EDUARDO DE PAULA ESTEPHAN

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina

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Autor: REED, Umbertina Conti ×

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  • article 28 Citação(ões) na Scopus
    The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations
    (2019) CRUZ, Pedro M. Rodriguez; COSSINS, Judith; ESTEPHAN, Eduardo de Paula; MUNELL, Francina; SELBY, Kathryn; HIRANO, Michio; MAROOFIN, Reza; MEHRJARDI, Mohammad Yahya Vahidi; CHOW, Gabriel; CARR, Aisling; MANZUR, Adnan; ROBB, Stephanie; MUNOT, Pinki; LIU, Wei Wei; BANKA, Siddharth; FRASER, Harry; GOEDE, Christian De; ZANOTELI, Edmar; REED, Umbertina Conti; SAGE, Abigail; GRATACOS, Margarida; MACAYA, Alfons; DUSL, Marina; SENDEREK, Jan; TOPF, Ana; HOFER, Monika; KNIGHT, Ravi; RAMDAS, Sithara; JAYAWANT, Sandeep; LOCHMUELLER, Hans; PALACE, Jacqueline; BEESON, David
    Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.
  • article 6 Citação(ões) na Scopus
    Congenital fiber type disproportion caused by TPM3 mutation: A report of two atypical cases
    (2020) MORENO, Cristiane Araujo Martins; ESTEPHAN, Eduardo de Paula; FAPPI, Alan; MONGES, Soledad; LUBIENIECKI, Fabiana; ABATH NETO, Osorio Lopes; REED, Umbertina Conti; DONKERVOORT, Sandra; HARMS, Matthew B.; BONNEMANN, Carsten; ZANOTELI, Edmar
    Congenital fiber type disproportion (CFTD) is a rare congenital myopathy subtype defined by slow type 1 hypotrophy in the absence of any other major structural findings such as rods, central nuclei or cores. Dominant missense changes in slow alpha-tropomyosin coded by TPM3 gene are the main cause of the CFTD. There are only a few reports of recessive loss-of-function mutations in TPM3 causing severe Nemaline Myopathy and CFTD. We present two patients harboring TPM3 mutations. The first is a novel homozygous missense variant with a mild CFTD clinical phenotype inherited in a recessive fashion. The second is a previously reported heterozygous mutation presenting within pronounced early axial involvement and dropped head. This report expands the genotype-phenotype correlation in the TPM3 myopathy showing a recessive mutation causing a mild clinical phenotype and also shows that TPM3 mutations should be part of the investigation in patients with dropped head.
  • article 2 Citação(ões) na Scopus
    Effect of the COVID-19 pandemic on patients with inherited neuromuscular disorders
    (2022) MORENO, Cristiane Araujo Martins; CAMELO, Clara Gontijo; SAMPAIO, Pedro Henrique Marte de Arruda; FONSECA, Alulin Tacio Quadros Santos Monteiro; ESTEPHAN, Eduardo de Paula; SILVA, Andre Macedo Serafim; PIROLA, Renann Nunes; SILVA, Luiz Henrique Libardi; LIMA, Karlla Danielle Ferreira; ALBUQUERQUE, Marco Antonio Veloso de; CAMELO FILHO, Antonio Edvan; MARQUES, Marcos Vinicius Oliveira; YANAGIURA, Mario Teruo; CAVALCANTE, Wagner Cid Palmeira; MATSUI JUNIOR, Ciro; ISIHI, Lucas Michielon de Augusto; MENDONCA, Rodrigo Holanda; POUZA, Ana Flavia Pincerno; CARVALHO, Mary Souza de; REED, Umbertina Conti; ZANOTELI, Edmar
    Background: The COVID-19 pandemic has brought substantial challenges for current practices in treating hereditary neuromuscular disorders (hNMDs). However, this infection has not been the only concern for these patients. Social distancing has compromised multidisciplinary assistance and physical activity, and has brought about several mental health issues. We presented a follow-up on 363 patients with hNMDs at a Brazilian tertiary center during the peak of the COVID-19 pandemic. Objective: We aimed to show the frequency and severity of SARS-CoV-2 infection among hNMD patients and to demonstrate the effects of the pandemic on life habits, disease progression and multidisciplinary supportive care status. Methods:Three hundred and sixty-three patients (58% male and 42% female) were followed for three months through three teleconsultations during the peak of the COVID-19 pandemic in Brazil. Results: There were decreases in the numbers of patients who underwent physical, respiratory and speech therapies. For several patients, their appetite (33%) and sleep habits (25%) changed. Physical exercises and therapies were interrupted for most of the patients. They reported new onset/worsening of fatigue (17%), pain (17%), contractions (14%) and scoliosis (7%). Irritability and sleep, weight and appetite changes, and especially diminished appetite and weight loss, were more frequent in the group that reported disease worsening. There was a low COVID-19 contamination rate (0.8%), and all infected patients had a mild presentation. Conclusion: The isolation by itself was protective from a COVID-19 infection perspective. However, this isolation might also trigger a complex scenario with life habit changes that are associated with an unfavorable course for the NMD.
  • article 15 Citação(ões) na Scopus
    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, Edmar
    The 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.
  • article 2 Citação(ões) na Scopus
    The Location of Disease-Causing DES Variants Determines the Severity of Phenotype and the Morphology of Sarcoplasmic Aggregates
    (2022) SILVA, Andre Macedo Serafim; RODRIGO, Patricia; MORENO, Cristiane Araujo Martins; MENDONCA, Rodrigo de Holanda; ESTEPHAN, Eduardo de Paula; CAMELO, Clara Gontijo; CAMPOS, Eliene Dutra; DIAS, Alexandre Torchio; NASCIMENTO, Amom Mendes; KULIKOWSKI, Leslie Domenici; OLIVEIRA, Acary Souza Bulle; REED, Umbertina Conti; GOLDFARB, Lev G.; OLIVE, Montse; ZANOTELI, Edmar
    Desmin (DES) is the main intermediate muscle filament that connects myofibrils individually and with the nucleus, sarcolemma, and organelles. Pathogenic variants of DES cause desminopathy, a disorder affecting the heart and skeletal muscles. We aimed to analyze the clinical features, morphology, and distribution of desmin aggregates in skeletal muscle biopsies of patients with desminopathy and to correlate these findings with the type and location of disease-causing DES variants. This retrospective study included 30 patients from 20 families with molecularly confirmed desminopathy from 2 neuromuscular referral centers. We identified 2 distinct patterns of desmin aggregates: well-demarcated subsarcolemmal aggregates and diffuse aggregates with poorly delimited borders. Pathogenic variants located in the 1B segment and the tail domain of the desmin molecule are more likely to present with early-onset cardiomyopathy compared to patients with variants in other segments. All patients with mutations in the 1B segment had well-demarcated subsarcolemmal aggregates, but none of the patients with variants in other desmin segments showed such histological features. We suggest that variants located in the 1B segment lead to well-shaped subsarcolemmal desmin aggregation and cause disease with more frequent cardiac manifestations. These findings will facilitate early identification of patients with potentially severe cardiac syndromes.
  • article 11 Citação(ões) na Scopus
    Clinical variability of early-onset congenital myasthenic syndrome due to biallelic RAPSN mutations in Brazil
    (2018) ESTEPHAN, Eduardo de Paula; ZAMBON, Antonio Alberto; MARCHIORI, Paulo Euripedes; SILVA, Andre Macedo Serafim da; CALDAS, Vitor Marques; MORENO, Cristiane Araujo Martins; REED, Umbertina Conti; HORVATH, Rita; TOPF, Ana; LOCHMUELLER, Hanns; ZANOTELI, Edmar
    Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN earlyonset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G > A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN earlyonset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in nonEuropean countries.
  • article 8 Citação(ões) na Scopus
    Nonlethal CHRNA1-Related Congenital Myasthenic Syndrome with a Homozygous Null Mutation
    (2017) ABATH NETO, Osorio; HEISE, Carlos Otto; MORENO, Cristiane de Araujo Martins; ESTEPHAN, Eduardo de Paula; MESROB, Lilia; LECHNER, Doris; BOLAND, Anne; DELEUZE, Jean-Francois; OLIVEIRA, Acary Souza Bulle; REED, Umbertina Conti; BIANCALANA, Valerie; LAPORTE, Jocelyn; ZANOTELI, Edmar