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
3 resultados
Resultados de Busca
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- A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome(2018) ESTEPHAN, Eduardo de Paula; SOBREIRA, Claudia Ferreira da Rosa; SANTOS, Andre Cleriston Jose dos; TOMASELLI, Pedro Jose; MARQUES JR., Wilson; ORTEGA, Roberta Paiva Magalhes; COSTA, Marcela Camara Machado; SILVA, Andre Macedo Serafim da; MENDONCA, Rodrigo Holanda; CALDAS, Vitor Marques; ZAMBON, Antonio Alberto; ABATH NETO, Osorio; MARCHIORI, Paulo Euripedes; HEISE, Carlos Otto; REED, Umbertina Conti; AZUMA, Yoshiteru; TOPF, Ana; LOCHMULLER, Hanns; ZANOTELI, EdmarThe most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.
- 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.
- STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility(2018) ZAHARIEVA, Irina T.; SARKOZY, Anna; MUNOT, Pinki; MANZUR, Adnan; O'GRADY, Gina; RENDU, John; MALFATTI, Eduardo; AMTHOR, Helge; SERVAIS, Laurent; URTIZBEREA, J. Andoni; ABATH NETO, Osorio; ZANOTELI, Edmar; DONKERVOORT, Sandra; TAYLOR, Juliet; DIXON, Joanne; POKE, Gemma; FOLEY, A. Reghan; HOLMES, Chris; WILLIAMS, Glyn; HOLDER, Muriel; YUM, Sabrina; MEDNE, Livija; QUIJANO-ROY, Susana; ROMERO, Norma B.; FAURE, Julien; FENG, Lucy; BASTAKI, Laila; DAVIS, Mark R.; PHADKE, Rahul; SEWRY, Caroline A.; BONNEMANN, Carsten G.; JUNGBLUTH, Heinz; BACHMANN, Christoph; TREVES, Susan; MUNTONI, FrancescoSH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with Ca(V)1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca(V)1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of Ca(V)1.1 sarcolemma mislocalization or impaired STAC3-Ca(V)1.1 interaction.