EDUARDO DE PAULA ESTEPHAN
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
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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conferenceObject SENSITIVITY OF NEUROPHYSIOLOGIC TESTS REGARDING THE NEUROMUSCULAR JUNCTION IN PATIENTS WITH CONGENITAL MYASTHENIC SYNDROMES(2019) CALDAS, Vitor Marques; ESTEPHAN, Eduardo de Paula; SILVA, Andre Macedo Serafim da; MENDONCA, Rodrigo de Holanda; HEISE, Carlos Otto; ZANOTELI, Edmar- 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, DavidNext 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.
- Increasing phenotypic annotation improves the diagnostic rate of exome sequencing in a rare neuromuscular disorder(2019) THOMPSON, Rachel; NTALIS, Anastasios Papakonstantinou; BELTRAN, Sergi; TOPF, Ana; ESTEPHAN, Eduardo de Paula; POLAVARAPU, Kiran; HOEN, Peter A. C't; MISSIER, Paolo; LOCHMULLER, HannsPhenotype-based filtering and prioritization contribute to the interpretation of genetic variants detected in exome sequencing. However, it is currently unclear how extensive this phenotypic annotation should be. In this study, we compare methods for incorporating phenotype into the interpretation process and assess the extent to which phenotypic annotation aids prioritization of the correct variant. Using a cohort of 29 patients with congenital myasthenic syndromes with causative variants in known or newly discovered disease genes, exome data and the Human Phenotype Ontology (HPO)-coded phenotypic profiles, we show that gene-list filters created from phenotypic annotations perform similarly to curated disease-gene virtual panels. We use Exomiser, a prioritization tool incorporating phenotypic comparisons, to rank candidate variants while varying phenotypic annotation. Analyzing 3,712 combinations, we show that increasing phenotypic annotation improved prioritization of the causative variant, from 62% ranked first on variant alone to 90% with seven HPO annotations. We conclude that any HPO-based phenotypic annotation aids variant discovery and that annotation with over five terms is recommended in our context. Although focused on a constrained cohort, this provides real-world validation of the utility of phenotypic annotation for variant prioritization. Further research is needed to extend this concept to other diseases and more diverse cohorts.
conferenceObject Concentric Needle Voluntary Jitter Assessment in Patients with Mitochondrial Myopathy(2019) CALDAS, Vitor Marques; ESTEPHAN, Eduardo de Paula; SILVA, Andre Macedo Serafim da; MENDONCA, Rodrigo de Holanda; CARVALHO, Mary Souza de; HEISE, Carlos Otto; ZANOTELLI, EdmarconferenceObject CLINICAL AND MOLECULAR SPECTRUM OF MYOFIBRILLAR MYOPATHY IN A BRAZILIAN COHORT(2019) SILVA, A. M. S.; MENDONCA, R. H.; CAMELO, C. G.; ESTEPHAN, E. P.; MORENO, C. A. M.; CARVALHO, M. S.; NASCIMENTO, A. M.; KULIKOWSKI, L. D.; DIAS, A. T.; OLIVEIRA, A. S. B.; REED, U. C.; ZANOTELI, E.- Clinical and molecular findings in a cohort of ANO5-related myopathy(2019) SILVA, Andre M. S.; COIMBRA-NETO, Antonio R.; SOUZA, Paulo Victor S.; WINCKLER, Pablo B.; GONCALVES, Marcus V. M.; CAVALCANTI, Eduardo B. U.; CARVALHO, Alzira A. D. S.; SOBREIRE, Claudia F. D. R.; CAMELO, Clara G.; MENDONCA, Rodrigo D. H.; ESTEPHAN, Eduardo D. P.; REED, Umbertina C.; MACHADO-COSTA, Marcela C.; DOURADO-JUNIOR, Mario E. T.; PEREIRA, Vanessa C.; CRUZEIRO, Marcelo M.; HELITO, Paulo V. P.; AIVAZOGLOU, Lais U.; CAMARGO, Leonardo V. D.; GOMES, Hudson H.; CAMARGO, Amaro J. S. D.; PINTO, Wladimir B. V. D. R.; BADIA, Bruno M. L.; LIBARDI, Luiz H.; YANAGIURA, Mario T.; OLIVEIRA, Acary S. B.; NUCCI, Anamarli; SAUTE, Jonas A. M.; FRANCA-JUNIOR, Marcondes C.; ZANOTELI, EdmarObjective ANO5-related myopathy is an important cause of limb-girdle muscular dystrophy (LGMD) and hyperCKemia. The main descriptions have emerged from European cohorts, and the burden of the disease worldwide is unclear. We provide a detailed characterization of a large Brazilian cohort of ANO5 patients. Methods A national cross-sectional study was conducted to describe clinical, histopathological, radiological, and molecular features of patients carrying recessive variants in ANO5. Correlation of clinical and genetic characteristics with different phenotypes was studied. Results Thirty-seven patients from 34 nonrelated families with recessive mutations of ANO5 were identified. The most common phenotype was LGMD, observed in 25 (67.5%) patients, followed by pseudometabolic presentation in 7 (18.9%) patients, isolated asymptomatic hyperCKemia in 4 (10.8%) patients, and distal myopathy in a single patient. Nine patients presented axial involvement, including one patient with isolated axial weakness. The most affected muscles according to MRI were the semimembranosus and gastrocnemius, but paraspinal and abdominal muscles, when studied, were involved in most patients. Fourteen variants in ANO5 were identified, and the c.191dupA was present in 19 (56%) families. Sex, years of disease, and the presence of loss-of-function variants were not associated with specific phenotypes. Interpretation We present the largest series of anoctaminopathy outside Europe. The most common European founder mutation c.191dupA was very frequent in our population. Gender, disease duration, and genotype did not determine the phenotype.