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
24 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 24
- 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.
- Inflammatory myopathies: an update for neurologists(2022) SILVA, Andre Macedo Serafim; CAMPOS, Eliene Dutra; ZANOTELI, EdmarIdiopathic inflammatory myopathies (IIM) are a heterogenous group of treatable myopathies. Patients present mainly to the rheumatologist and neurologists, complaining of acute or subacute onset of proximal weakness. Extramuscular manifestations may occur, including involvement of the lungs, skin, and joints. Classically, the diagnosis used to be made based on the creatine kinase level increase, abnormalities in electroneuromyography and presence of inflammatory infiltrates in the muscle biopsy. Recently, the importance of autoantibodies has increased, and now they may be identified in more than half of IIM patients. The continuous clinicoseropathological improvement in IIM knowledge has changed the way we see these patients and how we classify them. In the past, only polymyositis, dermatomyositis and inclusion body myopathy were described. Currently, immune-mediated necrotizing myopathy, overlap myositis and antisynthetase syndrome have been considered the most common forms of IIM in clinical practice, increasing the spectrum of classification. Patients previously considered to have polymyositis, in fact have these other forms of seropositive IIM. In this article, we reviewed the new concepts of classification, a practical way to make the diagnosis and how to plan the treatment of patients suffering from IIM.
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- Whole-Body MRI in Limb Girdle Muscular Dystrophy Type R1/2A: Correlation With Clinical Scores(2022) AIVAZOGLOU, Lais U.; GUIMARAES, Julio B.; COSTA, Maria Alice F.; AIHARA, Andre Yui; CARDOSO, Fabiano N.; PINTO, Wladimir B. V. De R.; SOUZA, Paulo Victor S. de; SILVA, Andre M. S. da; ZANOTELI, Edmar; OLIVEIRA, Acary S. B.; CARVALHO, Alzira A. S.; FERNANDES, Artur Da R. C.Introduction/Aim The most common limb girdle muscular dystrophy (LGMD) worldwide is LGMD type R1 (LGMDR1). The aim of this study was to correlate the MRI findings with functional scores and to describe the whole-body MRI (WBMRI) pattern in a LGMDR1 Brazilian cohort. Methods LGMDR1 patients under follow-up in three centers were referred for the study. Clinical data were collected and a functional evaluation was performed, consisting of Gardner-Medwin and Walton (GMW) and Brooke scales. All patients underwent a WBMRI study (1.5T) with axial T1 and STIR images. Fifty-one muscles were semiquantitatively assessed regarding fatty infiltration and muscle edema. Results The study group consisted of 18 patients. The highest fatty infiltration scores involved the serratus anterior, biceps femoris long head, adductor magnus, and lumbar erector spinae. There was a latero-medial and caudo-cranial descending gradient of involvement of the paravertebral muscles, with erector spinae being significantly more affected than the transversospinalis muscles (p < 0.05). A striped appearance that has been dubbed the ""pseudocollagen sign"" was present in 72% of the patients. There was a positive correlation between the MRI score and GMW (Rho:0.83) and Brooke (Rho:0.53) scores. Discussion WBMRI in LGMDR1 allows a global patient evaluation including involvement of the paraspinal muscles, usually an underestimated feature in the clinical and imaging study of myopathies. Knowledge of the WBMRI pattern of LGMDR1 involvement can be useful in the diagnostic approach and in future studies to identify the best target muscles to serve as outcome measures in clinical trials.
- 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.
- 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.
- FIREFISH Parts 1 and 2: 36-month safety and efficacy of risdiplam in Type 1 spinal muscular atrophy (SMA)(2022) SERVAIS, L.; BARANELLO, G.; BOESPFLUG-TANGUY, O.; DAY, J.; DECONINCK, N.; KLEIN, A.; MASSON, R.; MAZURKIEWICZ-BELDZINSKA, M.; MERCURI, E.; ROSE, K.; VLODAVETS, D.; XIONG, H.; ZANOTELI, E.; EL-KHAIRI, M.; GERBER, M.; GORNI, K.; KLETZL, H.; PALFREEMAN, L.; DODMAN, A.; GAKI, E.; DARRAS, B.
- Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization(2022) GURGEL-GIANNETTI, Juliana; SOUZA, Lucas Santos; YAMAMOTO, Guilherme L.; BELISARIO, Marina; LAZAR, Monize; CAMPOS, Wilson; PAVANELLO, Rita de Cassia M.; ZATZ, Mayana; REED, Umbertina; ZANOTELI, Edmar; OLIVEIRA, Acary Bulle; LEHTOKARI, Vilma-Lotta; CASELLA, Erasmo B.; MACHADO-COSTA, Marcela C.; WALLGREN-PETTERSSON, Carina; LAING, Nigel G.; NIGRO, Vincenzo; VAINZOF, MarizNemaline myopathy (NM), a structural congenital myopathy, presents a significant clinical and genetic heterogeneity. Here, we compiled molecular and clinical data of 30 Brazilian patients from 25 unrelated families. Next-generation sequencing was able to genetically classify all patients: sixteen families (64%) with mutation in NEB, five (20%) in ACTA1, two (8%) in KLHL40, and one in TPM2 (4%) and TPM3 (4%). In the NEB-related families, 25 different variants, 11 of them novel, were identified; splice site (10/25) and frame shift (9/25) mutations were the most common. Mutation c.24579 G>C was recurrent in three unrelated patients from the same region, suggesting a common ancestor. Clinically, the ""typical"" form was the more frequent and caused by mutations in the different NM genes. Phenotypic heterogeneity was observed among patients with mutations in the same gene. Respiratory involvement was very common and often out of proportion with limb weakness. Muscle MRI patterns showed variability within the forms and genes, which was related to the severity of the weakness. Considering the high frequency of NEB mutations and the complexity of this gene, NGS tools should be combined with CNV identification, especially in patients with a likely non-identified second mutation.
- Skeletal muscle gene expression in older adults with type 2 diabetes mellitus undergoing calorie-restricted diet and recreational sports training - a randomized clinical trial(2022) SOARES, Diana Bento da Silva; SHINJO, Samuel Katsuyuki; SANTOS, Aritania Sousa; JESUS, Joyce de Cassia Rosa de; SCHENK, Simon; CASTRO, Gabriela Salim de; ZANOTELI, Edmar; KRUSTRUP, Peter; SILVA, Maria Elizabeth Rossi da; SOUSA, Maysa Vieira deAims: This study aimed to evaluate the impact of a 12-week calorie-restricted diet and recreational sports training on gene expressions IL-15, ATROGIN-1 and MURF-1 in skeletal muscle of T2D patients. Methods: Older adults with T2D (n = 39, 60 +/- 6.0 years, BMI 33.5 +/- 0.6 kg/m(2)) were randomly allocated to Diet+Soccer (DS), Diet+Running (DR) or Diet (D). The training sessions were moderate-to-high-intensity and performed 3 x 40 min/week for 12-weeks. Gene expression from vastus lateralis muscle obtained by qRT-PCR, dual-energy X-ray and fasting blood testing measurements were performed before and after 12-weeks. Statistical analysis adopted were two-way ANOVA and Paired t-test for gene expression, and RM-ANOVA test for the remainder variables. Results: Total body weight was reduced in similar to 4 kg representing body fat mass in all groups after 12-weeks (P < 0.05). HbA1c values decreased in all groups post-intervention. Lipids profile improved in the training groups (P < 0.05) after 12-weeks. ATROGIN-1 and MURF-1 mRNA reduced in the DS (1.084 +/- 0.14 vs. 0.754 +/- 1.14 and 1.175 +/- 0.34 vs. 0.693 +/- 0.12, respectively; P < 0.05), while IL-15 mRNA increased in the DR (1.056 +/- 0.12 vs. 1.308 +/- 0.13; P < 0.05) after 12-weeks intervention. Conclusion: Recreational training with a moderate calorie-restricted diet can downregulates the expression of atrophy-associated myokines and increases the expression of anti-inflammatory gene IL-15.
- GGPS1-associated muscular dystrophy with and without hearing loss(2022) KAIYRZHANOY, Rauan; PERRY, Luke; ROCCA, Clarissa; ZAKI, Maha S.; HOSNY, Heba; MORENO, Cristiane Araujo Martins; PHADKE, Rahul; ZAHARIEVA, Irina; GONTIJO, Clara Camelo; BEETZ, Christian; PINI, Veronica; MOVAHEDINIA, Mojtaba; ZANOTELI, Edmar; DITROIA, Stephanie; VUILLAUMIER-BARROT, Sandrine; ISAPOF, Arnaud; MEHRJARDI, Mohammad Yahya Vahidi; GHASEMI, Nasrin; SARKOZY, Anna; MUNTONI, Francesco; WHALEN, Sandra; VONA, Barbara; HOULDEN, Henry; MAROOFIAN, RezaUltra-rare biallelic pathogenic variants in geranylgeranyl diphosphate synthase 1 (GGPS1) have recently been associated with muscular dystrophy/hearing loss/ovarian insufficiency syndrome. Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family. Our cohort replicated most of the previously described clinical features of GGPS1 deficiency; however, hearing loss was present in only 46% of the individuals. This report consolidates the disease-causing role of biallelic variants in GGPS1 and demonstrates that hearing loss and ovarian insufficiency might be a variable feature of the GGPS1-associated muscular dystrophy.
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