clinical scenario of the syndrome.
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- 2021
6. The heterozygous deletion c.1509_1510delAG in exon 14 of FUS causes an aggressive childhood-onset ALS with cognitive impairment
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Irene Meola, Maria Teresa Rinaudo, Giovanni de Marco, Christian Lunetta, Paola Origone, Emilio Albamonte, Adriano Chiò, Cristina Moglia, Paola Mandich, Valeria A. Sansone, Annarosa Lomartire, Rosario Vasta, Antonio Canosa, Andrea Calvo, Umberto Manera, and Paola Lanteri
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0301 basic medicine ,Proband ,Aging ,medicine.medical_specialty ,Heterozygote ,Juvenile amyotrophic lateral sclerosis ,Gene Expression ,Loss of Heterozygosity ,Gene mutation ,medicine.disease_cause ,FUS gene ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Cognitive Dysfunction ,RNA, Messenger ,Truncated FUS protein expression ,Child ,Genetic Association Studies ,Mutation ,biology ,business.industry ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Wild type ,Exons ,030104 developmental biology ,Endocrinology ,biology.protein ,Disease Progression ,RNA-Binding Protein FUS ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Antibody ,business ,030217 neurology & neurosurgery ,Nuclear localization sequence ,Developmental Biology - Abstract
We report a case of childhood-onset ALS with a FUS gene mutation presenting cognitive impairment and a rapid clinical progression. The patient, an 11-year-old girl, presented with right distal upper limb weakness and mild intellectual disability at the Griffith Mental Development Scales. The disease rapidly worsened and the patient became tetraplegic and bed-ridden 2 years after symptom onset. A c.1509_1510delAG mutation in exon 14 of the FUS gene was detected, resulting in a predicted truncated protein, p.G504Wfs*12, lacking the nuclear localization signal. The levels of FUS mRNA in the proband were not significantly different compared to controls. Western immunoblot analysis showed that one antibody (500-526) detected in the proband ~50% of the amount of FUS protein compared to controls, while 3 other antibodies (2-27, 400-450 and FUS C-terminal), which recognize both wild type and the mutated FUS, detected 60% to 75% of the amount of the protein. These findings indicate that p.G504Wfs*12 FUS is more prone to undergo post-translational modification respect to wild type FUS.
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- 2021
7. Genetic Workup for Charcot–Marie–Tooth Neuropathy: A Retrospective Single-Site Experience Covering 15 Years
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Chiara Gemelli, Alessandro Geroldi, Sara Massucco, Lucia Trevisan, Ilaria Callegari, Lucio Marinelli, Giulia Ursino, Mehrnaz Hamedani, Giulia Mennella, Silvia Stara, Giovanni Maggi, Laura Mori, Cristina Schenone, Fabio Gotta, Serena Patrone, Alessia Mammi, Paola Origone, Valeria Prada, Lucilla Nobbio, Paola Mandich, Angelo Schenone, Emilia Bellone, and Marina Grandis
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congenital, hereditary, and neonatal diseases and abnormalities ,Phenotype ,Genetic ,Space and Planetary Science ,Charcot–Marie–Tooth (CMT) disease ,Paleontology ,neuropathy ,genetic ,phenotype ,Neuropathy ,General Biochemistry, Genetics and Molecular Biology ,Ecology, Evolution, Behavior and Systematics - Abstract
Charcot–Marie–Tooth (CMT) disease is the most commonly inherited neurological disorder. This study includes patients affected by CMT during regular follow-ups at the CMT clinic in Genova, a neuromuscular university center in the northwest of Italy, with the aim of describing the genetic distribution of CMT subtypes in our cohort and reporting a peculiar phenotype. Since 2004, 585 patients (447 index cases) have been evaluated at our center, 64.9% of whom have a demyelinating neuropathy and 35.1% of whom have an axonal neuropathy. A genetic diagnosis was achieved in 66% of all patients, with the following distribution: CMT1A (48%), HNPP (14%), CMT1X (13%), CMT2A (5%), and P0-related neuropathies (7%), accounting all together for 87% of all the molecularly defined neuropathies. Interestingly, we observe a peculiar phenotype with initial exclusive lower limb involvement as well as lower limb involvement that is maintained over time, which we have defined as a “strictly length-dependent” phenotype. Most patients with this clinical presentation shared variants in either HSPB1 or MPZ genes. The identification of distinctive phenotypes such as this one may help to address genetic diagnosis. In conclusion, we describe our diagnostic experiences as a multidisciplinary outpatient clinic, combining a gene-by-gene approach or targeted gene panels based on clinical presentation.
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- 2022
8. Early onset demyelinating Charcot-Marie-Tooth disease caused by a novel in-frame isoleucine deletion in peripheral myelin protein 2
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Paola Lanteri, Paola Origone, Lucia Trevisan, Valeria Prada, Paola Mandich, Marina Grandis, Paola Fossa, Emilia Bellone, Alessandro Geroldi, Chiara Gemelli, Francesca Veneri, and Angelo Schenone
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Adult ,Male ,Biology ,Gene mutation ,medicine.disease_cause ,Myelin P2 Protein ,Genetic analysis ,DNA sequencing ,03 medical and health sciences ,symbols.namesake ,PMP2, CMT1, LIPIDS, NEUROPATHY ,Young Adult ,0302 clinical medicine ,Compact myelin ,Charcot-Marie-Tooth Disease ,Peripheral myelin protein 22 ,medicine ,Humans ,Age of Onset ,PMP2 ,Genetics ,Sanger sequencing ,Mutation ,CMT1 ,General Neuroscience ,NEUROPATHY ,Infant ,Pedigree ,030220 oncology & carcinogenesis ,symbols ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery ,LIPIDS - Abstract
Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot-Marie-Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in-frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT-associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic-addressing additional features.
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- 2020
9. A novel mutation of Twinkle in Perrault syndrome: A not rare diagnosis?
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Paola Mandich, Paola Origone, Emilia Bellone, Giuseppina Fugazza, Alessandro Geroldi, Federica Morani, Anna Rubegni, Claudia Nesti, Filippo M. Santorelli, Lucia Trevisan, Sabrina Fabbri, Fabio Gotta, and Merit Lamp
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Adult ,Pathology ,medicine.medical_specialty ,Ataxia ,Genetic counseling ,Hearing Loss, Sensorineural ,DNA Mutational Analysis ,Mutation, Missense ,Gene mutation ,Compound heterozygosity ,sensorineural hearing loss ,Mitochondrial Proteins ,03 medical and health sciences ,Sensory ataxia ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Twinkle ,Genetics (clinical) ,030304 developmental biology ,Neuropathy, ovarian dysgenesis, Perrault syndrome, sensorineural hearing loss, Twinkle, TWNK ,0303 health sciences ,ovarian dysgenesis ,Perrault syndrome ,medicine.diagnostic_test ,business.industry ,neuropathy ,TWNK ,030305 genetics & heredity ,DNA Helicases ,medicine.disease ,Gonadal Dysgenesis, 46,XX ,Pedigree ,Neuropathy ,Peripheral neuropathy ,Mutation ,Sensorineural hearing loss ,Female ,Pure tone audiometry ,medicine.symptom ,business - Abstract
Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype-phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.
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- 2020
10. Role of MAPT in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients
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Fabio Gotta, Paola Mandich, Fiore Manganelli, Alessandro Geroldi, Emilia Bellone, Francesca Sanguineri, Claudia Caponnetto, Corrado Cabona, Lucia Trevisan, Grazia Devigili, Paola Origone, and Merit Lamp
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Mutation ,business.industry ,SOD1 ,Disease ,Motor neuron ,medicine.disease ,medicine.disease_cause ,TARDBP ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Neurology ,C9orf72 ,Internal medicine ,medicine ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,business ,030217 neurology & neurosurgery ,Frontotemporal dementia - Abstract
The aim of our study was to evaluate the role of mutations in the MAPT gene in patients with pure amyotrophic lateral sclerosis (ALS). A cohort of 120 ALS patients, both sporadic and familial, without cognitive impairment was analyzed by next-generation sequencing with a multiple-gene panel comprising 23 genes, including MAPT, known to be associated with ALS and frontotemporal dementia. The presence of the C9orf72 expansion was also investigated. Twelve patients had mutations in the SOD1, TARDBP, MATR3, and FUS genes, while 10 patients carried the C9orf72 expansion. One female patient was found to carry the D348G mutation in MAPT, previously reported in an Italian family with lower motor neuron disease. Our patient presented both upper and lower motor neuron signs, early development of dyspnea, resting and kinetic tremor, and a slow disease course (> 11 years). The present case further broadens the clinical phenotype associated with MAPT mutations and suggests that, although rarely, MAPT mutations can cause ALS and, therefore, should be analyzed in ALS patients, especially in those with early breathing difficulties and long-lasting disease.
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- 2018
11. Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1
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Emilia Bellone, Simonetta Verdiani, Vincent Timmerman, Monica Bandettini di Poggio, Marco Barberis, Adriano Chiò, Vicky De Winter, Simona Capponi, Paola Mandich, Elias Adriaenssens, Paola Origone, Elena Cichero, Alessandro Geroldi, Paola Fossa, and Thomas Geuens
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0301 basic medicine ,Candidate gene ,HSP27 Heat-Shock Proteins ,Biology ,medicine.disease_cause ,Pathogenesis ,03 medical and health sciences ,Chaperone activity ,HSPB1 ,Molecular modelling ,SALS ,Genetics ,Genetics (clinical) ,0302 clinical medicine ,Mutant protein ,medicine ,Humans ,Genetic Predisposition to Disease ,Amyotrophic lateral sclerosis ,Heat-Shock Proteins ,Research Articles ,Aged ,Mutation ,Amyotrophic Lateral Sclerosis ,Protein turnover ,Middle Aged ,Motor neuron ,medicine.disease ,Phenotype ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Italy ,Female ,Human medicine ,Protein Multimerization ,030217 neurology & neurosurgery ,Molecular Chaperones ,Research Article - Abstract
Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.
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- 2016
12. Clinical epidemiology of amyotrophic lateral sclerosis in Liguria, Italy: An update of LIGALS register
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Monica Bandettini di Poggio, Paola Mandich, Claudia Caponnetto, Antonio Canosa, Romina Truffelli, Paola Origone, Carlo Scialò, Giovanni Novi, Giovanni Luigi Mancardi, and Maria Pia Sormani
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Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Pediatrics ,Population ,Prevalence ,Clinical epidemiology ,survival ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,Epidemiology ,medicine ,Humans ,Longitudinal Studies ,Registries ,Amyotrophic lateral sclerosis ,education ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Analysis of Variance ,education.field_of_study ,C9orf72 Protein ,business.industry ,Incidence (epidemiology) ,Proteins ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Survival Analysis ,Surgery ,DNA-Binding Proteins ,030104 developmental biology ,Italy ,Neurology ,epidemiology ,incidence ,motor neuron disease ,Neurology (clinical) ,Mutation ,Female ,business ,030217 neurology & neurosurgery - Abstract
Our objectives were: (1) to assess amyotrophic lateral sclerosis (ALS) incidence and its trend over time in Liguria, an Italian north-western region, performing an analysis of data prospectively collected from 1 January 2009 to 31 December 2014; (2) to determine the mean and median survival in the 2009-2014 Ligurian ALS incident cases; and (3) to evaluate the presence of disease prognostic factors. The Liguria Register for ALS (LIGALS) is an ongoing, multicentre prospective register enrolling all ALS incident cases in Liguria. Cases were identified using several concurrent sources. ALS diagnosis was based on El Escorial revised criteria (EEC-R). Two hundred and ninety-eight patients were enrolled in this study. The mean annual crude incidence rate in the 2009-2014 period was 3.11/100,000 population (95% CI 2.77-3.49); the point prevalence at 31 December 2014 was 7.85/100,000 (95% CI 6.54-9.36) population. Survival analysis demonstrated a median survival from symptom onset of 37.0 months (95% CI 32.0-42.0). In conclusion, ALS crude incidence in Liguria is higher compared to other Italian regions. Clinical and epidemiological data are comparable with those of the Italian ALS population. Survival analysis showed that higher age at onset, bulbar onset, definite EEC-R diagnostic category and a shorter diagnostic delay are related with worse outcomes.
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- 2016
13. Autosomal-dominant transthyretin (TTR)-related amyloidosis is not a frequent CMT2 neuropathy 'in disguise'
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Emilia Bellone, Stefano Tozza, Sabrina Fabbri, Chiara Gemelli, Lucia Trevisan, Fabio Gotta, Paola Origone, Marina Grandis, Lucio Santoro, Fiore Manganelli, Alessandro Geroldi, Merit Lamp, Paola Mandich, Rossella Gulli, Angelo Schenone, Grandis, Marina, Geroldi, Alessandro, Gulli, Rossella, Manganelli, Fiore, Gotta, Fabio, Lamp, Merit, Origone, Paola, Trevisan, Lucia, Gemelli, Chiara, Fabbri, Sabrina, Schenone, Angelo, Tozza, Stefano, Santoro, Lucio, Bellone, Emilia, and Mandich, Paola
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Male ,Axonal neuropathy ,endocrine system ,medicine.medical_specialty ,Systemic disease ,lcsh:Medicine ,030204 cardiovascular system & hematology ,TTR ,03 medical and health sciences ,0302 clinical medicine ,Polyneuropathy ,Humans ,Medicine ,Genetic Predisposition to Disease ,Pharmacology (medical) ,Letter to the Editor ,Genetics (clinical) ,CMT2 ,Amyloid Neuropathies, Familial ,biology ,business.industry ,Amyloidosis ,CMT2, Polyneuropathy, TTR, Genetics (clinical), Pharmacology (medical) ,lcsh:R ,nutritional and metabolic diseases ,General Medicine ,Middle Aged ,medicine.disease ,Dermatology ,Italian population ,Transthyretin ,Mutation ,Cohort ,biology.protein ,Female ,business ,030217 neurology & neurosurgery ,Red flags - Abstract
Transthyretin (TTR)-related familial amyloid polyneuropathy (TTR-FAP) is a life-threatening autosomal dominant, systemic disease. First symptoms usually occur from the second to over sixth decade of life with a length-dependent axonal neuropathy with prominent involvement of the small fibers and multi-organ systemic failure. Early diagnosis is pivotal for effective therapeutic options, but it is hampered by the heterogeneity of the clinical spectrum which can lead to misdiagnosis with other neurological condition/disorder such as axonal sensory-motor neuropathy (CMT2) as described in literature. The aim of our study was to search for TTR mutations in a large cohort of selected undiagnosed axonal sensory-motor neuropathy patients to establish if misdiagnosis is frequent or rare in the Italian population. No TTR pathogenic variants were found in our cohort. In conclusion, our study shows that TTR testing not should be straightforward recommended in CMT2 patients but only when “red flags” TTR’s features are present.
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- 2018
14. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
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Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
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Male ,Als gene ,Genome-wide association study ,FAMILIAL ALS ,ALS ,axonal transport ,cargo ,GWAS ,KIF5A ,WES ,WGS ,0302 clinical medicine ,80 and over ,Psychology ,Aetiology ,Aged, 80 and over ,0303 health sciences ,French ALS Consortium ,Kinesin ,KINESIN HEAVY-CHAIN ,Cognitive Sciences ,Human ,Hereditary spastic paraplegia ,Neuroscience(all) ,Single-nucleotide polymorphism ,TARGETED DISRUPTION ,Article ,03 medical and health sciences ,Genetics ,Humans ,Amino Acid Sequence ,Loss function ,Aged ,HEXANUCLEOTIDE REPEAT ,Neuroscience (all) ,MUTATIONS ,Amyotrophic Lateral Sclerosis ,3112 Neurosciences ,1702 Cognitive Science ,medicine.disease ,ITALSGEN Consortium ,Answer ALS Foundation ,030104 developmental biology ,ALS Sequencing Consortium ,Human medicine ,1109 Neurosciences ,030217 neurology & neurosurgery ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Kinesins ,Neurodegenerative ,Genetic analysis ,Genome ,AMYOTROPHIC-LATERAL-SCLEROSIS ,3124 Neurology and psychiatry ,Cohort Studies ,Pathogenesis ,Loss of Function Mutation ,Missense mutation ,2.1 Biological and endogenous factors ,Amyotrophic lateral sclerosis ,NYGC ALS Consortium ,General Neuroscience ,ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS ,Middle Aged ,Phenotype ,Settore MED/26 - NEUROLOGIA ,Neurological ,Project MinE ALS Sequencing Consortium ,Female ,Adult ,Biology ,GENOTYPE IMPUTATION ,Genome-Wide Association Study ,Young Adult ,NO ,Rare Diseases ,medicine ,SLAGEN Consortium ,Gene ,030304 developmental biology ,Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium ,Neurology & Neurosurgery ,Human Genome ,Neurosciences ,AXONAL-TRANSPORT ,Brain Disorders ,Family member ,DNA-DAMAGE ,MOTOR-NEURONS ,3111 Biomedicine ,Cohort Studie ,Genomic Translation for ALS Care (GTAC) Consortium ,Amyotrophic Lateral Sclerosi - Abstract
© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
- Published
- 2018
15. Spinocerebellar ataxia 17: full phenotype in a 41 CAG/CAA repeats carrier
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Davide Massucco, Federico Massa, Flavia Ticconi, Paola Mandich, Matteo Grazzini, Giovanni Abbruzzese, Lucia Trevisan, Fabio Gotta, Alessandro Geroldi, Roberta Marchese, Matteo Bauckneht, Paola Origone, Merit Lamp, and Emilia Bellone
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Movement disorders ,Case Report ,lcsh:RC346-429 ,Dysdiadochokinesia ,03 medical and health sciences ,0302 clinical medicine ,Dysmetria ,mental disorders ,Medicine ,Allele ,lcsh:Neurology. Diseases of the nervous system ,Genetics ,Dystonia ,Incomplete penetrance ,business.industry ,Parkinsonism ,Spinocerebellar ataxia, TBP gene, SCA17, Incomplete penetrance ,medicine.disease ,Penetrance ,nervous system diseases ,SCA17 ,030104 developmental biology ,Spinocerebellar ataxia ,Neurology (clinical) ,TBP gene ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Background Spinocerebellar ataxia 17 (SCA17) is one of the most heterogeneous forms of autosomal dominant cerebellar ataxias with a large clinical spectrum which can mimic other movement disorders such as Huntington disease (HD), dystonia and parkinsonism. SCA17 is caused by an expansion of CAG/CAA repeat in the Tata binding protein (TBP) gene. Normal alleles contain 25 to 40 CAG/CAA repeats, alleles with 50 or greater CAG/CAA repeats are pathological with full penetrance. Alleles with 43 to 49 CAG/CAA repeats were also reported and their penetrance is estimated between 50 and 80%. Recently few symptomatic individuals having 41 and 42 repeats were reported but it is still unclear whether CAG/CAA repeats of 41 or 42 are low penetrance disease-causing alleles. Thus, phenotypic variability like the disease course in subject with SCA17 locus restricted expansions remains to be fully understood. Case presentation The patients was a 63-year-old woman who, at 54 years, showed personality changes and increased frequency of falls. At 55 years of age neuropsychological tests showed executive attention and visuospatial deficit. At the age of 59 the patient developed dysarthria and a progressive cognitive deficit. The neurological examination showed moderate gait ataxia, dysdiadochokinesia and dysmetria, dysphagia, dysarthria and abnormal saccadic pursuit, severe axial asynergy during postural changes, choreiform dyskinesias. Molecular analysis of the TBP gene demonstrated an allele with 41 repeat suggesting that 41 CAG/CCG TBP repeats could be an allele associated with the full clinical spectrum of SCA17. Conclusions The described case with the other similar cases described in the literature suggests that 41 CAG/CAA trinucleotides should be considered as critical threshold in SCA17. We suggest that SCA17 diagnosis should be suspected in patients presenting with movement disorders associated with other neurodegenerative signs and symptoms.
- Published
- 2018
16. Two novel cases of compound heterozygous mutations in mitofusin2: Finding out the inheritance
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Emilia Bellone, Paola Origone, Merit Lamp, Fabio Gotta, Grazia Devigili, Alessandro Geroldi, Rossella Gulli, Carlo Sabbà, Patrizia Lastella, Paola Mandich, Margherita Patruno, and Nicoletta Resta
- Subjects
0301 basic medicine ,Adult ,medicine.medical_specialty ,Neurology ,Adolescent ,Genetic counseling ,MFN2 ,Disease ,Biology ,Compound heterozygosity ,Bioinformatics ,GTP Phosphohydrolases ,Mitochondrial Proteins ,03 medical and health sciences ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,medicine ,Humans ,Genetics (clinical) ,Genetics ,Inheritance (genetic algorithm) ,Major gene ,Phenotype ,Pedigree ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
MFN2 is the major gene involved in the axonal form of Charcot-Marie-Tooth disease. It usually has an autosomal dominant pattern of inheritance, but a few cases of homozygous or compound heterozygous mutations have been described. These patients usually present an earlier onset, more severe phenotype and their inheritance pattern can span from autosomal recessive to semidominant. Here we report two unrelated patients carrying two compound heterozygous MFN2 mutations. Both present a pure axonal neuropathy without any additional features. The first patient presents a mild clinical phenotype with onset in the 2nd decade, while the second patient shows a severe, early onset phenotype with loss of independent ambulation. Only a careful clinical examination as well as neurophysiological and genetic studies allowed us to establish the role and the transmission pattern of the identified variants. We discuss practical consequences of this finding in genetic counseling.
- Published
- 2016
17. Genetic Counseling Dilemmas for a Patient with Sporadic Amyotrophic Lateral Sclerosis, Frontotemporal DegenerationParkinson's Disease
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Vittorio Mantero, Andrea Rigamonti, Andrea Salmaggi, Angelo Aliprandi, Paola Mandich, Silvana Penco, Claudia Tarlarini, Paola Origone, Giuseppe Lauria, and Lucia Abate
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Pediatrics ,Parkinson's disease ,Genetic counseling ,Genetic Counseling ,Disease ,Parkinsonism ,03 medical and health sciences ,0302 clinical medicine ,Genetic ,medicine ,Dementia ,Humans ,Genetic Testing ,Amyotrophic lateral sclerosis ,Psychiatry ,Frontotemporal degeneration ,Genetic test ,Genetics (clinical) ,Genetic testing ,Aged ,medicine.diagnostic_test ,business.industry ,Amyotrophic Lateral Sclerosis ,Parkinson Disease ,Syndrome ,medicine.disease ,Pedigree ,Guam complex ,Parkinson disease ,Frontotemporal Dementia ,030104 developmental biology ,business ,030217 neurology & neurosurgery ,Frontotemporal dementia - Abstract
Amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and Parkinson's disease may be different expressions of the same neurodegenerative disease. However, association between ALS and parkinsonism-dementia complex (ALS-PDC) has only rarely been reported apart from the cluster detected in Guam. We report a patient presenting with ALS-PDC in whom pathological mutations/expansions were investigated. No other family members were reported to have any symptoms of a neurological condition. Our case demonstrates that ALS-PDC can occur as a sporadic disorder, even though the coexistence of the three clinical features in one patient suggests a single underlying genetic cause. It is known that genetic testing should be preferentially offered to patients with ALS who have affected first or second-degree relatives. However, this case illustrates the importance of genetic counseling for family members of patients with sporadic ALC-PDC in order to provide education on the low recurrence risk. Here, we dicuss the ethical, psychological and practical consequences for patients and their relatives.
- Published
- 2016
18. Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation
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Valeria Marini, Cecilia Garrè, Antonina Sidoti, Marco Forni, Alessandra Dorcaratto, Concetta Alafaci, Placido Bramanti, Aldo Amato, Paola Origone, Cristina Mareni, Luca Goitre, Valeria Capra, Maria Avolio, Rosalia D'Angelo, Saverio Francesco Retta, and Carmela Rinaldi
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Genetics ,Mutation ,General Neuroscience ,Biology ,medicine.disease_cause ,Molecular biology ,Pathology and Forensic Medicine ,Exon ,Cohort ,Mutation testing ,medicine ,Neurology (clinical) ,Multiplex ligation-dependent probe amplification ,Gene ,Exome sequencing ,Cohort study - Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K-Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three-gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at-risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified,nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255-4delGTA; c.1682-1683 delTA in CCM1; c.48A > G; c.82-83dupAG in CCM2; and c.395 + 1G > A in CCM3 genes [corrected].The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at-risk relatives.
- Published
- 2010
19. Enlarging clinical spectrum of FALS with TARDBP gene mutations: S393L variant in an Italian family showing phenotypic variability and relevance for genetic counselling
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Emilia Bellone, Paola Origone, Giovanni Luigi Mancardi, Giovanna Ferrandes, Elisabetta Ghiglione, Monica Bandettini di Poggio, Paola Mandich, and Claudia Caponnetto
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Male ,Genetic counseling ,Molecular Sequence Data ,Genetic Counseling ,Biology ,TARDBP ,Exon ,Bacterial Proteins ,medicine ,Humans ,Point Mutation ,Amino Acid Sequence ,Amyotrophic lateral sclerosis ,Aged ,Genetics ,Aged, 80 and over ,Family Health ,Transition (genetics) ,Amyotrophic Lateral Sclerosis ,TARDBP gene ,Genetic Variation ,Exons ,General Medicine ,Middle Aged ,medicine.disease ,Phenotype ,Introns ,Pedigree ,DNA-Binding Proteins ,genomic DNA ,Italy ,Neurology ,Female ,Neurology (clinical) - Abstract
The present study was aimed to enlarge the Italian ALS sample analysed for TARDBP gene mutations.Genomic DNA from 47 patients, 70 FTD patients and 158 controls was extracted from peripheral blood samples according to a standard protocol. The five coding exons (2-6) of the TARDBP gene and the flanking exon-intron boundaries were analysed by direct sequencing. Using ClustalW2 human TDP-43, protein sequence was aligned with TDP-43 protein sequence of different species.A heterozygous c.1178 C--T transition that leads to a change p.S393L was observed in a 75-years-old male patient and in his two affected siblings. A patient's brother had died at 69 years of age after a two-year history of ALS. In FTD patients no mutations were found.We describe a further Italian family with FALS, in which a variant (p.S393L) of the TARDBP gene was identified. Clinical course and phenotypic variability in three affected siblings is presented and relevance for genetic counselling of patients and their families is underlined. At the present state of knowledge, we suggest that the same guidelines established for SOD1 molecular testing could be proposed also for TARDBP analysis in FALS.
- Published
- 2009
20. Mutation Analysis of Oxisterol-Binding-Protein Gene in Patients with Age-Related Macular Degeneration
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Margherita Torrini, Valeria Marini, Cristina Mareni, Mario Vanzetti, Cristiana Marchese, Paola Origone, and Cecilia Garrè
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Male ,Receptors, Steroid ,medicine.medical_specialty ,genetic structures ,DNA Mutational Analysis ,OSBP2 Gene ,Biology ,Pathogenesis ,Macular Degeneration ,Risk Factors ,Internal medicine ,medicine ,Humans ,Allele ,Gene ,Alleles ,Genetics (clinical) ,Aged ,Aged, 80 and over ,Genetics ,Genetic Variation ,Single-strand conformation polymorphism ,Middle Aged ,Macular degeneration ,medicine.disease ,eye diseases ,Endocrinology ,Female ,sense organs ,Vitamin E deficiency ,Carrier Proteins ,Lipoprotein - Abstract
Allelic variants of several genes are increasingly recognized as susceptibility factors in age-related macular degeneration (AMD). Because of its metabolic characteristics the macula is sensitive to oxidative damage, and supplementation with antioxidants has been shown to be effective in slowing the progression of disease in AMD patients. The oxisterol-binding-protein (OSBP2) gene is expressed mainly in the retinal pigmented epithelium underlying the macular region. Its product specifically binds and transports oxisterols, the cytotoxic effects of which may be involved in macular damage. The aim of this study was to search for allelic variants of OSBP2 gene, as well as to evaluate several risk factors in 24 patients with AMD; 17 with nonexudative (NE) and 7 with neovascular (NV) form. Total cholesterol was elevated in 66% of the patients, high-density lipoprotein (HDL) cholesterol was reduced in 12%; vitamin A or vitamin E deficiency was not observed. OSBP2 gene analysis was performed in AMD patients and in 110 control subjects by single-stranded conformational polymorphism (SSCP) analysis followed by direct sequencing. Six allelic variants were detected: 2 nonpolymorphic unique exonic variants in 2 AMD subjects and 4 polymorphic variants (2 exonic and 2 intronic). These data indicate a possible role of OSBP2 gene in the pathogenesis of oxidative damage to the macula induced by oxysterols in AMD patients.
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- 2007
21. Complexities of Genetic Counseling for ALS: A Case of Two Siblings with Discordant Genetic Test Results
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Simonetta Verdiani, Paola Mandich, Claudia Caponnetto, Paola Origone, Giovanna Ferrandes, Fabio Gotta, Vittorio Mantero, and Emilia Bellone
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Male ,Genetic counseling ,DNA Mutational Analysis ,Genetic Counseling ,TARDBP ,Developmental psychology ,medicine ,Humans ,Genetic Testing ,Amyotrophic lateral sclerosis ,Genetics (clinical) ,Genetic testing ,Genes, Dominant ,Phenocopy ,Chromosome Aberrations ,medicine.diagnostic_test ,business.industry ,Siblings ,Amyotrophic Lateral Sclerosis ,Middle Aged ,medicine.disease ,Brother ,Human genetics ,Pedigree ,DNA-Binding Proteins ,Phenotype ,Mutation (genetic algorithm) ,Female ,business ,Clinical psychology - Abstract
Rapid advances in the genetics of amyotrophic lateral sclerosis (ALS) have dramatically changed the approach of clinicians and researchers to the motor neuron diseases. We report two siblings in whom the genetic study provided conflicting results, hence raising a number of issues which deserve to be considered by clinicians involved in genetic testing for ALS. The first patient died within 2 years of ALS onset, while her brother still manages to walk unaided, 7 years into onset. Genetic analyses, performed on the first patient as part of a research protocol, and as clinical genetic testing on the brother, provided different results. Results for Patient 1 were negative for all investigated genes, thus suggesting that her disease may be a phenocopy, while her brother carried an autosomal dominant TARDBP mutation (p.A382T). A multidisciplinary approach may help patients and clinicians face the emerging dilemmas in such a complex field. Sharing and updating of advances, not to mention uncertainties inherent to current knowledge, with patients and families may prove to be an effective way to support them and to make them aware of the present limits of our knowledge and of the blurred border between research and clinical practice.
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- 2014
22. The FIG4 gene does not play a major role in causing ALS in Italian patients
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Emilia Bellone, Simonetta Verdiani, Vittorio Mantero, Monica Bandettini di Poggio, Paola Origone, Gianluigi Mancardi, Claudia Caponnetto, Paola Mandich, and Alessandro Geroldi
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Genetics ,Flavoproteins ,SOD1 ,Amyotrophic Lateral Sclerosis ,Genetic Variation ,Biology ,medicine.disease ,TARDBP ,Phosphoric Monoester Hydrolases ,Cohort Studies ,nervous system ,Neurology ,Italy ,Mutation ,medicine ,Humans ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,Gene - Abstract
Mutations in several genes have been associated with amyotrophic lateral sclerosis (ALS). Only a few genes seem to account for significant percentage of ALS cases (SOD1, TARDBP, C9OFR72, FUS, OPTN,...
- Published
- 2013
23. Molecular characterization of an Italian series of sporadic GISTs
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Chiara Martinuzzi, G. Bianchi Scarrà, Roberto Fiocca, Sara Gargiulo, Paola Ghiorzo, Luca Mastracci, Paola Origone, Alberto Ballestrero, Linda Battistuzzi, C. Casella, Roberto Cusano, Anna Garuti, D. Comandini, Luisa Toffolatti, and A. P. Dei Tos
- Subjects
Male ,Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,medicine.disease_cause ,Polymerase Chain Reaction ,Piperazines ,Exon ,BRAF ,GIST ,KIT ,KRAS ,PDGFRA ,Aged, 80 and over ,Mutation ,GiST ,Gastroenterology ,General Medicine ,Middle Aged ,Prognosis ,Proto-Oncogene Proteins c-kit ,Oncology ,Benzamides ,Imatinib Mesylate ,Female ,medicine.drug ,Adult ,Proto-Oncogene Proteins B-raf ,Gastrointestinal Stromal Tumors ,Antineoplastic Agents ,Proto-Oncogene Proteins p21(ras) ,Proto-Oncogene Proteins ,Biomarkers, Tumor ,medicine ,Humans ,neoplasms ,Aged ,Retrospective Studies ,business.industry ,Imatinib ,digestive system diseases ,Pyrimidines ,Imatinib mesylate ,ras Proteins ,Cancer research ,business ,Follow-Up Studies - Abstract
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract. Most (80 %) contain activating mutations in the KIT receptor tyrosine kinase, roughly 10 % in platelet-derived growth factor receptor-alpha (PDGFRA). In a small subset, BRAF mutations are an alternative molecular pathway. GISTs respond well to imatinib, but low response is seen in patients with wild-type KIT or PDGFRA. Resistance has also been reported as a result of mutations in downstream effectors such as BRAF. We provide here a molecular characterization of a series of primary GISTs from Italian patients. Of 121 GIST cases diagnosed between 2000 and 2012, 83 were evaluated by PCR amplification and direct sequencing for mutations in KIT exons 8, 9, 11, 13, and 17, PDGFRA exons 12, 14, and 18, and BRAF exon 15. Eighty-one GISTs also underwent K-RAS testing. Sixty-four GISTs were positive: 55 had mutations in KIT and 9 in PDGFRA; 16 patients were mutation negative. Three samples came from NF1 patients and were KIT- and PDGFRA negative. Overall, we identified six novel mutations in KIT (p.K550_M552delinsL, p.Q556_W557delinsG p.Q556_G575del, p.W557_V559delinsQ p.P573_R588dup, p.G592_K593dup) and one novel mutation in PDGFRA (p.D842_N848delinsVDV), thus contributing to widening the spectrum of known mutations in GIST tumors and confirming the most frequently altered regions underlying GIST development. Among the 64 KIT- and PDGFRA-positive sporadic patients in our series, no BRAF or KRAS mutations were identified, suggesting that co-occurrence of these mutations is likely to be rare in the northwestern Italian population and not a frequent cause of primary resistance to imatinib in KIT-positive GIST patients.
- Published
- 2013
24. Clinical epidemiology of ALS in Liguria, Italy
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Carlo Scialò, Giovanni Luigi Mancardi, Vittorio Mantero, Simonetta Verdiani, Angelo Schenone, Claudia Caponnetto, Romina Truffelli, Paola Origone, Maria Pia Sormani, Paola Mandich, Monica Bandettini di Poggio, and Ligals
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Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Clinical epidemiology ,Risk Factors ,Epidemiology ,medicine ,Prevalence ,Humans ,Registries ,Amyotrophic lateral sclerosis ,Sex Distribution ,Survival rate ,Survival analysis ,Aged ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Incidence ,Amyotrophic Lateral Sclerosis ,Middle Aged ,medicine.disease ,Survival Analysis ,Survival Rate ,Neurology ,Italy ,Physical therapy ,Female ,Neurology (clinical) ,business ,Population-Based Registry ,Median survival - Abstract
Our objective was to assess the incidence and trends of amyotrophic lateral sclerosis (ALS) in Liguria, a north-west region of Italy, utilizing a prospective design. Liguria (1,615,064 residents in 2010) is the site of a multicentre-multisource prospective population based registry called LIGALS (Liguria Amyotrophic Lateral Sclerosis Registry). All incident ALS cases during the period 2009-2010 were enrolled and followed up. Cases were identified using several concurrent sources. ALS diagnosis was based on the revised El Escorial criteria. One hundred and four cases were enrolled, generating an annual crude incidence of 3.22/100,000 (95% CI 2.66-3.90), with a male/female ratio of 1.34. The annual standardized incidence, age and gender adjusted to the 2001 Italian population, was 2.51. At last observation on 1 March 2012, 45% of patients registered in the LIGALS had died, with a median survival of 45 months from symptoms onset. According to capture-recapture estimation, three patients were unobserved. For both genders, demographic and clinical features were collected. In conclusion, comparing these data to those of epidemiological studies with a similar prospective design, the occurrence of ALS is similar. The observed crude incidence was higher compared to other Italian studies, due in part to a very careful case ascertainment and in part to a high percentage of the elderly in Liguria.
- Published
- 2012
25. Expression and Genomic Configuration of GM-CSF, IL-3, M-CSF Receptor (C-FMS), Early Growth Response Gene-1 (EGR-1) and M-CSF Genes in Primary Myelodysplastic Syndromes
- Author
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M. Montera, Cristina Mareni, Giovanna Bianchi Scarrat, Paola Origone, Roberto Lerza, Giuseppina Fugazza, Elena D'Amato, Mario Sessarego, and Vito Pistoia
- Subjects
Male ,Cancer Research ,Receptor, Macrophage Colony-Stimulating Factor ,Biology ,Monocytes ,Germline ,Immediate early protein ,Immediate-Early Proteins ,medicine ,Humans ,Allele ,Autocrine signalling ,Gene ,Alleles ,Aged ,Early Growth Response Protein 1 ,Sequence Deletion ,Aged, 80 and over ,Chromosome Aberrations ,Regulation of gene expression ,Macrophage Colony-Stimulating Factor ,Myelodysplastic syndromes ,Granulocyte-Macrophage Colony-Stimulating Factor ,Nucleic Acid Hybridization ,Chromosome ,Hematology ,Fibroblasts ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Gene Expression Regulation ,Genes ,Oncology ,Chromosomes, Human, Pair 1 ,Karyotyping ,Myelodysplastic Syndromes ,Immunology ,Cancer research ,Chromosomes, Human, Pair 5 ,Female ,Interleukin-3 ,Transcription Factors - Abstract
Peripheral blood mononuclear cells from seventeen patients with primary myelodysplastic syndromes (MDS) in advanced stage were enriched for blasts and tested for (1) karyotype, (2) genomic configuration and (3) expression of IL-3, GM-CSF, FMS and EGR-1 genes which are all located on the long arm of chromosome 5. The expression of the M-CSF gene, that has been recently reassigned to the short arm of chromosome 1 (lp), was also investigated. Aims of the study were to (1) assess the potential role of the expression of these genes in the maintenance and expansion of the neoplastic clones and (2) search for constitutional losses or rearrangements of one allele followed by a deletion of the second allele of the same genes in the leukemic cells. The latter issue was investigated by comparing, in 8 cases, constitutive DNA from skin fibroblasts with leukemic DNA. Eleven of the 17 patients had abnormal karyotypes. The M-CSF gene was expressed in 6 cases and the FMS and the EGR-1 genes were expressed in 2 of the latter cases. An autocrine mechanism of growth could be hypothesized only for the 2 patients whose cells expressed both the M-CSF and FMS genes. No germline changes or rearrangements were observed in any of the genes studied. Thus, deregulation of genes encoding for certain hemopoietic growth factors or receptors does not seem to represent a major mechanism of MDS progression.
- Published
- 1994
26. Fast course ALS presenting with vocal cord paralysis: clinical features, bioinformatic and modelling analysis of the novel SOD1 Gly147Ser mutation
- Author
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Paola Origone, Paola Mandich, Alessandro Geroldi, Vittorio Mantero, Elena Cichero, Simonetta Verdiani, Claudia Caponnetto, Gianluigi Mancardi, Paola Fossa, and Emilia Bellone
- Subjects
Male ,Models, Molecular ,Protein Conformation ,DNA Mutational Analysis ,Molecular Sequence Data ,Biology ,Bioinformatics ,Fatal Outcome ,Superoxide Dismutase-1 ,medicine ,Missense mutation ,Animals ,Humans ,Point Mutation ,Vocal cord paralysis ,Amyotrophic lateral sclerosis ,Genetic testing ,Genetics ,medicine.diagnostic_test ,Superoxide Dismutase ,Point mutation ,Amyotrophic Lateral Sclerosis ,Computational Biology ,General Medicine ,Bilateral vocal cord paralysis ,Middle Aged ,medicine.disease ,Neurology ,Mutation (genetic algorithm) ,Neurology (clinical) ,Sequence Alignment ,Vocal Cord Paralysis - Abstract
In this report we describe a novel SOD1 mutation (Gly147Ser) in an Italian sporadic ALS patient. The patient presented with hoarseness due to bilateral vocal cord paralysis and a rapid clinical course. Mutational analysis of the SOD1 gene was carried out by direct sequencing. In silico bioinformatics analysis and molecular modelling was used to analyse the SOD1 function modifications produced by the mutated residue. A heterozygous c.442 G > A transition, which leads to a change at codon 147 resulting in a serine rather than glycine, was found in the patient. Bioinformatics analysis and molecular modelling strongly suggest a dramatic effect of Gly147Ser mutation on SOD1 function. In conclusion, Gly147Ser represent a new missense mutation whose effect may correlate with the peculiar clinical bulbar phenotype onset with bilateral vocal cord paresis and rapid clinical course of the disease. Ethical and psychological dilemmas about genetic testing in apparently sporadic subjects are still matter of debate.
- Published
- 2011
27. Mutation Analysis of CCM1, CCM2 and CCM3 Genes in a Cohort of Italian Patients with Cerebral Cavernous Malformation
- Author
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Rosalia, D'Angelo, Valeria, Marini, Carmela, Rinaldi, Paola, Origone, Alessandra, Dorcaratto, Maria, Avolio, Luca, Goitre, Marco, Forni, Valeria, Capra, Concetta, Alafaci, Cristina, Mareni, Cecilia, Garrè, Placido, Bramanti, Antonina, Sidoti, Saverio Francesco, Retta, and Aldo, Amato
- Subjects
Central Nervous System Vascular Malformations ,Male ,CCM genes ,Reverse Transcriptase Polymerase Chain Reaction ,Cerebral Cavernous Malformation (CCM) ,DNA Mutational Analysis ,Membrane Proteins ,Brain vascular pathologies ,molecular genetic analysis in Italian patients ,Pedigree ,brain vascular pathologies ,cerebral cavernous malformation ,Cohort Studies ,Italy ,Proto-Oncogene Proteins ,Humans ,Female ,Genetic Predisposition to Disease ,Apoptosis Regulatory Proteins ,Carrier Proteins ,KRIT1 Protein ,Microtubule-Associated Proteins ,Research Articles - Abstract
Cerebral cavernous malformations (CCMs) are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities. CCMs can occur as sporadic or familial autosomal dominant form. Familial cases are associated with mutations in CCM1[K‐Rev interaction trapped 1 (KRIT1)], CCM2 (MGC4607) and CCM3 (PDCD10) genes. In this study, a three‐gene mutation screening was performed by direct exon sequencing, in a cohort of 95 Italian patients either sporadic or familial, as well as on their at‐risk relatives. Sixteen mutations in 16 unrelated CCM patients were identified, nine mutations are novel: c.413T > C; c.601C > T; c.846 + 2T > G; c.1254delA; c.1255‐4delGTA; c.1681‐1682delTA in CCM1; c.48A > G; c.82‐83insAG in CCM2; and c.396G > A in CCM3 genes. The samples, negative to direct exon sequencing, were investigated by MLPA to search for intragenic deletions or duplications. One deletion in CCM1 exon 18 was detected in a sporadic patient. Among familial cases 67% had a mutation in CCM1, 5.5% in CCM2, and 5.5% in CCM3, whereas in the remaining 22% no mutations were detected, suggesting the existence of either undetectable mutations or other CCM genes. This study represents the first extensive research program for a comprehensive molecular screening of the three known genes in an Italian cohort of CCM patients and their at‐risk relatives.
- Published
- 2011
28. I112M SOD1 mutation causes ALS with rapid progression and reduced penetrance in four Mediterranean families
- Author
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Claudia Caponnetto, Enrique Syriani, Cecilia Garrè, Loretta Ferrera, Domenico Bordo, Valeria Marini, Josep Gamez, Miguel Morales, Paola Origone, and Cristina Pirro
- Subjects
Adult ,Models, Molecular ,Genotype ,Protein Conformation ,Mutation, Missense ,Penetrance ,Biology ,Homology (biology) ,Structure-Activity Relationship ,Superoxide Dismutase-1 ,amyotrophic lateral sclerosis ,haplotype ,phenotype-genotype correlation ,sod1 ,i112m mutation ,medicine ,Humans ,Point Mutation ,Amyotrophic lateral sclerosis ,Sicily ,Gene ,Genetics ,Protein Stability ,Superoxide Dismutase ,Amyotrophic Lateral Sclerosis ,Haplotype ,General Medicine ,Middle Aged ,medicine.disease ,Phenotype ,Founder Effect ,Pedigree ,Amino Acid Substitution ,Haplotypes ,Neurology ,Spain ,Genetic marker ,Disease Progression ,Neurology (clinical) ,Founder effect - Abstract
We evaluated a possible genotype-phenotype correlation and looked for a founder effect in four Mediterranean families carrying the I112M SOD1 mutation. The structural characteristics of the mutated protein were also analysed. Clinical data of FALS subjects from four families were evaluated. Mutational analysis of the SOD1 gene was carried out by direct sequencing. A haplotype study was carried out using 11 polymorphic markers flanking the SOD1 gene. Structural analysis was performed by means of homology modelling and molecular graphics methods. The clinical pattern of 17 FALS patients was characterized by prevalent spinal onset, mean age at onset of 47.1 years and mean duration of 20.7 months. Several obligate carriers were observed. These findings indicate that the I112M mutation is consistently associated with a uniform, fast-progressing phenotype with reduced penetrance of the disease. The haplotype analysis did not show a common haplotype among the Spanish families and the Italian family; however, a possible common founder could be hypothesized for Spanish families. From a structural viewpoint, mutation at codon 112 seems to confer a severe phenotype, probably related to altered protein functionality.
- Published
- 2011
29. Heterozygous D90A-SOD1 mutation in an Italian ALS patient with atypical presentation
- Author
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Paola Origone, Claudia Caponnetto, Maria Mascolo, and Paola Mandich
- Subjects
Adult ,Male ,medicine.medical_specialty ,Heterozygote ,animal structures ,Adult, Amyotrophic Lateral Sclerosis ,genetics/physiopathology, Heterozygote, Humans, Italy, Male, Middle Aged, Mutation, Superoxide Dismutase ,genetics ,Superoxide Dismutase ,Amyotrophic Lateral Sclerosis ,genetics/physiopathology ,General Medicine ,Middle Aged ,humanities ,Neurology ,Italy ,Family medicine ,Mutation ,medicine ,Medical genetics ,Humans ,Neurology (clinical) ,Presentation (obstetrics) - Abstract
Department of Oncology, Biology and Genetics, University of Genoa and U.O. Medical Genetics of Azienda Ospedaliera Universitaria S. Martino di Genova, Department of Neuroscience, Ophthalmology and Genetics Section of Neurology, and Department of Neuroscience, Ophthalmology and Genetics Section of Medical Genetics, University of Genoa and U.O. Medical Genetics of Azienda Ospedaliera Universitaria S. Martino di Genova, Italy
- Published
- 2009
30. Clinicopathologic and genetic analysis of siblings with NF1 and adult-onset gliomas
- Author
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Subramanian Hariharan, Raji P. Grewal, John E. Donahue, Paola Origone, and Cecial Garre
- Subjects
Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Pathology ,medicine.medical_specialty ,Neurofibromatosis 1 ,Astrocytoma ,In Vitro Techniques ,Malignancy ,Fatal Outcome ,Glioma ,medicine ,Humans ,Family history ,Sibling ,Neurofibromatosis ,neoplasms ,Pathological ,business.industry ,Brain Neoplasms ,Siblings ,medicine.disease ,nervous system diseases ,Pedigree ,Neurology ,Mutation ,Female ,Neurology (clinical) ,Headaches ,medicine.symptom ,business - Abstract
Background Neurofibromatosis Type 1 (NF1) is a common autosomal dominant neurogenetic disorder characterized by neoplasms involving the nervous system which typically present in children. The development of intracranial tumors in adults with NF1 is uncommon and to our knowledge, siblings with adult onset gliomas have not been previously reported. Objective To perform pathological, clinical and genetic analysis of an unusual family with NF1 and adult onset intracranial gliomas. Results A 39-year-old woman presented with seizures and aphasia and was diagnosed with an intracerebral tumor. Although there was no family history, she met the accepted clinical criteria for NF1. A biopsy was performed and pathological examination revealed an anaplastic pleomorphic xanthoastrocytoma (PXA). In spite of therapy, she died from complications of tumor recurrence. Her 32-year-old sister developed headaches and was diagnosed with a glioma. Although she did not meet the accepted clinical criteria for NF1, given that she has a sibling with NF1 and a malignancy observed in this disorder, we hypothesize that she also has NF1. Our genetic analysis indicated a shared haplotype in these siblings who developed brain tumors but not in an unaffected sister suggesting that both carry the NF1 disease-producing allele. This haplotype was inherited from their unaffected father indicating a paternal origin of the spontaneous putative mutation in the NF1 gene in this family. Conclusion NF1 should be a diagnostic consideration when siblings develop intracranial brain tumors even when they develop in adults. Our study supports and extends other reports that broaden the clinical and pathological spectrum of manifestations that can occur in NF1 to include not only adult-onset gliomas but uncommon histological subtypes such as PXA.
- Published
- 2005
31. Sod1 mutations in amyotrophic lateral sclerosis: results from a multicenter italian study
- Author
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Giuliana Lando, Marcello Giagheddu, Paola Origone, Giuseppe Bibbò, Vincenzo Mascia, Cecilia Garrè, Claudia Caponnetto, Carlo Carcassi, Michela Casula, Gabriele Siciliano, Alberto Del Corona, Valeria Marini, Silvana Penco, Alessandro Marocchi, Maria Cristina Patrosso, Stefania Battistini, Renzo Causarano, Sandro Orru, Fabia Giannini, Giuseppe Greco, Loretta Ferrera, and Paola Carrera
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genotype ,DNA Mutational Analysis ,SOD1 ,Glycine ,Gene mutation ,medicine.disease_cause ,Statistics, Nonparametric ,Cohort Studies ,Superoxide Dismutase-1 ,Serine ,Humans ,Medicine ,Missense mutation ,RNA, Messenger ,Cognitive decline ,Amyotrophic lateral sclerosis ,Aged ,Retrospective Studies ,Aged, 80 and over ,Family Health ,Mutation ,Polymorphism, Genetic ,Reverse Transcriptase Polymerase Chain Reaction ,Superoxide Dismutase ,business.industry ,Amyotrophic Lateral Sclerosis ,Autosomal dominant trait ,Exons ,Middle Aged ,Blotting, Northern ,medicine.disease ,Introns ,Pedigree ,Italy ,Neurology ,Female ,Neurology (clinical) ,business - Abstract
Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait. In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified. The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.
- Published
- 2005
32. Enlarging the clinical spectrum associated with C9orf 72 repeat expansions: Findings in an Italian cohort of patients with Parkinsonian syndromes and relevance for genetic counselling
- Author
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Rossella Gulli, Paola Mandich, Paola Origone, Roberta Marchese, Giovanni Abbruzzese, Simonetta Verdiani, Emilia Bellone, and Paola Ciotti
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Genetic counseling ,Disease ,Cohort Studies ,Parkinsonian syndromes ,Parkinsonian Disorders ,mental disorders ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Aged ,Communication ,DNA Repeat Expansion ,C9orf72 Protein ,business.industry ,Proteins ,Middle Aged ,medicine.disease ,Neurology ,Cohort ,Female ,Supranuclear Palsy, Progressive ,Neurology (clinical) ,business ,Frontotemporal dementia ,Cohort study - Abstract
Dear SirsAn expanded hexanucleotide repeat (GGGGCC) in the C9orf 72 gene was recently identified as an important cause of frontotemporal dementia (FTD), of motor neuron disease (ALS) or both (ALS-F...
- Published
- 2013
33. Search for loss of heterozygosity and mutation analysis of KRIT1 gene in CCM patients
- Author
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Valeria, Marini, Loretta, Ferrera, Francesca, Pigatto, Paola, Origone, Cecilia, Garrè, Alessandra, Dorcaratto, Giuseppe, Viale, Francesco, Alberti, and Cristina, Mareni
- Subjects
Hemangioma, Cavernous, Central Nervous System ,Proto-Oncogene Proteins ,DNA Mutational Analysis ,Humans ,Loss of Heterozygosity ,KRIT1 Protein ,Microtubule-Associated Proteins ,Ankyrin Repeat ,DNA Primers - Published
- 2004
34. Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test
- Author
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Loretta Ferrera, Valeria Marini, Paola Origone, Alessandra Dorcaratto, Giuseppe Viale, Cecilia Garrè, and Cristina Mareni
- Subjects
Hemangioma, Cavernous, Central Nervous System ,Genetic Linkage ,DNA Mutational Analysis ,Molecular Sequence Data ,Glycine ,Biology ,Polymerase Chain Reaction ,Genetic determinism ,Germline mutation ,Genetic linkage ,Proto-Oncogene Proteins ,medicine ,Humans ,Cysteine ,RNA, Messenger ,Gene ,Stroke ,KRIT1 Protein ,Polymorphism, Single-Stranded Conformational ,Genetics ,Vascular disease ,Middle Aged ,medicine.disease ,Pedigree ,Neurology ,Italy ,Mutation ,Rap1 ,Neurology (clinical) ,Microtubule-Associated Proteins ,Founder effect - Abstract
Familial cerebral cavernous malformation (CCM) exhibits autosomal dominant inheritance and is characterized by vascular disorders of the brain, which can lead to seizures, focal neurological deficits, hemorrhagic stroke, and migraine. Three CCM loci have been mapped, but the gene for only one locus--KRIT1 coding for Krev-1/rap1 interaction trapped 1 (KRIT1) protein, which is responsible for more than 40% of familial cases--has been identified. To date, a total of 72 mutations have been described, with one founder effect in the Mexican/Hispanic community. We report the case of an Italian family with CCM that has a novel KRIT1 gene mutation leading to a truncated KRIT1 protein. The protein truncation test (PTT) has been used as a rapid method of identifying germline mutations in the KRIT1 gene.
- Published
- 2003
35. Homozygous inactivation of NF1 gene in a patient with familial NF1 and disseminated neuroblastoma
- Author
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Katia Mazzocco, Gian Paolo Tonini, Bruno De Bernardi, Crocifissa Lo Cunsolo, Raffaella Defferrari, and Paola Origone
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Neurofibromatosis 1 ,Biology ,medicine.disease_cause ,Germline ,Neuroblastoma ,Germline mutation ,Fatal Outcome ,medicine ,Gene silencing ,Humans ,Point Mutation ,Gene Silencing ,Neurofibromatosis ,neoplasms ,Genetics (clinical) ,In Situ Hybridization, Fluorescence ,Polymorphism, Single-Stranded Conformational ,Genetics ,Mutation ,Reverse Transcriptase Polymerase Chain Reaction ,Point mutation ,Liver Neoplasms ,medicine.disease ,eye diseases ,nervous system diseases ,Tumor progression ,Chromosomes, Human, Pair 1 ,Child, Preschool ,Cancer research ,Bone Marrow Neoplasms ,Gene Deletion - Abstract
Neurofibromatosis type 1 (NF1) patients are susceptible to tumor development. In the present study we describe a child with NF1 and disseminated neuroblastoma whose death resulted from disease progression. The mother had cafe-au-lait spots suggesting a familial NF1. Neuroblastoma cells showed MYCN amplification and chromosome 1p36 deletion, common features associated with tumor progression in this malignancy. The NF1 gene displayed a germline T --> C transition of intron 14 in both the proband and mother DNA. This mutation, not yet previously described, occurs in a splicing donor site and produces a new mRNA variant observed together with normal NF1 mRNA. Furthermore, the SSCP analysis of the NF1 gene in tumor cells showed a somatic deletion encompassing the intron 26 and 27b of the paternal NF1 allele. Hence, neuroblastoma cells displayed both somatic and germline mutation of the NF1 gene. Our data suggest that, although rare, neuroblastoma in patients with NF1 may display homozygous gene inactivation.
- Published
- 2003
36. T137A variant is a pathogenetic SOD1 mutation associated with a slowly progressive ALS phenotype
- Author
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Claudia Caponnetto, Emilia Bellone, Elena Cichero, Paola Mandich, Paola Fossa, Paola Origone, Simonetta Verdiani, Gianluigi Mancardi, and Vittorio Mantero
- Subjects
Male ,Genetics ,Superoxide Dismutase ,business.industry ,Amyotrophic Lateral Sclerosis ,SOD1 ,Mutation, Missense ,General Medicine ,Biology ,medicine.disease ,Phenotype ,Text mining ,Neurology ,Mutation (genetic algorithm) ,medicine ,Humans ,Female ,Neurology (clinical) ,Amyotrophic lateral sclerosis ,business - Published
- 2012
37. The Genoa experience of prenatal diagnosis in NF1
- Author
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Paola Origone, Elisabetta Panucci, Domenico A. Coviello, Simona Costabel, Franco Ajmar, and Eugenio Bonioli
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Neurofibromatosis 1 ,Genetic Linkage ,Genetic counseling ,DNA Mutational Analysis ,Prenatal diagnosis ,Genetic Counseling ,Disease ,Malignancy ,Genetic determinism ,Genetic linkage ,Pregnancy ,Genes, Neurofibromatosis 1 ,medicine ,Humans ,Medical diagnosis ,Child ,Genetics (clinical) ,Genetics ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Incidence (epidemiology) ,Obstetrics and Gynecology ,Chromosome Mapping ,medicine.disease ,Pedigree ,Fetal Diseases ,Chorionic Villi Sampling ,Italy ,Child, Preschool ,Female ,business - Abstract
Department of Pediatrics, University of Genoa, ItalyType 1 neurofibromatosis (NF1) is an autosomal dominant disorder with an incidence of about 1 in 3500live births. Symptoms are highly variable from a few cafe`-au-lait spots and axillary freckling to plexiformneurofibromas, optic gliomas, pseudarthrosis, and malignancy. Since disease causing mutations aredispersed throughout the gene, prenatal diagnosis is usually performed in familial cases by linkage analysisand rarely by direct characterization of the mutation. We have characterized 48 families and haveperformed four prenatal diagnoses. In three cases, the linkage analysis was carried out using informativemarkers. A direct approach using the protein truncation test (PTT) and sequencing was performed in onecase in which a R1947X mutation was identified. The extreme variability of the phenotypic expression of theNF1 gene makes reproductive decisions in NF1 families very difficult, as molecular diagnosis cannot predictclinical expression of the disease. The psychological management of the couple is therefore difficult. In twoof the three examined families the reproductive choices were not influenced by the specific manifestations ofthe disease in that family. Copyright # 2000 John Wiley & Sons, Ltd.
- Published
- 2000
38. GIST mutational status and survival
- Author
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Paola Origone, C. Margarino, Valerio Belgrano, S. Di Domenico, F. De Cian, C. Bobbio, Roberto Fiocca, Luca Mastracci, V. Valle, and C. Ferretti
- Subjects
Oncology ,medicine.medical_specialty ,GiST ,business.industry ,Internal medicine ,medicine ,Mutational status ,Surgery ,General Medicine ,business - Published
- 2013
39. Neurofibromatosis eurofibromatosis type 1 (NF1): Identification of eight unreported mutations in NF1 gene in Italian patients
- Author
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Carlo Bellini, Franco Stanzial, Eugenio Bonioli, Paola Origone, Carmen La Rosa, Domenico A. Coviello, Guido Morcaldi, Claudio Castellan, Debora Sambarino, Barbara Banelli, and Cecilia Garrè
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,Single-strand conformation polymorphism ,Biology ,medicine.disease_cause ,Molecular biology ,Germline ,DNA sequencing ,Frameshift mutation ,DNA Mutational Analysis ,medicine ,Coding region ,Gene ,Genetics (clinical) - Abstract
In the present study the entire NF1 coding region was analyzed for mutations in 132 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 8 novel mutations. Clinical diagnosis of NF1 was established according to the NIH consensus criteria. We detected 59 truncated fragments, and 46 of them were characterized by SSCP and direct sequencing. Eight mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene. In two patients, premature termination was due to substitutions at nucleotide c.3982C>T (Q1298X) and c.7411C>T (Q2471X), respectively. Two other mutations were caused by the deletions (1756delA, 4699delA), and two by the insertions (c.5266_5267insT, c.7464_7465insTCCA) of a small number of nucleotides. Lastly, we found 2 splice-site mutations (c.2252-2A>C, c.2251+1G>A).
- Published
- 2003
40. Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients
- Author
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Simona Costabel, Carlo Bellini, Paola Origone, Alessandro De Luca, Rita Mingarelli, Carmen La Rosa, Domenico A. Coviello, Eugenio Bonioli, Cecilia Garrè, Anna Buccino, Franco Ajmar, and Bruno Dallapiccola
- Subjects
Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,Mutation ,Single-strand conformation polymorphism ,Biology ,medicine.disease_cause ,Germline ,DNA sequencing ,Stop codon ,DNA Mutational Analysis ,medicine ,Coding region ,Gene ,Genetics (clinical) - Abstract
The entire NF1 coding region was analyzed for mutations in a panel of 108 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 10 mutations which have never been reported before. Clinical diagnosis of NF1 was established according to the NIH consensus criteria in 100 individuals, while 8 were young children with only multiple cafe-au-lait spots. We detected 46 truncated fragments, and 24 of them were fully characterized by SSCP and direct sequencing. Of the 24, 14 were known mutations (R304X, R681X, Q682X, R1306X, R1362X, R1513X, R1748X, Q1794X, R1947X, Y2264X, R2237X, 2674delA, 6789delTTAC, 2027insC). The other 10 mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene (K810X, Q2595X, 6772delT, 7190delCT, 7331delA, 1021insTT, 3921insT, 4106insTA, 7149insC, 2033insCG / 2034delA). PTT in a large number of Italian NF1 patients supports the usefulness of this method for characterization of mutations in disorders where the responsible gene is very large and the disease-causing mutations often create a stop codon. In agreement with previous reports, no mutational hotspots within the NF1 gene were detected.
- Published
- 2002
41. Lack of association of PON polymorphisms with sporadic ALS in an Italian population
- Author
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Giuseppe Greco, Michele Benigni, Claudia Ricci, Maria Cristina Patrosso, Claudia Caponnetto, Christian Lunetta, Massimo Corbo, Cristina Cereda, Lorenzo Verriello, Fabio Giannini, Lorena Cozzi, Stefania Battistini, Pamela Milani, Paola Origone, Renzo Causarano, and Silvana Penco
- Subjects
Male ,Aging ,Genotype ,DNA Mutational Analysis ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Pathogenesis ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Gene ,Aged ,Genetics ,Chi-Square Distribution ,biology ,Aryldialkylphosphatase ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Haplotype ,Paraoxonase ,Middle Aged ,medicine.disease ,Italian population ,Italy ,biology.protein ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Developmental Biology - Abstract
Paraoxonase (PON) gene polymorphisms have been associated with susceptibility to sporadic amyotrophic lateral sclerosis (ALS). We have investigated the role of the previously associated single nucleotide polymorphisms rs854560, rs662, and rs6954345 in 350 ALS patients and 376 matched controls from Italy. No significant association was observed at genotype and haplotype level. Our data suggest that PON polymorphisms are not involved in ALS pathogenesis in an Italian population.
- Published
- 2011
42. Linkage studies in Italian families with familial adenomatous polyposis
- Author
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Angelo Lonoce, Anna Straface, Franco Ajmar, Cristina Mareni, Maria Pina Montera, Paola Origone, Maria Lucia Caruso, Nicola Palasciano, Ginevra Guanti, Alessandro Stella, Maurizio Ponz de Leon, Mattia Gentile, Romano Sassatelli, and Francesco Susca
- Subjects
Adult ,Genetic Markers ,Male ,Genetic Linkage ,Molecular Sequence Data ,Biology ,Familial adenomatous polyposis ,Restriction fragment ,Genetic linkage ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Linkage (software) ,Recombination, Genetic ,Base Sequence ,Genetic heterogeneity ,Haplotype ,Chromosome Mapping ,DNA ,Sequence Analysis, DNA ,medicine.disease ,Human genetics ,Pedigree ,Adenomatous Polyposis Coli ,Italy ,Genetic marker ,biology.protein ,Chromosomes, Human, Pair 5 ,Female ,Lod Score ,Polymorphism, Restriction Fragment Length - Abstract
Linkage analysis was performed on 188 subjects belonging to 18 Italian families segregating for familial adenomatous polyposis (FAP) using 7 polymorphic markers (5 restriction fragment length and 2 dinucleotide repeat polymorphisms) mapping in 5q21. A two-point linkage analysis performed with the LINKAGE program gave significant lod scores (> 3) between the Pi227, C11p11, YN5.64, YN5.48 probes and the disease, whereas the ECB27, CB83 and EF5.44 markers showed lower lod scores. Some 11 recombination events were identified from the analysis of 101 meioses. The best map that we could determine confirmed that reported in previous studies. The location of the new marker, CB83, lying between YN5.64 and YN5.48, remains imprecise. No genetic heterogeneity was detected, with all the families showing linkage for at least one of the probes. One 34-year-old individual having an affected haplotype was however classified as healthy after clinical examinations. The results confirm the applicability of the linkage approach for presymptomatic diagnosis of FAP.
- Published
- 1993
43. Erratum: Novel MC1R variants in ligurian melanoma patients and controls
- Author
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Graeme A. Shepherd, Francesca Lantieri, Paola Origone, Monica Barile, Sara Gliori, Lorenza Pastorino, William Bruno, Richard A. Sturm, Giovanna Bianchi-Scarrà, and Roberto Cusano
- Subjects
Genetics ,Melanoma ,Mutation (genetic algorithm) ,medicine ,Biology ,medicine.disease ,Genetics (clinical) - Abstract
The corresponding author's name was printed incorrectly in the original version of this Mutation in Brief. Please find it correctly listed here as Giovanna Bianchi-Scarra. This change will be reflected in PubMed indexing.
- Published
- 2004
44. Erratum: Neurofibromatosis type 1 (NF1): Identification of eight unreported mutations in NF1 gene in Italian patients
- Author
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Debora Sambarino, Barbara Banelli, Claudio Castellan, Carmen La Rosa, Guido Morcaldi, Carlo Bellini, Franco Stanzial, Domenico A. Coviello, Paola Origone, Eugenio Bonioli, and Cecilia Garrè
- Subjects
Genetics ,Type (biology) ,Mutation (genetic algorithm) ,medicine ,Identification (biology) ,Neurofibromatosis ,Biology ,medicine.disease ,Gene ,Genetics (clinical) - Abstract
In the original version of this article, the title was incorrect. Please find the correct title given here. The publisher deeply regrets this error. The original article to which this Erratum refers was published in Human Mutation 22:179–180 Human Mutation(2003) 22(2) 179–180
- Published
- 2003
45. Involvement of chromosomal region 9q34 in a case of variant Ph1 translocation t(22;22)
- Author
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Franco Ajmar, Paola Origone, Cristina Mareni, Domenico A. Coviello, and Mario Sessarego
- Subjects
Cancer Research ,medicine.medical_specialty ,Chromosomal translocation ,Chromosome 9 ,Biology ,Philadelphia chromosome ,Translocation, Genetic ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Humans ,Philadelphia Chromosome ,neoplasms ,Genetics ,Cytogenetics ,breakpoint cluster region ,Chromosome ,Karyotype ,Hematology ,medicine.disease ,Molecular biology ,Chromosome Banding ,Oncology ,Leukemia, Myeloid ,Chromosomal region ,Chromosomes, Human, Pair 9 - Abstract
In a patient with chronic myelocytic leukemia chromosome analysis showed a translocation (22;22) (q13;q11). Chromosomes 9 were apparently not involved. Using somatic cell hybrids and a v-abl probe, we demonstrated the translocation of c-abl sequences from chromosome 9 to chromosome 22q-. This confirms the hypothesis that the translocation of c-abl oncogene is essential for the development of Ph1 positive CML.
- Published
- 1986
46. Translocation t(9;9)(p13;q34) in Philadelphia-negative chronic myeloid leukemia with breakpoint cluster region rearrangement
- Author
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Paola Origone, Raffaella Defferrari, Franco Ajmar, Cristina Mareni, Mario Sessarego, R. Vimercati, and Eugenio Damasio
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Cancer Research ,medicine.medical_specialty ,Chromosomal translocation ,Biology ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,Translocation, Genetic ,chemistry.chemical_compound ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,Molecular Biology ,Southern blot ,Gene Rearrangement ,Cytogenetics ,breakpoint cluster region ,Chromosome ,Myeloid leukemia ,Karyotype ,Middle Aged ,Molecular biology ,Chromosome Banding ,Blotting, Southern ,chemistry ,Karyotyping ,Multigene Family ,Female ,Chromosomes, Human, Pair 9 ,DNA - Abstract
Chromosome analysis showed a t(9;9)(p13;q34) in a patient with chronic myeloid leukemia (CML) without a Philadelphia (Ph) chromosome in all examined cells. Southern blot analysis of leukocyte DNA revealed rearrangement of breakpoint cluster region (bcr) within the 5.8-kb bcr sequences as in Ph-positive CML patients. The findings confirm that the 9q34 and 22q11 bands are always involved in CML independent of the chromosomal evidence. It is suggested that Ph-negative bcr-positive CML may have variant translocations, as in the case of the t(9;9) reported here.
- Published
- 1989
47. Molecular analysis of Philadelphia-negative myeloproliferative syndromes with i(17q)
- Author
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Franco Ajmar, Francesco Frassoni, Paola Origone, Cristina Mareni, Mario Sessarego, and Raffaella Defferrari
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Isochromosome ,Biology ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,Myelogenous ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Genetics ,medicine ,Humans ,Molecular Biology ,Chromosome Aberrations ,breakpoint cluster region ,Cytogenetics ,Karyotype ,Gene rearrangement ,medicine.disease ,Molecular biology ,Chromosome Banding ,Chromosome 17 (human) ,Karyotyping ,Chronic myelogenous leukemia ,Chromosomes, Human, Pair 17 - Abstract
We report two cases of myeloproliferative syndromes in which the only karyotypic abnormality was an isochromosome of the long arm of chromosome 17. Because i(17q) is a nonrandom structural aberration found in nearly 12% of cases of Philadelphia (Ph)-positive chronic myelogenous leukemia (CML), we carried out a molecular analysis of the breakpoint cluster region (bcr) to verify the presence of genomic rearrangements characteristic of CML. The interest of the study was strengthened by the fact that i(17q) is frequently seen in CML and by recent reports showing that genomic changes of c-abl and bcr genes can be present even in the absence of a Ph chromosome. One of the two patients showed the presence of a rearranged fragment within the bcr, suggesting a Ph-positive CML diagnosis.
- Published
- 1989
48. Amplification of c-myc and pvt-1 homologous sequences in acute nonlymphatic leukemia
- Author
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Sigurdur Ingvarsson, Cristina Mareni, Janos Sumeigi, George Klein, Domenico A. Coviello, Paola Origone, Mario Sessarego, and Charlotte Asker
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Male ,Cancer Research ,medicine.medical_specialty ,Locus (genetics) ,Biology ,Homologous Sequences ,Sequence Homology, Nucleic Acid ,Gene duplication ,Proto-Oncogenes ,medicine ,Humans ,Leukemia ,Base Sequence ,Cytogenetics ,Gene Amplification ,Karyotype ,Hematology ,Amplicon ,Middle Aged ,medicine.disease ,Molecular biology ,Oncology ,Karyotyping ,Acute Disease ,Nucleic acid - Abstract
Leukemic cells with double minute (DM) chromosomes from an ANLL(M1) patient were found to carry 10-15 fold amplified c-myc sequences. The linked pvt-1-like locus was amplified at the same level, suggesting that the c-myc amplicon is at least 300 kb in size.
- Published
- 1988
49. An Italian dominant FALS Leu144Phe SOD1 mutation: Genotype-phenotype correlation
- Author
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Claudia Caponnetto, Valeria Marini, Antonio Amoroso, Domenico Bordo, Cecilia Garrè, Paola Origone, Silvana Penco, Domenica Rizzi, and Loretta Ferrera
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Genotype ,Phenylalanine ,SOD1 ,DNA Mutational Analysis ,Disease ,Biology ,Polymerase Chain Reaction ,Genotype phenotype ,Superoxide Dismutase-1 ,Leucine ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Bulbar signs ,Gene ,Aged ,Family Health ,Superoxide Dismutase ,Amyotrophic Lateral Sclerosis ,Female ,Italy ,Mutation ,Phenotype ,medicine.disease ,Mutation (genetic algorithm) ,Neurology (clinical) - Abstract
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease. Mutations of the Cu/Zn superoxide dismutase gene (SOD1) are responsible for 20% of autosomal dominant familial ALS (FALS).RESULTS: We examined the clinical features of the first Italian FALS with the Leu144Phe SOD1 mutation. Seven affected members were identified in a six‐generation pedigree. A slowly progressive course (20.4±14.6 years) was observed in five patients. One patient died of cardiac failure two years after the onset of the disease. The propositus is still alive. Neurological manifestations began in the legs in all patients, while bulbar signs were absent or appeared late in the course of the disease.DISCUSSION: There is evidence of a correlation between this mutation and a slowly progressive phenotype of ALS. Moreover this rare mutation might derive from a common ancestor.
50. C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population
- Author
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Mario, Sabatellia, Francesca Luisa Conforti, Marcella, Zollinoc, Gabriele, Morad, Maria Rosaria Monsurrò, Paolo, Volanti, Kalliopi, Marinoud, Fabrizio, Salvig, Massimo, Corbo, Fabio, Giannini, Stefania, Battistini, Silvana, Penco, Christian, Lunetta, Aldo, Quattrone, Antonio, Gambardella, Giancarlo, Logroscino, Isabella, Simone, Ilaria, Bartolomei, Fabrizio, Pisano, Gioacchino, Tedeschi, Amelia, Conte, Rossella, Spataro, Vincenzo La Bella, Claudia, Caponnetto, Gianluigi, Mancardi, Paola, Mandich, Patrizia, Sola, Jessica, Mandrioli, Renton, Alan E., Elisa, Majounie, Yevgeniya, Abramzon, Francesco, Marrosu, Maria Giovanna Marrosu, Maria Rita Murru, Maria Alessandra Sotgiu, Maura, Pugliatti, Rodolico, Carmelo, the ITALSGEN Consortium: Stefania Cammarosano, Giuseppe, Fuda, Antonio, Canosa, Sara, Gallo, Laura, Papetti, Giuseppe Lauria Pinter, Marco, Luigetti, Serena, Lattante, Giuseppe, Marangi, Tiziana, Colletti, Claudia, Ricci, Paola, Origone, Gianluca, Floris, Antonino, Cannas, Valeria, Piras, Emanuela, Costantino, Carla, Pani, Parish, Leslie D., Paola, Cossu, Giuliana, Solinas, Lucia, Ulgheri, Anna, Ticca, Francesco, Izzo, Anna, Laiola, Francesca, Trojsi, Portaro, Simona, William, Sproviero, Cristina, Moglia, Andrea, Calvo, Irene, Ossola, Maura, Brunetti, Traynor, Bryan J., Giuseppe, Borghero, Gabriella, Restagno, Adriano, Chiò, Sabatelli, M, Conforti, Fl, Zollino, M, Mora, G, Monsurro', Maria Rosaria, Volanti, P, Marinou, K, Salvi, F, Corbo, M, Giannini, F, Battistini, S, Penco, S, Lunetta, C, Quattrone, A, Gambardella, A, Logroscino, G, Simone, I, Bartolomei, I, Pisano, F, Tedeschi, Gioacchino, Conte, A, Spataro, R, La Bella, V, Caponnetto, C, Mancardi, G, Mandich, P, Sola, P, Mandrioli, J, Renton, Ae, Majounie, E, Abramzon, Y, Marrosu, F, Marrosu, Mg, Murru, Mr, Sotgiu, Ma, Pugliatti, M, Rodolico, C, ITALSGEN Consortium: Cammarosano, Stefania, Fuda, Giuseppe, Canosa, Antonio, Gallo, Sara, Papetti, Laura, Lauria Pinter, Giuseppe, Luigetti, Marco, Lattante, Serena, Marangi, Giuseppe, Colletti, Tiziana, Ricci, Claudia, Origone, Paola, Floris, Gianluca, Cannas, Antonino, Piras, Valeria, Costantino, Emanuela, Pani, Carla, Parish, Leslie D, Cossu, Paola, Solinas, Giuliana, Lucia, U. l. g. h. e. r. i., Ticca, Anna, Izzo, Francesco, Laiola, Anna, Trojsi, Francesca, Portaro, Simona, Sproviero, William, Moglia, C, Calvo, A, Ossola, I, Brunetti, M, Traynor, Bj, Borghero, G, Restagno, G, Chiò, A., Sabatelli, M., Conforti, F., Zollino, M., Mora, G., Monsurrò, M., Volanti, P., Marinou, K., Salvi, F., Corbo, M., Giannini, F., Battistini, S., Penco, S., Lunetta, C., Quattrone, A., Gambardella, A., Logroscino, G., Simone, I., Bartolomei, I., Pisano, F., Tedeschi, G., Conte, A., Spataro, R., LA BELLA, V., Caponnetto, C., Mancardi, G., Mandich, P., Sola, P., Mandrioli, J., Renton, A., Majounie, E., Abramzon, Y., Marrosu, F., Marrosu, M., Murru, M., Sotgiu, M., Pugliatti, M., Rodolico, C., Italsgen, C., Moglia, C., Calvo, A., Ossola, I., Brunetti, M., Traynor, B., Borghero, G., and Restagno, G.
- Subjects
Male ,Aging ,Survival ,Pedigree chart ,Settore MED/03 - GENETICA MEDICA ,Repetitive Sequences ,0302 clinical medicine ,C9orf72 ,Polymorphism (computer science) ,Risk Factors ,Prevalence ,Amyotrophic lateral sclerosis ,Genetics ,0303 health sciences ,education.field_of_study ,General Neuroscience ,Single Nucleotide ,Middle Aged ,3. Good health ,Settore MED/26 - NEUROLOGIA ,Italy ,Female ,Settore MED/26 - Neurologia ,Frontotemporal dementia ,Genetic Markers ,Population ,C9ORF72 ,Biology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,education ,amyotrophic lateral sclerosis ,C9orf672 ,frontotemporal dementia ,survival ,Amyotrophic lateral sclerosi ,030304 developmental biology ,Repetitive Sequences, Nucleic Acid ,sporadic ,C9orf72 Protein ,Nucleic Acid ,Amyotrophic lateral sclerosis, C9ORF72, Frontotemporal dementia, Survival ,Genetic Variation ,Proteins ,medicine.disease ,Settore BIO/18 - Genetica ,Neurology (clinical) ,Geriatrics and Gerontology ,ALS ,Trinucleotide repeat expansion ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (familial ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1,757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1,523 from mainland Italy. Sixty (3.7%) of 1,624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally-matched control samples (1,238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived one year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucloetide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the commonest mutation in Italy and the second more common in Sardinia.
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