OSORIO LOPES ABATH NETO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
8 resultados
Resultados de Busca
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- One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia(2016) ABRAHAO, Agessandro; NETO, Osorio Abath; KOK, Fernando; ZANOTELI, Edmar; SANTOS, Bibiana; PINTO, Wladimir Bocca Vieira de Rezende; BARSOTTINI, Orlando Graziani Povoas; OLIVEIRA, Acary Souza Bulle; PEDROSO, Jose LuizBackground: VCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare. Methods: We reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations. Results: Each individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A> T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern. Conclusion: This study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn9lTyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.
- Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients(2017) NETO, Osorio Abath; MORENO, Cristiane de Araujo Martins; MALFATTI, Edoardo; DONKERVOORT, Sandra; BOHM, Johann; GUIMARAES, Julio Brandao; FOLEY, A. Reghan; MOHASSEL, Payam; DASTGIR, Jahannaz; BHARUCHA-GOEBEL, Diana Xerxes; MONGES, Soledad; LUBIENIECKI, Fabiana; COLLINS, James; MEDNE, Livija; SANTI, Mariarita; YUM, Sabrina; BANWELL, Brenda; SALORT-CAMPANA, Emmanuelle; RENDU, John; FAURE, Julien; YIS, Uluc; EYMARD, Bruno; CHERAUD, Chrystel; SCHNEIDER, Raphael; THOMPSON, Julie; LORNAGE, Xaviere; MESROB, Lilia; LECHNER, Doris; BOLAND, Anne; DELEUZE, Jean-Francois; REED, Umbertina Conti; OLIVEIRA, Acary Souza Bulle; BIANCALANA, Valerie; ROMERO, Norma B.; BONNEMANN, Carsten G.; LAPORTE, Jocelyn; ZANOTELI, EdmarMutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in Comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients.
- Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues(2017) BIANCALANA, Valerie; SCHEIDECKER, Sophie; MIGUET, Marguerite; LAQUERRIERE, Annie; ROMERO, Norma B.; STOJKOVIC, Tanya; NETO, Osorio Abath; MERCIER, Sandra; VOERMANS, Nicol; TANNER, Laura; ROGERS, Curtis; OLLAGNON-ROMAN, Elisabeth; ROPER, Helen; BOUTTE, Celia; BEN-SHACHAR, Shay; LORNAGE, Xaviere; VASLI, Nasim; SCHAEFER, Elise; LAFORET, Pascal; POUGET, Jean; MOERMAN, Alexandre; PASQUIER, Laurent; MARCORELLE, Pascale; MAGOT, Armelle; KUSTERS, Benno; STREICHENBERGER, Nathalie; TRANCHANT, Christine; DONDAINE, Nicolas; SCHNEIDER, Raphael; GASNIER, Claire; CALMELS, Nadege; KREMER, Valerie; NGUYEN, Karine; PERRIER, Julie; KAMSTEEG, Erik Jan; CARLIER, Pierre; CARLIER, Robert-Yves; THOMPSON, Julie; BOLAND, Anne; DELEUZE, Jean-Francois; FARDEAU, Michel; ZANOTELI, Edmar; EYMARD, Bruno; LAPORTE, JocelynX-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.
- Clinical and Histologic Findings in ACTA1-Related Nemaline Myopathy: Case Series and Review of the Literature(2017) MORENO, Cristiane de Araujo Martins; NETO, Osorio Abath; DONKERVOORT, Sandra; HU, Ying; REED, Umbertina Conti; OLIVEIRA, Acary Sousa Bulle; BONNEMANN, Carsten; ZANOTELI, EdmarBACKGROUND: Nemaline myopathy is a rare congenital disease of skeletal muscle characterized by muscle weakness and hypotonia, as well as the diagnostic presence of nemaline rods in skeletal muscle fibers. Nemaline myopathy is genetically and phenotypically heterogeneous and, so far, mutations in 11 different genes have been associated with this disease. Dominant mutations in ACTA1 are the second most frequent genetic cause of nemaline myopathy and can lead to a variety of clinical and histologic phenotypes. PATIENTS AND METHODS: We present a series of ACTA1-related cases from a Brazilian cohort of 23 patients with nemaline myopathy, diagnosed after Sanger sequencing the entire coding region of ACTA1, and review the literature on ACTA1-related nemaline myopathy. RESULTS: The study confirmed ACTAI mutations in four patients, including one with intranuclear rods, one with large intracytoplasmic aggregates, and two with nemaline intracytoplasmic rods. A repeat muscle biopsy in one patient did not show histological progression. CONCLUSION: Despite the recognized phenotypic variability in ACTA1-related nemaline myopathy, clinical and histological presentations appear to correlate with the position of the mutation, which confirms emerging genotype/phenotype correlations and better predict the prognosis of affected patients.
- Integrative Data Mining Highlights Candidate Genes for Monogenic Myopathies(2014) NETO, Osorio Abath; TASSY, Olivier; BIANCALANA, Valerie; ZANOTELI, Edmar; POURQUIE, Olivier; LAPORTE, JocelynInherited myopathies are a heterogeneous group of disabling disorders with still barely understood pathological mechanisms. Around 40% of afflicted patients remain without a molecular diagnosis after exclusion of known genes. The advent of high-throughput sequencing has opened avenues to the discovery of new implicated genes, but a working list of prioritized candidate genes is necessary to deal with the complexity of analyzing large-scale sequencing data. Here we used an integrative data mining strategy to analyze the genetic network linked to myopathies, derive specific signatures for inherited myopathy and related disorders, and identify and rank candidate genes for these groups. Training sets of genes were selected after literature review and used in Manteia, a public web-based data mining system, to extract disease group signatures in the form of enriched descriptor terms, which include functional annotation, human and mouse phenotypes, as well as biological pathways and protein interactions. These specific signatures were then used as an input to mine and rank candidate genes, followed by filtration against skeletal muscle expression and association with known diseases. Signatures and identified candidate genes highlight both potential common pathological mechanisms and allelic disease groups. Recent discoveries of gene associations to diseases, like B3GALNT2, GMPPB and B3GNT1 to congenital muscular dystrophies, were prioritized in the ranked lists, suggesting a posteriori validation of our approach and predictions. We show an example of how the ranked lists can be used to help analyze high-throughput sequencing data to identify candidate genes, and highlight the best candidate genes matching genomic regions linked to myopathies without known causative genes. This strategy can be automatized to generate fresh candidate gene lists, which help cope with database annotation updates as new knowledge is incorporated.
- A Study of a Cohort of X-Linked Myotubular Myopathy at the Clinical, Histologic, and Genetic Levels(2016) NETO, Osorio Abath; SILVA, Marina Rodrigues e; MARTINS, Cristiane de Araujo; OLIVEIRA, Acary de Souza Bulle; REED, Umbertina Conti; BIANCALANA, Valerie; PESQUERO, Joao Bosco; LAPORTE, Jocelyn; ZANOTELI, EdmarBACKGROUND: Myotubular myopathy is a rare X-linked congenital myopathy characterized by marked neonatal hypotonia and respiratory insufficiency, facial and ocular involvement, and muscle biopsy with prominent central nuclei in the majority of muscle fibers. It is caused by mutations in MTM1, which codes for the phosphoinositides phosphatase myotubularin. In this work, we established and detailed a new cohort of six patients at the clinical, histologic, and genetic levels. PATIENTS AND METHODS: Patients were recruited after screening 3065 muscle biopsy reports from two large biopsy banks in Sao Paulo, Brazil from the years 2008 to 2013, and from referrals to a neuromuscular outpatient clinic between 2011 and 2013. We reviewed biopsy slides, evaluated patients, and Sanger sequenced MTM1 in the families. RESULTS: All patients but one had classic phenotypes with a stable course after a severe onset. Two patients died suddenly from hypovolemic shock. Muscle biopsies had been performed in five patients, all of whom showed a classic pattern with a predominance of centrally located nuclei and increased oxidative activity in the center of the fibers. Two patients showed necklace fibers, and two families had novel truncating mutations in MTM1. CONCLUSIONS: X-linked myotubular myopathy is rare in the Brazilian population. Necklace fibers might be more prevalent in this condition than previously reported. Direct Sanger sequencing of MTM1 on clinical suspicion avoids the need of a muscle biopsy.
- DNM2 mutations in a cohort of sporadic patients with centronuclear myopathy(2015) NETO, Osorio Abath; MARTINS, Cristiane de Araujo; CARVALHO, Mary; CHADI, Gerson; SEITZ, Katia Werneck; OLIVEIRA, Acary Souza Bulle; REED, Umbertina Conti; LAPORTE, Jocelyn; ZANOTELI, EdmarCentronuclear myopathy (CNM) is a rare congenital muscle disease characterized by fibers with prominent centralized nuclei in muscle biopsies. The disease is clinically heterogeneous, ranging from severe neonatal hypotonic phenotypes to adult-onset mild muscle weakness, and can have multiple modes of inheritance in association with various genes, including MTM1, DNM2, BIN1 and RYR1. Here we analyzed 18 sporadic patients with clinical and histological diagnosis of CNM and sequenced the DNM2 gene, which codes for the dynamin 2 protein. We found DNM2 missense mutations in two patients, both in exon 8, one known (p.E368K) and one novel (p.F372C), which is found in a position of presumed pathogenicity and appeared de novo. The patients had similar phenotypes characterized by neonatal signs followed by improvement and late childhood reemergence of slowly progressive generalized muscle weakness, elongated face with ptosis and ophthalmoparesis, and histology showing fibers with radiating sarcoplasmic strands (RSS). These patients were the only ones in the series to present this histological marker, which together with previous reports in the literature suggest that, when RSS are present, direct sequencing of DNM2 mutation hot spot regions should be the first step in the molecular diagnosis of CNM, even in sporadic cases.
- Limb-girdle muscular dystrophy type 2A in Brazilian children(2015) ALBUQUERQUE, Marco Antonio Veloso de; NETO, Osorio Abath; SILVA, Francisco Marcos Alencar da; ZANOTELI, Edmar; REED, Umbertina ContiCalpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. Objective: To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method: We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results: All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion: In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder.