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
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- 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.
- 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.
- 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.