Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization

Nemaline 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

Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization

Nemaline 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

Mau desempenho escolar: uma visão atual

Este estudo tem como objetivo uma revisão atualizada sobre o tema de mau desempenho escolar para profissionais da área de saúde e educação. Aborda aspectos atuais da educação, de aprendizagem e das principais condições envolvidas em mau desempenho escolar. Apresenta dados atualizados sobre os principais aspectos da neurobiologia, epidemiologia, etiologia, quadro clínico, comorbidades, diagnóstico, intervenção precoce e tratamento das principais patologias envolvidas. Trata-se de uma revisão abrangente, não sistemática da literatura sobre aprendizagem, desempenho escolar, transtorno de aprendizagem (dislexia, discalculia e disgrafia), transtorno de déficit de atenção/hiperatividade (TDA/H) e transtorno de desenvolvimento de coordenação (TDC). O mau desempenho escolar é um sintoma frequente em nossas crianças com graves repercussões emocionais, sociais e econômicas. Uma visão atualizada do tema facilita o raciocínio clínico, o diagnóstico correto e o tratamento adequado

Mitochondrial cardioencephalomyopathy due to a novel SCO2 mutation in a Brazilian patient: case report and literature review

Submitted by Nuzia Santos ([email protected]) on 2019-06-19T15:55:54Z No. of bitstreams: 1 Mitochondrial Cardioencephalomyopathy.pdf: 479414 bytes, checksum: 597b5f7fb79cf70e2eec80ce570bde7a (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2019-06-19T16:00:58Z (GMT) No. of bitstreams: 1 Mitochondrial Cardioencephalomyopathy.pdf: 479414 bytes, checksum: 597b5f7fb79cf70e2eec80ce570bde7a (MD5)Made available in DSpace on 2019-06-19T16:00:58Z (GMT). No. of bitstreams: 1 Mitochondrial Cardioencephalomyopathy.pdf: 479414 bytes, checksum: 597b5f7fb79cf70e2eec80ce570bde7a (MD5) Previous issue date: 2013Universidade Federal de Minas Gerais. Faculdade de Medicina. Departamento de Pediatrica. Serviço de Neurologia Pediatrica. Belo Horizonte, MG, BrasilFundação Oswaldo Cruz. Instituto Rene Rachou. Belo Horizonte, MG, BrasilUniversidade Federal de Minas Gerais. Faculdade de Medicina. Belo Horizonte, MG, BrasilUniversidade de São Paulo. Centro de Estudos do Genoma Humano. São Paulo, SP, BrasilUniversidade de São Paulo. Centro de Estudos do Genoma Humano. São Paulo, SP, BrasilDepartment of Neurology. Columbia University Medical Center. New York, New YorkOBJECTIVES: To review all patients with SCO2 mutations and to describe a Brazilian patient with cardioencephalomyopathy carrying compound heterozygous mutations in SCO2, one being the known pathogenic p.E140K mutation and the other a novel 12-base pair (bp) deletion at nucleotides 1519 through 1530 (c.1519_1530del). DESIGN: Case report and literature review. SETTING: University hospital. PATIENT: Infant girl presenting with an encephalomyopathy, inspiratory stridor, ventilator failure, progressive hypotonia, and weakness, leading to death. MAIN OUTCOME MEASURES: Clinical features, neuroimaging findings, muscle biopsy with histochemical analysis, and genetic studies. RESULTS: This infant girl was the first child of healthy, nonconsanguineous parents. She developed progressive muscular hypotonia and ventilatory failure. At the end of the first month of life, she developed cardiomegaly and signs of cardiac failure. Routine blood tests showed lactic acidosis and mild elevation of the creatine kinase level. Brain magnetic resonance imaging showed increased T2 and fluid-attenuated inversion recovery signals in the putamen bilaterally. Nerve conduction studies showed severe axonal sensorimotor neuropathy. Muscle biopsy revealed a neurogenic pattern with mitochondrial proliferation and total absence of cytochrome- c oxidase histochemical stain. Sequencing of SCO2 showed that the patient had compound heterozygote SCO2 mutations: the previously described c.1541G>A (p.E140K) mutation and a novel 12-bp deletion at nucleotides 1519 through 1530 (c.1519_1530del). The patient died at age 45 days. CONCLUSIONS: Our findings and the literature review indicate that it is important to consider the diagnosis of mitochondrial disease in newborns with hypotonia and cardiomyopathy. In our case, the accurate diagnosis of SCO2 mutations is particularly important for genetic counseling

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil

ABSTRACT Objective The aim of this study was to translate and adapt the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to Portuguese for use in Brazil. Methods The scale was applied in 20 pediatric patients with mitochondrial disease, in three groups: myopathy (n = 4); Leigh syndrome (n = 8); and encephalomyopathy (n = 8). Scores were obtained for the various dimensions of the NPMDS, and comparisons were drawn between the groups. Results There was a statistically significant difference between the myopathy group and the Leigh syndrome group (p = 0.0085), as well as between the myopathy and encephalomyopathy groups (p = 0.01). Conclusions The translation of the NPMDS, and its adaptation to the socioeconomic and cultural conditions in Brazil, make the NPMDS score useful as an additional parameter in the evaluation and monitoring of pediatric patients with MD in Brazil

Case report Necklace fibers as histopathological marker in a patient with severe form of X-linked myotubular myopathy

Abstract X-linked myotubular myopathy due to mutations in the MTM1 gene is classically characterized by a severe neonatal phenotype and a typical muscle biopsy presenting globular and centrally located nuclei in muscle myofibers. Recently, four patients with mild late-onset form have been described, a male with a hemizygous mutation and three females with heterozygous mutations in the MTM1 gene. The muscle biopsies were performed at 13-35 years of age and a new histological marker, the necklace fibers, was described. Here, we report two siblings with the pathogenic c.664 C > T mutation in the MTM1 gene, presenting a severe muscle weakness and respiratory impairment requiring ventilatory support since the first months of life until death, at the age of 36 months and 5 months. In the older brother the muscle biopsy, performed at the age of 30 months, showed almost 100% of necklace fibers, which were not present in the younger one submitted to muscle biopsy at 5 months of age. Our findings confirm the necklace fibers can be a histopathological finding of MTM1 myopathies, even in the severe neonatal form, and suggest that the necklace fibers appear or increase in number over time

Necklace fibers as histopathological marker in a patient with severe form of X-linked myotubular myopathy

X-linked myotubular myopathy due to mutations in the MTM1 gene is classically characterized by a severe neonatal phenotype and a typical muscle biopsy presenting globular and centrally located nuclei in muscle myofibers. Recently, four patients with mild late-onset form have been described, a male with a hemizygous mutation and three females with heterozygous mutations in the MTM1 gene. The muscle biopsies were performed at 13-35 years of age and a new histological marker, the necklace fibers, was described. Here, we report two siblings with the pathogenic c.664 C > T mutation in the MTM1 gene, presenting a severe muscle weakness and respiratory impairment requiring ventilatory support since the first months of life until death, at the age of 36 months and 5 months. In the older brother the muscle biopsy, performed at the age of 30 months, showed almost 100% of necklace fibers, which were not present in the younger one submitted to muscle biopsy at 5 months of age. Our findings confirm the necklace fibers can be a histopathological finding of MTM1 myopathies, even in the severe neonatal form, and suggest that the necklace fibers appear or increase in number over time. (C) 2012 Elsevier B.V. All rights reserved.Fapemig/Fapesp-CEPID/CNQpFapemig/FapespCEPID/CNQ

Central core disease due to recessive mutations in RYR1 gene: Is it more common than described?

Central core disease (CCD) is an autosomal-dominant congenital myopathy, with muscle weakness and malignant hyperthermia (MH) susceptibility. We identified two of nine Brazilian CCD families carrying two mutations in the RYR1 gene. the heterozygous parents were clinically asymptomatic, and patients were mildly affected, differing from the few autosomal-recessive cases described previously. Recessive inheritance in CCD may therefore be more common than previously appreciated, which has important implications for genetic counseling and MH prevention in affected families.Univ São Paulo, Dept Genet, Human Genome Res Ctr, IB, BR-05508900 São Paulo, BrazilSarah Network Rehabil Hosp, Dept Pathol, Dept Genet, Belo Horizonte, MG, BrazilSarah Network Rehabil Hosp, Neurophysiol Clin, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Dept Pathol, FMUSP, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Anesthesiol, São Paulo, BrazilUniv Fed Minas Gerais, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, Dept Pathol, FMUSP, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Anesthesiol, São Paulo, BrazilWeb of Scienc

Deletion of the RMGA and CHD2 genes in a child with epilepsy and mental deficiency

We describe a novel chromosome microdeletion at 15q26.1 detected by oligo-array-CGH in a 6-year-old girl presenting with global development delay, epilepsy, autistic behavior and facial dysmorphisms. Although these features are often present in Angelman syndrome, no alterations were present in the methylation pattern of the Prader-Willi-Angelman critical region. The deletion encompasses only 2 genes: CHD2, which is part of a gene family already involved in CHARGE syndrome, and RGMA which exerts a negative control on axon growth. Deletion of either or both genes could cause the phenotype of this patient. These results provide a further chromosome region requiring evaluation in patients presenting Angelman features. (C) 2011 Elsevier Masson SAS. All rights reserved.FAPESPFAPESP [98/14254-2, 2009/00898-1]CNPqCNP