50 results on '"De Carvalho, Mamede"'
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2. Novel approaches to diagnosis and management of hereditary transthyretin amyloidosis
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Carroll, Antonia, Dyck, P James, de Carvalho, Mamede, Kennerson, Marina, Reilly, Mary M, Kiernan, Matthew C, and Vucic, Steve
- Abstract
Hereditary transthyretin amyloidosis (ATTRv) is a severe, adult-onset autosomal dominant inherited systemic disease predominantly affecting the peripheral and autonomic nervous system, heart, kidney and the eyes. ATTRv is caused by mutations of the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. Typically, the neuropathy associated with ATTRv is characterised by a rapidly progressive and disabling sensorimotor axonal neuropathy with early small-fibre involvement. Carpal tunnel syndrome and cardiac dysfunction frequently coexist as part of the ATTRv phenotype. Although awareness of ATTRv polyneuropathy among neurologists has increased, the rate of misdiagnosis remains high, resulting in significant diagnostic delays and accrued disability. A timely and definitive diagnosis is important, given the emergence of effective therapies which have revolutionised the management of transthyretin amyloidosis. TTR protein stabilisers diflunisal and tafamidis can delay the progression of the disease, if treated early in the course. Additionally, TTR gene silencing medications, patisiran and inotersen, have resulted in up to 80% reduction in TTR production, leading to stabilisation or slight improvement of peripheral neuropathy and cardiac dysfunction, as well as improvement in quality of life and functional outcomes. The considerable therapeutic advances have raised additional challenges, including optimisation of diagnostic techniques and management approaches in ATTRv neuropathy. This review highlights the key advances in the diagnostic techniques, current and emerging management strategies, and biomarker development for disease progression in ATTRv.
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- 2022
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3. Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
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- 2021
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4. Plasma Creatinine Level Does Not Predict Respiratory Function in Amyotrophic Lateral Sclerosis
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Morgadinho, João, Pronto-Laborinho, Ana Catarina, Conceição, Vasco A., Gromicho, Marta, Pinto, Susana, Swash, Michael, and de Carvalho, Mamede
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In amyotrophic lateral sclerosis (ALS) lower plasma creatinine level has been associated with shorter survival and faster functional decline. It has not been clear if creatinine is associated with respiratory outcome. We analyzed retrospectively a population of unselected ALS patients. Multiple-regression and Cox-regression analyses were performed. We included 233 patients, mean age 62.8, mean disease duration of 18.6 months. At baseline, creatinine was significantly associated with ALSFRS-R, but not with its decline rate. No predictive value was disclosed for FVC, or their decline rate, or with survival. We did not confirm that creatinine is a marker of respiratory outcome.
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- 2021
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5. Split-hand and split-limb phenomena in amyotrophic lateral sclerosis: pathophysiology, electrophysiology and clinical manifestations
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Corcia, Philippe, Bede, Peter, Pradat, Pierre-Francois, Couratier, Philippe, Vucic, Steve, and de Carvalho, Mamede
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting the upper and lower motor neurons. A key clinical feature of ALS is the absence of accurate, early-stage diagnostic indicators. ‘Split-hand syndrome’ was first described in ALS at the end of the last century and a considerable body of literature suggests that the split-hand phenomenon may be an important clinical feature of ALS. Considering the published investigations, it is conceivable that the ‘split-hand syndrome’ results from the associated upper and lower motor neuron degeneration, whose interaction remains to be fully clarified. Additionally, other split syndromes have been described in ALS involving upper or lower limbs, with a nuanced description of clinical and neurophysiological manifestations that may further aid ALS diagnosis. In this review, we endeavour to systematically present the spectrum of the ‘split syndromes’ in ALS from a clinical and neurophysiology perspective and discuss their diagnostic and pathogenic utility.
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- 2021
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6. Natural history and survival in stage 1 Val30Met transthyretin familial amyloid polyneuropathy
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Coelho, Teresa, Inês, Mónica, Conceição, Isabel, Soares, Marta, de Carvalho, Mamede, and Costa, João
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- 2018
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7. Impact of SARS-CoV-2 Infection Among Non-Invasive Ventilated ALS Patients
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Santos, Miguel Oliveira, Domingues, Sara, Gromicho, Marta, Pinto, Susana, and de Carvalho, Mamede
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The impact of SARS-CoV-2 infection among neuromuscular diseases with respiratory involvement, including amyotrophic lateral sclerosis (ALS), is still to be elucidated. We aim to characterize the clinical outcome of ALS patients non-invasive ventilated (NIV), following SARS-CoV-2 infection. We analyzed retrospectively our patients followed regularly at our ALS clinic, from the beginning of the COVID-19 pandemic (middle March 2020) to March 2021. We included patients on NIV with a documented SARS-CoV-2 infection. We recorded demographic and clinical data, including from the acute infectious illness. Three men with spinal-onset ALS are described, mean age of onset was 55±9.1 years (45–61), and mean disease duration was 17.5±15.9 months (6.1–41). All of them were wheelchair-bounded, with a mean ALSFRS-R of 15.3±0.6 (15–16). One patient used NIV 15 hours/day, 2 between 4 to 7 hours/day, and all used assisted coughing twice daily. None had coexistent comorbidities. They were managed for SARS-CoV-2 infection as outpatients with fluticasone, bronchodilators, azithromycin and increasing frequency of assisted coughing. Supplemental oxygen (mean of 2 liters per minute) was needed in two patients, and one required NIV also during the daytime. Total recovery from SARS-CoV-2 infection was observed in all, despite being in an advanced stage of their disease, with severe respiratory involvement. Prompt medical treatment is recommended for ALS patients with severe disease infected by SARS-CoV-2.
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- 2021
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8. Laryngeal electromyography in amyotrophic lateral sclerosis
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Martins, Melina Pazian, de Lima, Fabrício Diniz, Bernardes Leoni, Tauana, Martinez, Alberto R M, Nubiato Crespo, Agricio, André Teixeira Kimaid, Paulo, Nucci, Anamarli, de Carvalho, Mamede, and Franca Jr, Marcondes C
- Abstract
BackgroundBulbar involvement is a hallmark of amyotrophic lateral sclerosis (ALS), but surprisingly very few studies have addressed the frequency, pattern and clinical relevance of laryngeal involvement in the disease.MethodsTwenty-six patients with spinal-onset ALS underwent nasofibroscopy (NF), followed by laryngeal electromyography (LEMG). We also studied resting activity and motor unit potentials of the genioglossus and masseter muscles.ResultsTwenty-four patients presented neurogenic changes in at least one laryngeal muscle. There were fibrillation and/or fasciculation potentials associated with chronic neurogenic changes in the same muscle in 16 patients; of these, 9 had no alteration in the genioglossus. We found no patient with tongue neurogenic changes and normal LEMG. NF was abnormal in 14 patients; in the remaining 12, LEMG identified neurogenic changes in 11 of them.ConclusionLEMG is able to identify laryngeal denervation in patients with ALS, sometimes before clinical manifestations are noticed. This technique may be a useful diagnostic tool for selected patients with suspicion of ALS.
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- 2020
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9. Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion
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Oliveira Santos, Miguel, Caldeira, Inês, Gromicho, Marta, Pronto-Laborinho, Ana, and de Carvalho, Mamede
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A hexanucleotide repeat expansion in the C9orf72gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients.
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- 2017
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10. Physiology of the fasciculation potentials in amyotrophic lateral sclerosis: which motor units fasciculate?
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de Carvalho, Mamede and Swash, Michael
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We set out to study whether in amyotrophic lateral sclerosis (ALS) fasciculation potentials (FPs) arise from the most excitable motor units (MUs). We studied 70 patients with ALS and 18 subjects with benign fasciculation syndrome (BFS). Of the 56 eligible ALS patients, 31 had signs of reinnervation in the right first dorsal interosseous muscle selected for study, and 25 did not. Two needle electrodes were placed in different MUs in each studied muscle. We defined the most excitable MU as that first activated by minimal voluntary contraction. In muscles without reinnervation, the recording site with most frequent FPs had a higher probability of showing the first recruited MU (p< 0.001). No significant difference was found in other patients or in BFS subjects. In very early affected muscles, fasciculating MUs are the most likely to be recruited volitionally. This probably represents hyperexcitability at lower motor neuronal level.
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- 2017
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11. Fasciculation in amyotrophic lateral sclerosis: origin and pathophysiological relevance
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de Carvalho, Mamede, Kiernan, Matthew C, and Swash, Michael
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This review considers the origin and significance of fasciculations in neurological practice, with an emphasis on fasciculations in amyotrophic lateral sclerosis (ALS), and in benign fasciculation syndromes. Fasciculation represents a brief spontaneous contraction that affects a small number of muscle fibres, causing a flicker of movement under the skin. While an understanding of the role of fasciculation in ALS remains incomplete, fasciculations derive from ectopic activity generated in the motor system. A proximal origin seems likely to contribute to the generation of fasciculation in the early stages of ALS, while distal sites of origin become more prominent later in the disease, associated with distal motor axonal sprouting as part of the reinnervation response that develops secondary to loss of motor neurons. Fasciculations are distinct from the recurrent trains of axonal firing described in neuromyotonia. Fasciculation without weakness, muscle atrophy or increased tendon reflexes suggests a benign fasciculation syndrome, even when of sudden onset. Regardless of origin, fasciculations often present as the initial abnormality in ALS, an early harbinger of dysfunction and aberrant firing of motor neurons.
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- 2017
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12. Phlebology Implications in Amyotrophic Lateral Sclerosis
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de Carvalho, Mamede
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Franciscan Guillaume de Saint Pathus (1250-1315) described a patient with deep vein thrombosis in his work “La vie et les miracles de Saint Louis,”1but from then, science has developed, and now we are aware of the most relevant risk factors for this frequent medical complication: aging; pregnancy; chronic medical diseases; viral and bacterial infections; immobilization; surgeries, particularly major orthopedic and vascular interventions; trauma; malignancies; iatrogenic, especially hormonal and intravenous treatments; and inherited thrombophilias. In most of these risk conditions, a proinflammatory reaction is present.
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- 2023
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13. C9orf72expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis
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Miltenberger-Miltenyi, Gabriel, Conceicão, Vasco A, Gromicho, Marta, Pronto-Laborinho, Ana Catarina, Pinto, Susana, Andersen, Peter M, and de Carvalho, Mamede
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- 2019
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14. Teaching Video NeuroImage: Disabling Jaw Clonus in a Patient With Bulbar-Onset Amyotrophic Lateral Sclerosis Successfully Treated With Botulinum Toxin
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Oliveira Santos, Miguel, Schön, Miguel, Valadas, Anabela, and de Carvalho, Mamede
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Jaw clonus is a rare neurologic finding associated with supranuclear lesions of the trigeminal nerve. It is rare in amyotrophic lateral sclerosis (ALS).1We describe a 63-year-old patient with ALS who presented with a disabling and sustained jaw clonus, reduced by mouth resting and elicited by mouth opening (Video 1). Association of baclofen (25 mg/3id), tizanidine (2 mg/id), and benzodiazepine treatments were ineffective. Onabotulinum toxin A injections were administered into the temporal (13 units) and masseter (25 units) muscles bilaterally. She experienced a complete relief of her symptom up to 4–5 months, with no side effects (Video 1). She confirmed improvement in quality of life.
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- 2022
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15. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis
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van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick A A, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry TC, Tazelaar, Gijs H P, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine A M, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, Blauw, Hylke M, van der Kooi, Anneke J, de Visser, Marianne, Goris, An, Weber, Markus, Shaw, Christopher E, Smith, Bradley N, Pansarasa, Orietta, Cereda, Cristina, Del Bo, Roberto, Comi, Giacomo P, D'Alfonso, Sandra, Bertolin, Cinzia, Sorarù, Gianni, Mazzini, Letizia, Pensato, Viviana, Gellera, Cinzia, Tiloca, Cinzia, Ratti, Antonia, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Arcuti, Simona, Capozzo, Rosa, Zecca, Chiara, Lunetta, Christian, Penco, Silvana, Riva, Nilo, Padovani, Alessandro, Filosto, Massimiliano, Muller, Bernard, Stuit, Robbert Jan, Blair, Ian, Zhang, Katharine, McCann, Emily P, Fifita, Jennifer A, Nicholson, Garth A, Rowe, Dominic B, Pamphlett, Roger, Kiernan, Matthew C, Grosskreutz, Julian, Witte, Otto W, Ringer, Thomas, Prell, Tino, Stubendorff, Beatrice, Kurth, Ingo, Hübner, Christian A, Leigh, P Nigel, Casale, Federico, Chio, Adriano, Beghi, Ettore, Pupillo, Elisabetta, Tortelli, Rosanna, Logroscino, Giancarlo, Powell, John, Ludolph, Albert C, Weishaupt, Jochen H, Robberecht, Wim, Van Damme, Philip, Franke, Lude, Pers, Tune H, Brown, Robert H, Glass, Jonathan D, Landers, John E, Hardiman, Orla, Andersen, Peter M, Corcia, Philippe, Vourc'h, Patrick, Silani, Vincenzo, Wray, Naomi R, Visscher, Peter M, de Bakker, Paul I W, van Es, Michael A, Pasterkamp, R Jeroen, Lewis, Cathryn M, Breen, Gerome, Al-Chalabi, Ammar, van den Berg, Leonard H, and Veldink, Jan H
- Abstract
To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
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- 2016
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16. Integrative biomarker discovery in neurodegenerative diseases
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Carreiro, André V., Mendonça, Alexandre, de Carvalho, Mamede, and Madeira, Sara C.
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Data mining has been widely applied in biomarker discovery resulting in significant findings of different clinical and biological biomarkers. With developments in technology, from genomics to proteomics analysis, a deluge of data has become available, as well as standardized data repositories. Nonetheless, researchers are still facing important challenges in analyzing the data, especially when considering the complexity of pathways involved in biological processes and diseases. Data from single sources appear unable to explain complex processes, such as those involved in brain‐related disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, thus raising the need for a more comprehensive perspective. A possible solution relies on data and model integration, where several data types are combined to provide complementary views. This in turn can result in the discovery of previously unknown biomarkers by unraveling otherwise hidden relationships between data from different sources, and/or validate such composite biomarkers in more powerful predictive models. WIREs Syst Biol Med2015, 7:357–379. doi: 10.1002/wsbm.1310 For further resources related to this article, please visit the WIREs website.
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- 2015
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17. Origin of Fasciculations in Amyotrophic Lateral Sclerosis and Benign Fasciculation Syndrome
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de Carvalho, Mamede and Swash, Michael
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IMPORTANCE Fasciculation potentials (FPs) may arise proximally or distally within the peripheral nervous system. We recorded FPs in the tibialis anterior using 2 concentric needle electrodes, ensuring by slight voluntary contraction and electrical nerve stimulation that each electrode recorded motor unit potentials innervated by different axons. OBSERVATIONS Time-locked FPs recorded from both electrodes, suggesting a spinal origin, were most frequent in benign fasciculation syndrome (44%) (P < .001) and amyotrophic lateral sclerosis without reinnervation (27%). Fewer time-locked FPs were found (14%) in the reinnervated tibialis anterior in amyotrophic lateral sclerosis (P < .001). CONCLUSIONS AND RELEVANCE We conclude that in chronic partial denervation FPs are more likely to arise distally and that FPs in benign fasciculation syndrome more frequently arise proximally.
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- 2013
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18. Author Correction: Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology
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van Rheenen, Wouter, van der Spek, Rick A. A., Bakker, Mark K., van Vugt, Joke J. F. A., Hop, Paul J., Zwamborn, Ramona A. J., de Klein, Niek, Westra, Harm-Jan, Bakker, Olivier B., Deelen, Patrick, Shireby, Gemma, Hannon, Eilis, Moisse, Matthieu, Baird, Denis, Restuadi, Restuadi, Dolzhenko, Egor, Dekker, Annelot M., Gawor, Klara, Westeneng, Henk-Jan, Tazelaar, Gijs H. P., van Eijk, Kristel R., Kooyman, Maarten, Byrne, Ross P., Doherty, Mark, Heverin, Mark, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Shatunov, Aleksey, Ticozzi, Nicola, Cooper-Knock, Johnathan, Smith, Bradley N., Gromicho, Marta, Chandran, Siddharthan, Pal, Suvankar, Morrison, Karen E., Shaw, Pamela J., Hardy, John, Orrell, Richard W., Sendtner, Michael, Meyer, Thomas, Başak, Nazli, van der Kooi, Anneke J., Ratti, Antonia, Fogh, Isabella, Gellera, Cinzia, Lauria, Giuseppe, Corti, Stefania, Cereda, Cristina, Sproviero, Daisy, D’Alfonso, Sandra, Sorarù, Gianni, Siciliano, Gabriele, Filosto, Massimiliano, Padovani, Alessandro, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Brunetti, Maura, Canosa, Antonio, Grassano, Maurizio, Beghi, Ettore, Pupillo, Elisabetta, Logroscino, Giancarlo, Nefussy, Beatrice, Osmanovic, Alma, Nordin, Angelica, Lerner, Yossef, Zabari, Michal, Gotkine, Marc, Baloh, Robert H., Bell, Shaughn, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Millecamps, Stéphanie, Meininger, Vincent, Salachas, François, Mora Pardina, Jesus S., Assialioui, Abdelilah, Rojas-García, Ricardo, Dion, Patrick A., Ross, Jay P., Ludolph, Albert C., Weishaupt, Jochen H., Brenner, David, Freischmidt, Axel, Bensimon, Gilbert, Brice, Alexis, Durr, Alexandra, Payan, Christine A. M., Saker-Delye, Safa, Wood, Nicholas W., Topp, Simon, Rademakers, Rosa, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Ripke, Stephan, Braun, Alice, Kraft, Julia, Whiteman, David C., Olsen, Catherine M., Uitterlinden, Andre G., Hofman, Albert, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M., Amouyel, Philippe, Traynor, Bryan J., Singleton, Andrew B., Mitne Neto, Miguel, Cauchi, Ruben J., Ophoff, Roel A., Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, van Deerlin, Vivianna M., Grosskreutz, Julian, Roediger, Annekathrin, Gaur, Nayana, Jörk, Alexander, Barthel, Tabea, Theele, Erik, Ilse, Benjamin, Stubendorff, Beatrice, Witte, Otto W., Steinbach, Robert, Hübner, Christian A., Graff, Caroline, Brylev, Lev, Fominykh, Vera, Demeshonok, Vera, Ataulina, Anastasia, Rogelj, Boris, Koritnik, Blaž, Zidar, Janez, Ravnik-Glavač, Metka, Glavač, Damjan, Stević, Zorica, Drory, Vivian, Povedano, Monica, Blair, Ian P., Kiernan, Matthew C., Benyamin, Beben, Henderson, Robert D., Furlong, Sarah, Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Ngo, Shyuan T., Nicholson, Garth A., Pamphlett, Roger, Rowe, Dominic B., Steyn, Frederik J., Williams, Kelly L., Mather, Karen A., Sachdev, Perminder S., Henders, Anjali K., Wallace, Leanne, de Carvalho, Mamede, Pinto, Susana, Petri, Susanne, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Curtis, Charles J., Breen, Gerome, Glass, Jonathan D., Brown, Robert H., Landers, John E., Shaw, Christopher E., Andersen, Peter M., Groen, Ewout J. N., van Es, Michael A., Pasterkamp, R. Jeroen, Fan, Dongsheng, Garton, Fleur C., McRae, Allan F., Davey Smith, George, Gaunt, Tom R., Eberle, Michael A., Mill, Jonathan, McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Wray, Naomi R., Tsai, Ellen, Runz, Heiko, Franke, Lude, Al-Chalabi, Ammar, Van Damme, Philip, van den Berg, Leonard H., and Veldink, Jan H.
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- 2022
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19. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
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Hop, Paul J., Zwamborn, Ramona A.J., Hannon, Eilis, Shireby, Gemma L., Nabais, Marta F., Walker, Emma M., van Rheenen, Wouter, van Vugt, Joke J.F.A., Dekker, Annelot M., Westeneng, Henk-Jan, Tazelaar, Gijs H.P., van Eijk, Kristel R., Moisse, Matthieu, Baird, Denis, Al Khleifat, Ahmad, Iacoangeli, Alfredo, Ticozzi, Nicola, Ratti, Antonia, Cooper-Knock, Jonathan, Morrison, Karen E., Shaw, Pamela J., Basak, A. Nazli, Chiò, Adriano, Calvo, Andrea, Moglia, Cristina, Canosa, Antonio, Brunetti, Maura, Grassano, Maurizio, Gotkine, Marc, Lerner, Yossef, Zabari, Michal, Vourc’h, Patrick, Corcia, Philippe, Couratier, Philippe, Mora Pardina, Jesus S., Salas, Teresa, Dion, Patrick, Ross, Jay P., Henderson, Robert D., Mathers, Susan, McCombe, Pamela A., Needham, Merrilee, Nicholson, Garth, Rowe, Dominic B., Pamphlett, Roger, Mather, Karen A., Sachdev, Perminder S., Furlong, Sarah, Garton, Fleur C., Henders, Anjali K., Lin, Tian, Ngo, Shyuan T., Steyn, Frederik J., Wallace, Leanne, Williams, Kelly L., Neto, Miguel Mitne, Cauchi, Ruben J., Blair, Ian P., Kiernan, Matthew C., Drory, Vivian, Povedano, Monica, de Carvalho, Mamede, Pinto, Susana, Weber, Markus, Rouleau, Guy A., Silani, Vincenzo, Landers, John E., Shaw, Christopher E., Andersen, Peter M., McRae, Allan F., van Es, Michael A., Pasterkamp, R. Jeroen, Wray, Naomi R., McLaughlin, Russell L., Hardiman, Orla, Kenna, Kevin P., Tsai, Ellen, Runz, Heiko, Al-Chalabi, Ammar, van den Berg, Leonard H., Van Damme, Philip, Mill, Jonathan, Veldink, Jan H., Veldink, Jan H., van den Berg, Leonard H., Moed, Matthijs, Al-Chalabi, Ammar, Wray, Naomi R., Hardiman, Orla, Chio, Adriano, and Mill, Jonathan
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation–based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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- 2022
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20. Reduced Myocardial 123-Iodine Metaiodobenzylguanidine Uptake
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Coutinho, Maria C. Azevedo, Cortez-Dias, Nuno, Cantinho, Guilhermina, Conceição, Isabel, Oliveira, António, Bordalo e Sá, Armando, Gonçalves, Susana, Almeida, Ana G., de Carvalho, Mamede, and Diogo, António Nunes
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Transthyretin familial amyloid polyneuropathy is a hereditary form of amyloidosis characterized by sensorimotor and autonomic neuropathy, cardiac conduction defects, and infiltrative cardiomyopathy. Previous studies have suggested that myocardial sympathetic denervation assessed by 123-iodine metaiodobenzylguanidine (MIBG) imaging occurs early in disease progression. However, its prognostic significance was never evaluated. We aimed to study the long-term prognostic value of myocardial sympathetic denervation detected by MIBG imaging in transthyretin familial amyloid polyneuropathy.
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- 2013
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21. Awaji Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis: A Systematic Review
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Costa, João, Swash, Michael, and de Carvalho, Mamede
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OBJECTIVE To estimate the potential diagnostic added value of the Awaji criteria for diagnosis of amyotrophic lateral sclerosis (ALS), which have been compared with the previously accepted gold standard the revised El Escorial criteria in several studies. DATA SOURCES MEDLINE and Web of Science (until October 2011). STUDY SELECTION We searched for studies testing the diagnostic accuracy of the Awaji criteria vs the revised El Escorial criteria in patients referred with suspected ALS. DATA EXTRACTION Evaluation and data extraction of identified studies were done independently. The Quality Assessment of Diagnostic Accuracy Studies list was used to assess study quality. We determined the proportion of patients classified as having probable/definite ALS and derived indices of diagnostic performance (sensitivity, specificity, and diagnostic odds ratio). Quantitative data synthesis was accomplished through random-effects meta-analysis, and heterogeneity was assessed with the I2 test. DATA SYNTHESIS Eight studies were included (3 prospective and 5 retrospective) enrolling 1187 patients. Application of Awaji criteria led to a 23% (95% CI, 12% to 33%; I2 = 84%) increase in the proportion of patients classified as having probable/definite ALS. Diagnostic performance of the Awaji criteria was higher than the revised El Escorial criteria (pooled sensitivity: 81.1% [95% CI, 72.2% to 90.0%; I2 = 91%] vs 62.2% [95% CI, 49.4% to 75.1%; I2 = 93%]; pooled diagnostic odds ratio, 35.8 [95% CI, 15.2 to 84.7; I2 = 3%] vs 8.7 [95% CI, 2.2 to 35.6; I2 = 50%]). Diagnostic accuracy of Awaji criteria was higher in bulbar- than in limb-onset cases. CONCLUSION The Awaji criteria have a significant clinical impact allowing earlier diagnosis and clinical trial entry in ALS.
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- 2012
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22. Amyotrophic lateral sclerosis
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de Carvalho, Mamede and Swash, Michael
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The aim is to review recent publications on amyotrophic lateral sclerosis (ALS).
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- 2011
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23. Diagnosis, Pathogenesis and Therapeutic Targets in Amyotrophic Lateral Sclerosis
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Costa, Julia, Gomes, Catarina, and de Carvalho, Mamede
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Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of the motor system. The diagnosis is clinical, but additional investigations such as electromyography, transcranial magnetic stimulation and neuroimaging have demonstrated their usefulness in supporting diagnosis. Exhaustive research for the identification of molecular markers in the cerebrospinal fluid and plasma of ALS patients have been made; however, at present, there are no validated biomarkers for the disease. Between 5 to 10% of the ALS cases have a positive familial history, up to now eleven genes have been identified as associated with the disease. The most studied gene encodes for cupper, zinc superoxide dismutase enzyme. The identified abnormal genes potentially allow the generation of experimental cell and animal models to study the mechanisms of the disease and to test potential therapeutic compounds. The pathological characteristics of ALS include protein aggregation, proteasome inhibition, impaired axonal transport, mitochondria damage and apoptosis, oxidative stress, glutamate induced excitotoxicity, neuroinflammation and transcriptional dysfunction. Many compounds targeted to one or more of these mechanisms have been tested in multiple clinical trials. Nonetheless, nowadays only one drug, riluzole, has demonstrated a positive effect in the disease progression, but a number of recent compounds are promising in ALS therapy.
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- 2010
24. Family history of neurodegenerative disorders in patients with amyotrophic lateral sclerosis: population-based case–control study
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Campos, Catarina Falcão, Gromicho, Marta, Uysal, Hilmi, Grosskreutz, Julian, Kuzma-Kozakiewicz5, Magdalena, Pinto, Susana, Petri, Susanne, and de Carvalho, Mamede
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- 2020
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25. Can Selection of Rapidly Progressing Patients Shorten Clinical Trials in Amyotrophic Lateral Sclerosis?
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de Carvalho, Mamede and Swash, Michael
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BACKGROUND The marked variability in progression of amyotrophic lateral sclerosis (ALS) requires large numbers of patients to detect a significant effect in current clinical trial designs. OBJECTIVE To test the utility of a lead-in period to assess rate of progression so that patients with rapidly progressive ALS can be selected for subsequent clinical trials. DESIGN Prospective study. SETTING The ALS Center, University of Lisbon, Lisbon, Portugal. PATIENTS Fifty-seven consecutively recruited patients assessed at diagnosis and 3 months later (end of lead-in period). INTERVENTIONS Change in ALS Functional Rating Scale (ALS-FRS) score was analyzed to establish a statistically significant cutoff point to define patients with rapid (group 1) or slow (group 2) progression. Patients from both groups were reexamined 1 and 3 months after the lead-in period. MAIN OUTCOME MEASURES Changes in ALS-FRS score, motor unit number estimation, and neurophysiologic index, and resultant grouping of patients according to rate of progression at 1 and 3 months. RESULTS Both the 80th percentile and 2 SDs above the mean of the change in ALS-FRS score identified the same patients. Twelve patients showed rapid progression (group 1) and 45 showed slow progression (group 2). One month after the lead-in period there was a significant reduction in ALS-FRS score, motor unit number estimation, and neurophysiologic index in group 1, and after 3 months all these measurements changed significantly in both groups. CONCLUSIONS This strategy of selecting patients with rapidly progressing ALS for inclusion in exploratory, short phase II clinical trials offers substantial savings in costs and time, and could accelerate the process of testing potentially useful drugs for the treatment of ALS.Arch Neurol. 2006;63:557-560 --
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- 2006
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26. Clinical trials in ALS A review of the role of clinical and neurophysiological measurements
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de Carvalho, Mamede, Costa, João, and Swash, Michael
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We have reviewed all the published clinical trials of ALS and, from those considered sufficiently large, and containing a control group, we have evaluated their methodology with regard to statistical power. This implies a critical analysis of the endpoint measurements. We have concluded that clinical endpoints used in clinical trials of ALS have frequently been insufficiently sensitive, nonlinear, or even not intuitively highly relevant to the disease. We suggest that the ALSFRS, perhaps also MUNE and the Neurophysiological Index, may be the best measures currently available. These techniques have complementary characteristics that allow them to be used to address different aspects of the disease and its treatment in various trials designs. In the past some trials may have failed to demonstrate a treatment effect because the chosen endpoint measures and the trial design were inappropriate.
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- 2005
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27. Biochemical characterization of plasma in amyotrophic lateral sclerosis: Amino acid and protein composition
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Palma, Angelina, de Carvalho, Mamede, Barata, Nuno, Evangelista, Teresinha, Chicau, Paula, Regalla, Manuela, and Costa, Júlia
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In this work, we have studied the amino acid and protein composition of the plasma from a group of 32 ALS patients. As controls, groups of 10 healthy subjects (HC) and 32 patients with other neuromuscular disorders have been analysed. When the HC group was compared with the ALS group there were significant decreases of His (39±18 to 24±9 µM, p<0.01) and Ala (313±62 to 237±66 µM, p<0.05), and a significant increase of Asn (89±41 to 118±24 µM, p<0.05), for the ALS group. When the three groups were compared, we observed significant decreased concentrations of Ser, His, Thr, Ala, Arg, Tyr, Met, Cys, Ile, and significant increases of Asn, Phe and Lys. An increase of proteolytic products of α2- macroglobulin (α2-M), an acute-phase serum glycoprotein that functions as a protease inhibitor, has been observed for a subgroup of ALS patients by Western blot. Furthermore, the detection of α2-M during disease progression has shown increases of the intact subunit and of a proteolytic product for two of the four patients analysed. Another acute-phase glycoprotein, haptoglobin, which regulates haemoglobin degradation, was not increased for the same group of patients. The results obtained suggested that diet supplementation with His and Ala and modulation of α2-M might have some beneficial effects on the course of ALS.
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- 2005
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28. Neurophysiological measures in amyotrophic lateral sclerosis: Markers of progression in clinical trials
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de Carvalho, Mamede, Chio, Adriano, Dengler, Reinhard, Hecht, Martin, Weber, Markus, and Swash, Michael
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In this review we evaluate clinical neurophysiological methods, originally described for use in diagnosis that can be applied to measurement of change during the progress of amyotrophic lateral sclerosis (ALS). Such measurements are potentially important in clinical trials, and also in clinical practice. We have assessed methods for lower and upper motor neuron function, including conventional EMG, nerve conduction and F-wave studies, the derived Neurophysiological Index, motor unit counting methods (MUNE), and transcranial magnetic motor cortex stimulation. We have also addressed the validity of measurements of electromechanical coupling. Methods for measuring muscle strength are beyond the scope of this review. We conclude that MUNE, M-wave amplitude and the Neurophysiological Index are sufficiently reliable, sensitive, and relevant to the clinical problem of ALS, to be used in clinical trials in the disease. Transcranial magnetic stimulation is of limited value, but a combination of the measurements made as part of this technique may also be useful. We conclude that clinical neurophysiological techniques should now be used in measuring change in clinical trials in ALS.
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- 2005
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29. Clinical and therapeutic implications of presymptomatic gene testing for familial amyloidotic polyneuropathy (FAP)
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de Lourdes Sales-Luís, Maria, Conceição, Isabel, and de Carvalho, Mamede
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AbstractPresymptomatic gene testing for familial amyloidotic polyneuropathies (FAP) is integrated in genetic counseling protocols common to other “Later onset, hereditary, autosomal dominant, no cure diseases” namely Huntington's Disease (HD) and Machado-Joseph disease (MJD). However, presymptomatic gene testing has specific clinical and therapeutic implications for FAP. Moreover, at least in Portugal, FAP ATTR Val30Met is a serious health problem. The most important implications are: the possibility of family planning including prenatal and preimplantation diagnosis; treatment with liver transplantation (TX); clinical follow-up according to protocols for early diagnosis which will allow patients to access therapy in useful time. This concept of useful time in FAP treatment is discussed. The growing possibilities of different therapeutic approaches are considered.In conclusion, presymptomatic gene testing for FAP may have a positive impact on candidate quality and prolongation of life, and on the future of disease studies.
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- 2003
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30. Clinical and genetic characterization of families with triple A (Allgrove) syndrome
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Houlden, Henry, Smith, Stephen, de Carvalho, Mamede, Blake, Julian, Mathias, Christopher, Wood, Nicholas W., and Reilly, Mary M.
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Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype–phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.
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- 2002
31. Clinical and genetic characterization of families with triple A (Allgrove) syndrome.
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Houlden, Henry, Smith, Stephen, De Carvalho, Mamede, Blake, Julian, Mathias, Christopher, Wood, Nicholas W, and Reilly, Mary M
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Triple A (Allgrove) syndrome is characterized by achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. Affected individuals have between two and four of these relatively common clinical problems; hence the diagnosis is often difficult in all but the classical presentation. The inheritance is autosomal recessive, and most cases of triple A have no family history. Using genetic linkage analysis in a small number of families, a locus on chromosome 12q13 was identified. The triple A gene was identified recently at this locus and called ALADIN (alacrima, achalasia, adrenal insufficiency neurologic disorder). Mutations in this gene were reported in families from North Africa and Europe. The majority of mutations were homozygous. We have identified 20 families with between two and four of the clinical features associated with the triple A syndrome. Sequencing of the triple A gene revealed five families that had a total of nine compound heterozygous mutations, and one Portuguese family (previously published) had two homozygous mutations; these changes were spread throughout the triple A gene in exons 1, 2, 7, 8, 10, 11, 12, 13 and 16, and the poly(A) tract. Those bearing mutations had the classical triple A syndrome of achalasia, alacrima, adrenal abnormalities and a progressive neurological syndrome. We identified a spectrum of associated neurological abnormalities in these cases, including pupil and cranial nerve abnormalities, frequent optic atrophy, autonomic neuropathy and upper and lower motor neurone signs including distal motor neuropathy and amyotrophy with severe selective ulnar nerve involvement. In these families, we have made genotype-phenotype correlations. Mutations in the triple A gene are thus an important cause of this clinically heterogeneous syndrome, and sequencing represents an important diagnostic investigation. Identifying further mutations and defining their phenotype along with functional protein analysis will help to characterize this neuroendocrine gene.
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- 2002
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32. Long-term quantitative evaluation of liver transplantation in familial amyloid polyneuropathy (Portuguese V30M)
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de Carvalho, Mamede, Conceiçato, Isabel, Bentes, Carla, and Sales Luis, M. L.
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Familial amyloid polyneuropathy (FAP) is associated with massive endoneurial and extracellular deposition of amyloid, which is formed from a mutated transthyretin (TTR) protein. Ninety percent of TTR protein is produced in liver. Liver transplantation (LT) is the only treatment that can halt FAP clinical progression.We studied 35 LT patients. The mean age of the first symptoms was 36.6 years (ranging from 27 to 56), 19 were males, and 16 females, they underwent LT after a mean time of 5 years of symptomatic disease. Fifteen patients followed for more than 24 months after LT had periodic evaluations with clinical and neurophysiological scores (CS and NS). Ten were first evaluated before LT (mean follow-up time of 44 months after LT), and 5 were evaluated only after LT (for a mean time of 41 months). Five patients were followed periodically before LT (mean time of 44 months) to study the natural course of this condition.The mortality rate was of 14% in the first 6 months and was related to known complications of the surgery. No deaths occurred in the period 6 months to 1 year after LT. Five patients (14%) died 1-2 years after LT, 4 of whom were transplanted in advance stages. in the survival group, CS tended to stabilize shortly after LT and to remain invariable later on. The NS progressed in the first year followingLT, and subsequently it did not increase significantly. LT changed the natural course of FAP-I.
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- 2002
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33. Allgrove syndrome in adulthood
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Bentes, Carla, Santos‐Bento, Mariana, de Sá, Joāo, de Lurdes Sales Luís, Maria, and de Carvalho, Mamede
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A 35‐year‐old man with a past history of achalasia developed progressive spastic tetraparesis, distal limb atrophy, dysarthria, and dysphagia. A clinical diagnosis of amyotrophic lateral sclerosis (ALS) was considered before neurophysiological investigation, which disclosed a polyneuropathy and a prolonged central conduction time. One year later, the patient developed dysautonomic symptoms. Following confirmation of adrenal insufficiency, a diagnosis of Allgrove syndrome was made. This is a rare case, and we emphasize its clinical similarity with ALS. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 292–296, 2001
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- 2001
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34. Reproducibility of neurophysiological and myometric measurement in the ulnar nerve–abductor digiti minimi system
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de Carvalho, Mamede, Lopes, Arminda, Scotto, Manuel, and Swash, Michael
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Reliability in strength and neurophysiological measurements is important in evaluating progression of neuromuscular diseases. No data are available on the variability of neurophysiological parameters as compared with maximal voluntary isometric contraction (MVIC) in the same muscles, in healthy subjects. A control population of 26 healthy subjects was studied twice on different days. We evaluated the reliability of neurophysiological parameters obtained from bilateral ulnar nerve stimulation, recording the response over the abductor digiti minimi (ADM) muscle, including distal motor latency, compound muscle potential amplitude and area, F‐wave frequency and mean F‐wave latency, and the derived neurophysiological index that we have described previously. MVIC force was measured in each session in both ADM muscles. The variances between the grouped data obtained in the two recording sessions were identical, indicating a low intrinsic variability with this experimental methodology. Comparison of the mean values obtained in the two sessions revealed no statistically significant differences. The reliability of these neurophysiological and strength measurements in the same nerve/muscle system suggests they may be useful in comparing the dynamics of weakness and neurophysiological change in neuromuscular disease. © 2001 John Wiley & Sons, Inc. Muscle Nerve 24: 1391–1395, 2001
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- 2001
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35. Nerve conduction studies in amyotrophic lateral sclerosis
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de Carvalho, Mamede and Swash, Michael
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We studied 137 ulnar nerves and abductor digiti minimi (ADM) muscles in 70 patients with amyotrophic lateral sclerosis (ALS), and correlated the results with ADM strength graded on the Medical Research Council (MRC) scale, to address the potential value of a standardized neurophysiological assessment of this nerve–muscle system. The ulnar nerves of 35 normal subjects matched for age, gender, and height served as controls. Reduced compound muscle action potential (CMAP) amplitude and area in the ADM muscle recordings correlated strongly with weakness. Distal motor latency, proximal conduction time, and F‐wave frequency were abnormal with minimally detectable weakness. In weaker ADM muscles, conduction velocities and F‐wave latencies were also abnormal. Conduction block was never observed and sensory potentials were normal. An “ALS neurophysiological index” was derived from these ulnar nerve studies and consisted of the expression: (CMAP amplitude/DML) × F frequency —, where F frequency was expressed as the number of F responses recorded in 20 trials. This index was strongly correlated with ADM weakness (r= 0.74, P< 0.001). Neurophysiological studies restricted to a single nerve–muscle system, the ulnar nerve/ADM, appear potentially useful in objectively assessing change in ALS. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 344–352, 2000
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- 2000
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36. Cortical muscle representation in amyotrophic lateral sclerosis patients: Changes with disease evolution
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de Carvalho, Mamede, Miranda, Pedro Cavaleiro, Luís, Maria Lourdes Sales, and Ducla‐Soares, Eduardo
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Transcranial magnetic stimulation (TMS) mapping was performed regularly on 11 patients with amyotrophic lateral sclerosis (ALS). Map area decreased by 25% (P= 0.03) and normalized volume decreased by 47% (P= 0.01) in those patients who were mapped four times over a period of 11.6 months. The center of gravity (CoG) position moved randomly along the interaural line by distances larger than could be explained by experimental error (P= 0.002). Central conduction time, threshold, and motor evoked potential:compound muscle action potential (MEP:CMAP) amplitude ratio did not change significantly with time (P> 0.05). There were significant linear correlations between strength and CMAP amplitude and between map area and volume. No correlation was found between strength or CMAP amplitude and area or volume. The changes in map parameters were attributed primarily to loss of cortical cells. These results indicate that map parameters may be more sensitive to cortical neuronal loss than other TMS parameters. © 1999 John Wiley & Sons, Inc. Muscle Nerve 22: 1684–1692, 1999
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- 1999
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37. Fasciculation potentials: A study of amyotrophic lateral sclerosis and other neurogenic disorders
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de Carvalho, Mamede and Swash, Michael
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We studied fasciculation potentials in amyotrophic lateral sclerosis (ALS), and in other neurogenic disorders, in strength and single‐fiber electromyography‐matched muscles. Benign fasciculations were studied in 3 normal subjects. Fasciculations were more stable and easier to recruit voluntarily in the early phase of ALS; later, fasciculations were more unstable, more complex, and less likely to be voluntarily recruited. Stable fasciculations, representing part of large, reinnervated motor units, and probably arising from distal axonal sprouts, usually had a higher firing rate than more complex and unstable fasciculations. In weak muscles in ALS, fasciculations were generally more unstable than in other neurogenic disorders. In normal‐strength muscles fasciculations are less complex in ALS than in other disorders. Benign fasciculations have a high firing rate and normal morphologic parameters. In ALS fasciculations arise proximally early in the disease and distally in the later stages. Fasciculation may be important in excitotoxic cell death in ALS. © 1998 John Wiley & Sons, Inc. Muscle Nerve21:336–344.
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- 1998
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38. Paralytic shellfish poisoning: clinical and electrophysiological observations
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de Carvalho, Mamede, Jacinto, Jorge, Ramos, Natalia, de Oliveira, Victor, Pinho e Melo, Teresa, and de Sá, João
- Abstract
Abstract: In paralytic shellfish poisoning a mollusc contaminated with a toxin (saxitoxin) causes a potentially lethal disease, clinically characterised by gastrointestinal and neurological symptoms, of which possible respiratory depression is the most serious. The toxin acts by blocking the sodium channels. We report 9 Portuguese patients with this disease. The mollusc was identified as Mytilus edulis, contaminated with the dinoflagellate Gymnodinium catenatum, and the toxin saxitoxin. Our patients had a benign clinical course with cerebellar ataxia as the most severe neurological impairment. Eight out of 9 patients had neurophysiological investigations, the largest number so far reported. Motor and sensory conduction velocities and amplitudes were normal. The proximal conduction times, as assessed by F waves, showed delayed conduction and decreased frequency, which returned to normal in few weeks. The somatosensory evoked potentials confirmed normal peripheral and central sensory conduction. The rich vascular supply at root level of the sodium channels of the proximal motor nerves may explain the greater vulnerability to toxin damage. The typically transient and quickly reversible nerve dysfunction caused by ion channel blockade is reported.
- Published
- 1998
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39. Magnetic stimulation in Alzheimer’s disease
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de Carvalho, Mamede, de Mendonça, Alexandre, Miranda, Pedro C., Garcia, Carlos, and Luís, Maria Lourdes Sales
- Abstract
Alzheimer’s disease (AD) is a common cause of dementia in which some clinical motor abnormalities have been described. We used transcranial magnetic stimulation in order to test the hypothesis that the change in the motor cortex might cause modifications in motor excitability. Fourteen mildly to moderately affected AD patients were compared with 11 controls matched for age, height and sex. The motor evoked potential threshold value for the relaxed abductor digiti minimi was lower in the AD patients than in the control group for both left and right hemispheres (P< 0.05). No statistically significant difference was found comparing the left and the right hemispheres thresholds in each population. The mean interside threshold differences were small and not significantly different between patients and controls. The spinal motor neuron excitability, as evaluated by F/M and H/M waves amplitude ratios, showed no difference between the groups, reinforcing the motor cortex increased excitability hypothesis to explain this difference. Degeneration of inhibitory gabaergic terminals might be the basis for the increased cortical excitability in the motor cortex of the Alzheimer patients; postsynaptic changes in the GABAAreceptors might also affect inhibitory gabaergic transmission. The increased excitability found by transcranial magnetic stimulation in the motor cortex is important for understanding the emergence of seizures and myoclonus in this disease.
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- 1997
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40. Explainable Models of Disease Progression in ALS: Learning from Longitudinal Clinical Data with Recurrent Neural Networks and Deep Model Explanation
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Müller, Marcel, Gromicho, Marta, de Carvalho, Mamede, and Madeira, Sara C.
- Abstract
•Deep learning coupled with deep model explanation used to draw insights into disease progression.•Recurrent Neural Networks with LSTMs and SHAP values used to predict and explain clinical endpoint from longitudinal clinical data.•Deep learning used to predict and explain decline in breathing capability in ALS patients.•Need for non-invasive respiratory ventilation (NIV) in ALS predicted using deep learning from patients’ follow-up.•Deep model explanation supports previous results relating neck weakness to disease outcome and respiratory decline in ALS.
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- 2021
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41. Rare Variant Burden Analysis within Enhancers Identifies CAV1as an ALS Risk Gene
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Cooper-Knock, Johnathan, Zhang, Sai, Kenna, Kevin P., Moll, Tobias, Franklin, John P., Allen, Samantha, Nezhad, Helia Ghahremani, Iacoangeli, Alfredo, Yacovzada, Nancy Y., Eitan, Chen, Hornstein, Eran, Elhaik, Eran, Celadova, Petra, Bose, Daniel, Farhan, Sali, Fishilevich, Simon, Lancet, Doron, Morrison, Karen E., Shaw, Christopher E., Al-Chalabi, Ammar, Blair, Ian, Wray, Naomi, Kiernan, Matthew, Neto, Miguel Mitne, Chio, Adriano, Cauchi, Ruben, Robberecht, Wim, van Damme, Philip, Corcia, Phillippe, Couratier, Phillipe, Hardiman, Orla, McLaughlin, Russel, Gotkine, Marc, Drory, Vivan, Ticozzi, Nicola, Silani, Vincenzo, Veldink, Jan, van den Berg, Leonard, de Carvalho, Mamede, Pardina, Jesus Mora, Povedano, Monica, Andersen, Peter, Wber, Markus, Başak, Nazli, Al-Chalabi, Ammar, Shaw, Christopher, Shaw, Pamela, Morrison, Karen, Landers, John, Glass, Jonathan, Veldink, Jan H., Kirby, Janine, Snyder, Michael P., and Shaw, Pamela J.
- Abstract
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2expression in neurons. Additional enrichment of ALS-associated mutations within CAV1exons positions CAV1as an ALS risk gene. We propose CAV1/CAV2overexpression as a personalized medicine target for ALS.
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- 2020
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42. What Is Really New in Progressive Muscle Atrophy?
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de Carvalho, Mamede and Swash, Michael
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- 2009
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43. Quantitating progression in ALS
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de Carvalho, Mamede, Scotto, Manuel, Lopes, Arminda, and Swash, Michael
- Abstract
The authors prospectively studied the value of clinical and neurophysiologic measurements in assessing progression in ALS. Motor unit number estimation (MUNE) and the neurophysiologic index (NI) were significantly correlated with ADM strength (maximal voluntary isometric contraction force in the abductor digiti minimi muscle MVIC-ADM). MUNE and the NI were reliable, but the NI showed a lower variation. On assessing progression at 3, 6, and 12 months, MUNE, NI, and MVIC-ADM showed the highest rate of change. The NI is a potentially useful new neurophysiologic measurement.
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- 2005
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44. Cramps, muscle pain, and fasciculations
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de Carvalho, Mamede and Swash, Michael
- Abstract
Fasciculation and cramps without weakness or muscle atrophy are recognized as a benign syndrome. The authors report a patient with cramp and fasciculation, which persisted for 1 year without abnormal motor unit morphology on EMG before progressive weakness, muscle atrophy, and EMG abnormalities developed. This observation raises the possibility that lower motor neuron hyperexcitability may precede motor neuron death in motor neuron disease.
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- 2004
- Full Text
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45. Sialorrhoea and reversals in ALS functional rating scale
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Pinto, Susana, Gromicho, Marta, and de Carvalho, Mamede
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- 2017
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46. Mitochondrial Neurogastrointestinal Encephalomyopathy: Novel Pathogenic Mutation in Thymidine Phosphorylase Gene in a Patient from Cape Verde Islands
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Falcão de Campos, Catarina, Oliveira Santos, Miguel, Roque, Rafael, Conceição, Isabel, and de Carvalho, Mamede
- Abstract
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the gene encoding the Thymidine Phosphorylase (TP). It is clinically characterized by severe gastrointestinal dysmotility, cachexia, palpebral ptosis, ophthalmoparesis, sensorimotor polyneuropathy and leukoencephalopathy. The diagnosis is established by the presence of typical clinical and neuroimaging features, positive family history, and abnormal genetic test. A 19-year-old Cape Verdean patient with a history since childhood of recurrent episodes of nausea, vomiting, diarrhoea and painful abdominal distension associated with progressive motor disability with difficulty in climbing stairs and running and clumsiness with her hands. The diagnostic workup was suggestive of MNGIE. Genetic screening of the TYMP gene identified a novel mutation (c. 1283 G>A). Patients with MNGIE have significant comorbidity and mortality, and they are frequently misdiagnosed. A better acknowledgment of this disorder is essential to permit an earlier diagnosis and to improve disease management.
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- 2019
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47. Integrative biomarker discovery in neurodegenerative diseases
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Carreiro, André V., Mendonça, Alexandre, de Carvalho, Mamede, and Madeira, Sara C.
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- 2016
- Full Text
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48. Axial myoclonus after ischemic stroke
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Alves, Pedro Nascimento, de Carvalho, Mamede, Peralta, Rita, Geraldes, Ruth, Fonseca, Ana Catarina, and Pinho e Melo, Teresa
- Abstract
Myoclonus is an unusual manifestation of stroke.1We report a 67-year-old woman admitted with an acute ischemic stroke in the right thalamo-capsular and hippocampal areas (figure). Becoming upright produced marked postural instability, due to an apparent reduction in cervical and dorsal axial muscle tone. EMG disclosed negative myoclonus in left upper limb and right paraspinal muscles, and both negative and positive myoclonus in left paraspinal muscles (video on the Neurology® Web site at Neurology.org). No epileptic activity was observed on EEG.
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- 2015
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49. Reproducibility of corticomotor threshold: Some observations
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de Carvalho, Mamede, Miranda, Pedro Cavaleiro, Jardim, Lígia, Gabriel, Fernanda, and Falcão, Filipa
- Published
- 1999
- Full Text
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50. A tentative interpretation of electromyographic regional differences in bulbar- and limb-onset ALS
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de Carvalho, Mamede and Bentes, Carla
- Published
- 2000
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