UMBERTINA CONTI REED
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina - Docente
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject PROPOSING OF A LESS COSTLY STRATEGY FOR MOLECULAR DIAGNOSIS OF CONGENITAL MYASTHENIC SYNDROME IN BRAZIL.(2018) ESTEPHAN, E. P.; SILVA, M. A. S.; ZAMBON, A. A.; REED, U. C.; TOPF, A.; LOCHMUELLER, H.; ZANOTELI, E.- 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.
- Severe brain involvement in 5q spinal muscular atrophy type 0(2019) MENDONCA, Rodrigo H.; ROCHA, Antonio J.; LOZANO-ARANGO, Andres; DIAZ, Astry B.; CASTIGLIONI, Claudia; SILVA, Andre M. S.; REED, Umbertina C.; KULIKOWSKI, Leslie; PARAMONOV, Ida; CUSCO, Ivon; TIZZANO, Eduardo F.; ZANOTELI, EdmarSpinal muscular atrophy (SMA) type 0 is the most severe form of SMA, associated with the SMN1 gene and manifesting at birth. Most patients die in the first weeks of life. In this work, we present 3 patients with SMA type 0 who survived >1 year and presented diffuse and progressive brain abnormalities on magnetic resonance imaging, which are not usually seen in patients with SMA. Thus, severe brain involvement may likely be the full end manifestation of an already extreme SMA phenotype caused by substantial reduction of the SMN protein in the brain. ANN NEUROL 2019
- 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, EdmarDesmin (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.
- CLINICAL AND IMAGING HALLMARKS OF THE MYH7-RELATED MYOPATHY WITH SEVERE AXIAL INVOLVEMENT(2018) DABAJ, Ivana; CARLIER, Robert Y.; GOMEZ-ANDRES, David; NETO, Osorio Abath; BERTINI, Enrico; D'AMICO, Adele; FATTORI, Fabiana; PEREON, Yann; CASTIGLIONI, Claudia; RODILLO, Eliana; CATTERUCCIA, Michela; GUIMARAES, Julio Brandao; OLIVEIRA, Acary Souza Bulle; REED, Umbertina Conti; MESROB, Lilia; LECHNER, Doris; BOLAND, Anne; DELEUZE, Jean-Francois; MALFATTI, Edoardo; BONNEMANN, Carsten; LAPORTE, Jocelyn; ROMERO, Norma; FELTER, Adrien; QUIJANO-ROY, Susana; MORENO, Cristiane Araujo Martins; ZANOTELI, EdmarIntroduction: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. Methods: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. Results: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration (""inverted-collagen-VI sign"") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. Discussion: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7-related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes.
- Reply to ""Global Central Nervous System Atrophy in Spinal Muscular Atrophy Type 0""(2019) MENDONCA, Rodrigo H.; ROCHA, Antonio J.; LOZANO-ARANGO, Andres; DIAZ, Astry B.; CASTIGLIONI, Claudia; SILVA, Andre M. S.; REED, Umbertina C.; KULIKOWSKI, Leslie; PARAMONOV, Ida; CUSCO, Ivon; TIZZANO, Eduardo F.; ZANOTELI, Edmar
- Congenital myasthenic syndrome: Correlation between clinical features and molecular diagnosis(2022) ESTEPHAN, Eduardo P.; ZAMBON, Antonio A.; THOMPSON, Rachel; POLAVARAPU, Kiran; JOMAA, Danny; TOPF, Ana; HELITO, Paulo V. P.; HEISE, Carlos O.; MORENO, Cristiane A. M.; SILVA, Andre M. S.; KOUYOUMDJIAN, Joao A.; MORITA, Maria da Penha; REED, Umbertina C.; LOCHMULLER, Hanns; ZANOTELI, EdmarObjectives To present phenotype features of a large cohort of congenital myasthenic syndromes (CMS) and correlate them with their molecular diagnosis. Methods Suspected CMS patients were divided into three groups: group A (limb, bulbar or axial weakness, with or without ocular impairment, and all the following: clinical fatigability, electrophysiology compatible with neuromuscular junction involvement and anticholinesterase agents response), group B (limb, bulbar or axial weakness, with or without ocular impairment, and at least one of additional characteristics noted in group A) and group C (pure ocular syndrome). Individual clinical findings and the clinical groups were compared between the group with a confirmed molecular diagnosis of CMS and the group without molecular diagnosis or with a non-CMS molecular diagnosis. Results Seventy-nine patients (68 families) were included in the cohort: 48 in group A, 23 in group B and 8 in group C. Fifty-one were considered confirmed CMS (30 CHRNE, 5 RAPSN, 4 COL13A1, 3 DOK7, 3 COLQ, 2 GFPT1, 1 CHAT, 1 SCN4A, 1 GMPPB, 1 CHRNA1), 7 probable CMS, 5 non-CMS and 16 unsolved. The chance of a confirmed molecular diagnosis of CMS was significantly higher for group A and lower for group C. Some individual clinical features, alterations on biopsy and electrophysiology enhanced specificity for CMS. Muscle imaging showed at least mild alterations in the majority of confirmed cases, with preferential involvement of soleus, especially in CHRNE CMS. Conclusions Stricter clinical criteria increase the chance of confirming a CMS diagnosis, but may lose sensitivity, especially for some specific genes.
- Severe axial muscular involvement in Laing distal myopathy with a thumbprint finding on MRI(2016) DABAJ, I.; MORENO, C. Araujo Martins; ABATH NETO, O.; BERTINI, E.; CASTIGLIONI, C.; GUIMARAES, J. Brandao; REED, U. Conti; MESROB, L.; LECHNER, D.; FIORILLO, C.; MALFATI, E.; BOLAND, A.; DELEUZE, J.; BONNEMANN, C.; LAPORTE, J.; ROMERO, N.; GOMEZ, D.; QUIJANO-ROY, S.; CARLIER, R.; ZANOTELI, E.