EDMAR ZANOTELI
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
53 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 53
- Clinical and genetic spectrum of a large cohort of patients with delta-sarcoglycan muscular dystrophy(2022) ALONSO-PEREZ, Jorge; GONZALEZ-QUEREDA, Lidia; BRUNO, Claudio; PANICUCCI, Chiara; ALAVI, Afagh; NAFISSI, Shahriar; NILIPOUR, Yalda; ZANOTELI, Edmar; ISIHI, Lucas Michielon de Augusto; MELEGH, Bela; HADZSIEV, Kinga; MUELAS, Nuria; VILCHEZ, Juan J.; DOURADO, Mario Emilio; KADEM, Naz; KUTLUK, Gultekin; UMAIR, Muhammad; YOUNUS, Muhammad; PEGORANO, Elena; BELLO, Luca; CRAWFORD, Thomas O.; SUAREZ-CALVET, Xavier; TOPF, Ana; GUGLIERI, Michela; MARINI-BETTOLO, Chiara; GALLANO, Pia; STRAUB, Volker; DIAZ-MANERA, JordiSarcoglycanopathies include four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. Delta-sarcoglycanopathy (LGMDR6) is the least frequent and is considered an ultra-rare disease. Our aim was to characterize the clinical and genetic spectrum of a large international cohort of LGMDR6 patients and to investigate whether or not genetic or protein expression data could predict a disease's severity. This is a retrospective study collecting demographic, genetic, clinical and histological data of patients with genetically confirmed LGMDR6 including protein expression data from muscle biopsies. We contacted 128 paediatric and adult neuromuscular units around the world that reviewed genetic data of patients with a clinical diagnosis of a neuromuscular disorder. We identified 30 patients with a confirmed diagnosis of LGMDR6 of which 23 patients were included in this study. Eighty-seven per cent of the patients had consanguineous parents. Ninety-one per cent of the patients were symptomatic at the time of the analysis. Proximal muscle weakness of the upper and lower limbs was the most common presenting symptom. Distal muscle weakness was observed early over the course of the disease in 56.5% of the patients. Cardiac involvement was reported in five patients (21.7%) and four patients (17.4%) required non-invasive ventilation. Sixty per cent of patients were wheelchair-bound since early teens (median age of 12.0 years). Patients with absent expression of the sarcoglycan complex on muscle biopsy had a significant earlier onset of symptoms and an earlier age of loss of ambulation compared to patients with residual protein expression. This study confirmed that delta-sarcoglycanopathy is an ultra-rare neuromuscular condition and described the clinical and molecular characteristics of the largest yet-reported collected cohort of patients. Our results showed that this is a very severe and quickly progressive disease characterized by generalized muscle weakness affecting predominantly proximal and distal muscles of the limbs. Similar to other forms of sarcoglycanopathies, the severity and rate of progressive weakness correlates inversely with the abundance of protein on muscle biopsy.
- Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related RYR1 mutations(2023) SONNE, Alexander; ANTONOVIC, Anna Katarina; MELHEDEGAARD, Elise; AKTER, Fariha; ANDERSEN, Jesper L.; JUNGBLUTH, Heinz; WITTING, Nanna; VISSING, John; ZANOTELI, Edmar; FORNILI, Arianna; OCHALA, JulienAimConditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1-related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy-related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin. MethodsWe used skeletal muscle tissues from five patients with RYR1-related congenital myopathy and compared those with five controls and five patients with RYR1-related rhabdomyolysis/myalgia. We then defined post-translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant-ATP chase experiments and performed molecular dynamics (MD) simulations. ResultsLC/MS revealed two additional phosphorylations (Thr1309-P and Ser1362-P) and one acetylation (Lys1410-Ac) on the & beta;/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35-Ac, Lys663-Ac, Lys763-Ac, Lys1171-Ac, Lys1360-Ac, and Lys1733-Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant-ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered-relaxed conformation. ConclusionsAltogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype.
conferenceObject RAINBOWFISH: Preliminary Efficacy and Safety Data in Risdiplam-Treated Infants with Presymptomatic SMA(2022) FINKEL, Richard S.; FARRAR, Michelle A.; VLODAVETS, Dmitry; SERVAIS, Laurent; ZANOTELI, Edmar; AL-MUHAIZEA, Mohammad; NELSON, Leslie; PRUFER, Alexandra; WANG, Yi; FISHER, Carolyn; GERBER, Marianne; GORNI, Ksenija; KLETZL, Heidemarie; PALFREEMAN, Laura; SCALCO, Renata; BERTINI, Enrico- Risk factors and future directions for preventing and diagnosing exertional rhabdomyolysis(2021) CARNEIRO, Andreia; VIANA-GOMES, Diego; MACEDO-DA-SILVA, Janaina; LIMA, Giscard Humberto Oliveira; MITRI, Simone; ALVES, Sergio Rabello; KOLLIARI-TURNER, Alexander; ZANOTELI, Edmar; AQUINO NETO, Francisco Radler de; PALMISANO, Giuseppe; PESQUERO, Joao Bosco; MOREIRA, Josino Costa; PEREIRA, Marcos DiasExertional rhabdomyolysis may occur when an individual is subjected to strenuous physical exercise. It is occasionally associated with myoglobinuria (i.e. ""cola-colored"" urine) alongside muscle pain and weakness. The pathophysiology of exertional rhabdomyolysis involves striated muscle damage and the release of cellular components into extracellular fluid and bloodstream. This can cause acute renal failure, electrolyte abnormalities, arrhythmias and potentially death. Exertional rhabdomyolysis is observed in high-performance athletes who are subjected to intense, repetitive and/or prolonged exercise but is also observed in untrained individuals and highly trained or elite groups of military personnel. Several risk factors have been reported to increase the likelihood of the condition in athletes, including: viral infection, drug and alcohol abuse, exercise in intensely hot and humid environments, genetic polymorphisms (e.g. sickle cell trait and McArdle disease) and epigenetic modifications. This article reviews several of these risk factors and proposes screening protocols to identify individual susceptibility to exertional rhabdomyolysis as well as the relevance of proteomics for the evaluation of potential biomarkers of muscle damage.
- Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial(2022) MASSON, Riccardo; MAZURKIEWICZ-BELDZINSKA, Maria; ROSE, Kristy; SERVAIS, Laurent; XIONG, Hui; ZANOTELI, Edmar; BARANELLO, Giovanni; BRUNO, Claudio; DAY, John W.; DECONINCK, Nicolas; KLEIN, Andrea; MERCURI, Eugenio; VLODAVETS, Dmitry; WANG, Yi; DODMAN, Angela; EL-KHAIRI, Muna; GORNI, Ksenija; JABER, Birgit; KLETZL, Heidemarie; GAKI, Eleni; FONTOURA, Paulo; DARRAS, Basil T.Background Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods FIREFISH is an ongoing, multicentre, open-label, two-part study. hi FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0.2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0.25 mg/kg. Infants younger than 5 months started at 0.04 mg/kg (infants between 1 month and 3 months old) or 0.08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0.2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings Between March 13 and Nov 19,2018,41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p<0.0001 compared with the performance criterion derived from the natural history of untreated infants with type 1 spinal muscular atrophy). No infants could stand alone (0 [90% CI 0-7]) or walk alone (0 [0-7]) after 24 months of treatment. The most frequently reported adverse event was upper respiratory tract infection, in 22 infants (54%); the most common serious adverse events were pneumonia in 16 infants (39%) and respiratory distress in three infants (7%). Interpretation Treatment with risdiplam over 24 months resulted in continual improvements in motor function and achievement of developmental motor milestones. The FIREFISH open-label extension phase will provide additional evidence regarding long-term safety and efficacy of risdiplam.
- ANCHOVY: A retrospective cohort study of the natural history of type 1 spinal muscular atrophy (SMA) using medical record data(2021) ZANOTELI, E.; CANCES, C.; VLODAVETS, D.; COMI, G.; MASSON, R.; MAZURKIEWICZ-BELDZINSKA, M.; SAITO, K.; DODMAN, A.; EL-KHAIRI, M.; GORNI, K.; GRAVESTOCK, I.; HOFFART, J.; SCALCO, R.; DARRAS, B.
- FIREFISH Parts 1 and 2: 12-month pooled safety and efficacy outcomes of risdiplam (RG7916) in infants with Type 1 spinal muscular atrophy (SMA)(2020) SERVAIS, L.; BLOESPFLUG-TANGUY, O.; DARRAS, B.; DAY, J.; DECONINCK, N.; KLEIN, A.; MASSON, R.; MAZURKIEWICZ-BELDZINSKA, M.; MERCURI, E.; ROSE, K.; VLODAVETS, D.; XIONG, H.; ZANOTELI, E.; DODMAN, A.; EL-KHAIRI, M.; GERBER, M.; GORNI, K.; KLETZL, H.; SCALCO, R.; BARANELLO, G.
- International retrospective natural history study of LMNA-related congenital muscular dystrophy(2021) YAOU, Rabah Ben; YUN, Pomi; DABAJ, Ivana; NORATO, Gina; DONKERVOORT, Sandra; XIONG, Hui; NASCIMENTO, Andres; MAGGI, Lorenzo; SARKOZY, Anna; MONGES, Soledad; BERTOLI, Marta; KOMAKI, Hirofumi; MAYER, Michele; MERCURI, Eugenio; ZANOTELI, Edmar; CASTIGLIONI, Claudia; MARINI-BETTOLO, Chiara; D'AMICO, Adele; DECONINCK, Nicolas; DESGUERRE, Isabelle; ERAZO-TORRICELLI, Ricardo; GURGEL-GIANNETTI, Juliana; ISHIYAMA, Akihiko; KLEINSTEUBER, Karin S.; LAGRUE, Emmanuelle; LAUGEL, Vincent; MERCIER, Sandra; MESSINA, Sonia; POLITANO, Luisa; RYAN, Monique M.; SABOURAUD, Pascal; SCHARA, Ulrike; SICILIANO, Gabriele; VERCELLI, Liliana; VOIT, Thomas; YOON, Grace; ALVAREZ, Rachel; MUNTONI, Francesco; PIERSON, Tyler M.; GOMEZ-ANDRES, David; FOLEY, A. Reghan; QUIJANO-ROY, Susana; BONNEMANN, Carsten G.; BONNE, GiseleMuscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.
conferenceObject FIREFISH Part 2: Efficacy and Safety of Risdiplam (RG7916) in Infants with Type 1 Spinal Muscular Atrophy (SMA)(2020) SERVAIS, Laurent; BARANELLO, Giovanni; MASSON, Riccardo; MAZURKIEWICZ-BELDZINSKA, Maria; ROSE, Kristy; VLODAVETS, Dmitry; XIONG, Hui; ZANOTELI, Edmar; EL-KHAIRI, Muna; FUERST-RECKTENWALD, Sabine; GERBER, Marianne; GORNI, Ksenija; KLETZL, Heidemarie; SCALCO, Renata; DARRAS, Basil T.- Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study(2022) SCHIAVA, Marianela; IKENAGA, Chiseko; VILLAR-QUILES, Rocio Nur; CABALLERO-AVILA, Marta; TOPF, Ana; NISHINO, Ichizo; KIMONIS, Virginia; UDD, Bjarne; SCHOSER, Benedikt; ZANOTELI, Edmar; SOUZA, Paulo Victor Sgobbi; TASCA, Giorgio; LLOYD, Thomas; MUNAIN, Adolfo Lopez-de; PARADAS, Carmen; PEGORARO, Elena; NADAJ-PAKLEZA, Aleksandra; BLEECKER, Jan De; BADRISING, Umesh; ALONSO-JIMENEZ, Alicia; KOSTERA-PRUSZCZYK, Anna; MIRALLES, Francesc; SHIN, Jin-Hong; BEVILACQUA, Jorge Alfredo; OLIVE, Montse; VORGERD, Matthias; KLEY, Rudi; BRADY, Stefen; WILLIAMS, Timothy; DOMINGUEZ-GONZALEZ, Cristina; PAPADIMAS, George K.; WARMAN, Jodi; CLAEYS, Kristl G.; VISSER, Marianne de; MUELAS, Nuria; LAFORET, Pascal; MALFATTI, Edoardo; ALFANO, Lindsay N.; NAIR, Sruthi S.; MANOUSAKIS, Georgios; KUSHLAF, Hani A.; HARMS, Matthew B.; NANCE, Christopher; RAMOS-FRANSI, Alba; RODOLICO, Carmelo; HEWAMADDUMA, Channa; CETIN, Hakan; GARCIA-GARCIA, Jorge; PAL, Endre; FARRUGIA, Maria Elena; LAMONT, Phillipa J.; QUINN, Colin; NEDKOVA-HRISTOVA, Velina; PERIC, Stojan; LUO, Sushan; OLDFORS, Anders; TAYLOR, Kate; RALSTON, Stuart; STOJKOVIC, Tanya; WEIHL, Conrad; DIAZ-MANERA, JordiBackground Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. Methods Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. Results Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8 +/- 9.6 years and mean age of onset 45.6 +/- 9.3 years. Mean diagnostic delay was 7.7 +/- 6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8 +/- 7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC Conclusion This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.