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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- Professor Luiz Alcides Manreza IN MEMORIAM(2012) BACHESCHI, Luiz Alberto; TARICCO, Mario Augusto; REED, Umbertina Conti
- Clinical Manifestation of Nebulin-Associated Nemaline Myopathy(2023) MORENO, Cristiane Araujo Martins; ARTILHEIRO, Mariana Cunha; FONSECA, Alulin Tacio Quadros Santos Monteiro; CAMELO, Clara Gontijo; MEDEIROS, Gisele Chagas de; SASSI, Fernanda Chiarion; ANDRADE, Claudia Regina Furquim de; DONKERVOORT, Sandra; SILVA, Andre Macedo Serafim; DALFIOR-JUNIOR, Luiz; ABATH-NETO, Osorio Lopes; REED, Umbertina Conti; BOENNEMANN, Carsten; ZANOTELI, EdmarBackground and ObjectivesNemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar involvement. There is currently not enough data regarding the progression of the disease. In this study, we present a genotypic and phenotypic spectrum of 33 patients with NM caused by NEB variants (NM-NEB) classified according to age groups and the use of ventilatory support. We focused on interventional support, genotype-phenotype correlation, and association between respiratory, bulbar, and motor systems in groups of patients stratified by age and by the use of ventilatory support (VS). MethodsClinical and genetic data from patients with NM-NEB followed up in one specialized center were collected through regular consultations. Patients were evaluated regarding motor, bulbar, and respiratory functions. ResultsThirty-three patients with NM-NEB were evaluated consisting of 15 females and 18 males with an average age of 18 (+/- 12) years and a median of 17 (+/- 11) years. 32% of patients with NM-NEB used a G tube, 35% were not able to walk without support, and 55% needed VS. Scoliosis and dysphagia were more common among patients who used VS. Described for the first time, half of the patients presented tongue atrophy in a triple furrow pattern, and the presence of the atrophy was associated with dysphagia. Comparing the patients grouped by age, we found that, proportionally, older patients had more scoliosis and respiratory dysfunction than younger groups, suggesting the progression of the disease in these domains. In addition to that, we showed that VS use was associated with scoliosis and dysphagia. DiscussionNM-NEB is a very debilitating disease. There is an association between scoliosis and respiratory dysfunction while patients using VS have more often scoliosis than the no-VS group. Triple furrow tongue atrophy is a novel and frequent finding, which is directly associated with dysphagia. Grouping patients by age suggested disease stability in motor and swallow function, but a progression in respiratory dysfunction and skeletal deformities. All observations are relevant in the management care of patients with NM.
- Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy(2014) MARQUES, Tanyse Bahia Carvalho; NEVES, Juliana de Carvalho; PORTES, Leslie Andrews; SALGE, Joao Marcos; ZANOTELI, Edmar; REED, Umbertina ContiObjective: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. Methods: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. Results: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. Conclusions: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis.
- Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid(2011) DARBAR, Illora A.; PLAGGERT, Paulo G.; RESENDE, Maria Bernadete D.; ZANOTELI, Edmar; REED, Umbertina C.Background: Spinal muscular atrophy (SMA) is an autosomal recessive disorder that affects the motoneurons of the spinal anterior horn, resulting in hypotonia and muscle weakness. The disease is caused by deletion or mutation in the telomeric copy of SMN gene (SMN1) and clinical severity is in part determined by the copy number of the centromeric copy of the SMN gene (SMN2). The SMN2 mRNA lacks exon 7, resulting in a production of lower amounts of the full-length SMN protein. Knowledge of the molecular mechanism of diseases has led to the discovery of drugs capable of increasing SMN protein level through activation of SMN2 gene. One of these drugs is the valproic acid (VPA), a histone deacetylase inhibitor. Methods: Twenty-two patients with type II and III SMA, aged between 2 and 18 years, were treated with VPA and were evaluated five times during a one-year period using the Manual Muscle Test (Medical Research Council scale-MRC), the Hammersmith Functional Motor Scale (HFMS), and the Barthel Index. Results: After 12 months of therapy, the patients did not gain muscle strength. The group of children with SMA type II presented a significant gain in HFMS scores during the treatment. This improvement was not observed in the group of type III patients. The analysis of the HFMS scores during the treatment period in the groups of patients younger and older than 6 years of age did not show any significant result. There was an improvement of the daily activities at the end of the VPA treatment period. Conclusion: Treatment of SMA patients with VPA may be a potential alternative to alleviate the progression of the disease.
- Nemaline Myopathy in Brazilian Patients: Molecular and Clinical Characterization(2022) GURGEL-GIANNETTI, Juliana; SOUZA, Lucas Santos; YAMAMOTO, Guilherme L.; BELISARIO, Marina; LAZAR, Monize; CAMPOS, Wilson; PAVANELLO, Rita de Cassia M.; ZATZ, Mayana; REED, Umbertina; ZANOTELI, Edmar; OLIVEIRA, Acary Bulle; LEHTOKARI, Vilma-Lotta; CASELLA, Erasmo B.; MACHADO-COSTA, Marcela C.; WALLGREN-PETTERSSON, Carina; LAING, Nigel G.; NIGRO, Vincenzo; VAINZOF, MarizNemaline 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.
- Combining neuropsychological tests to improve the assessment of arithmetic difficulties in children with ADHD(2020) REZENDE, Angelo R. T.; PACHECO, Sandra P.; BRANCO, Sulamy C. C.; FERNANDES, Rosangela D. C.; BOLDRINI, Carla R.; DORIA FILHO, Ulysses; BAZAN, Paulo R.; AMARO JUNIOR, Edson; REED, Umbertina Conti; CASELLA, Erasmo BarbanteObjective: To compare the ways of evaluating arithmetic skills in Brazilian children with ADHD by combining three validated neuropsychological tests and determining whether they are sensitive to the methylphenidate treatment. Methods: Forty-two children (9-12 years old) participated in the present study: 20 were children with ADHD (DSM-IV) and 22 were age-matched controls. A classification criterion was used for each test separately and one,fortheir combination to detect the presence of arithmetic difficulties at two time points: baseline (time 1); and when children with ADHD were taking 0.3-0.5 mg/kg of methylphenidate (time 2). The study also assessed children's subtraction performance, combining parts of these tests. Results: Separately, the tests were only sensitive to differences between groups without medication. However, by combining the three neuropsychological tests, we observed a difference and detected a reduction in arithmetic difficulties associated with the methylphenidate treatment. The same effects were found in subtraction exercises, which require a borrowing procedure. Conclusions: The present study detected arithmetic difficulties in Brazilian children with ADHD and the effects of methylphenidate. Given this improvement in sensitivity, combining tests could be a promising alternative when working with limited samples.
- Mutations in INPPSK, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment(2017) WIESSNER, Manuela; ROOS, Andreas; MUNN, Christopher J.; VISWANATHAN, Ranjith; WHYTE, Tamieka; COX, Dan; SCHOSER, Benedikt; SEWRY, Caroline; ROPER, Helen; PHADKE, Rahul; BETTOLO, Chiara Marini; BARRESI, Rita; CHARLTON, Richard; BONNEMANN, Carsten G.; NETO, Osorio Abath; REED, Umbertina C.; ZANOTELI, Edmar; MORENO, Cristiane Araujo Martins; ERTL-WAGNER, Birgit; STUCKA, Rolf; GOEDE, Christian De; SILVA, Tamiris Borges da; HATHAZI, Denisa; DELL'AICA, Margherita; ZAHEDI, Rene P.; THIELE, Simone; MULLER, Juliane; KINGSTON, Helen; MUELLER, Susanna; CURTIS, Elizabeth; WALTER, Maggie C.; STROM, Tim M.; STRAUB, Volker; BUSHBY, Kate; MUNTONI, Francesco; SWAN, Laura E.; LOCHMULLER, Hanns; SENDEREK, JanPhosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Down regulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.
- Therapeutic advances in 5q-linked spinal muscular atrophy(2018) REED, Umbertina Conti; ZANOTELI, EdmarSpinal muscular atrophy (SMA) is a severe and clinically-heterogeneous motor neuron disease caused, in most cases, by a homozygous mutation in the SMN1 gene. Regarding the age of onset and motor involvement, at least four distinct clinical phenotypes have been recognized. This clinical variability is, in part, related to the SMN2 copy number. By now, only supportive therapies have been available. However, promising specific therapies are currently being developed based on different mechanisms to increase the level of SMN protein; in particular, intrathecal antisense oligonucleotides that prevent the skipping of exon 7 during SMN2 transcription, and intravenous SMN1 insertion using viral vector. These therapeutic perspectives open a new era in the natural history of the disease. In this review, we intend to discuss the most recent and promising therapeutic strategies, with special consideration to the pathogenesis of the disease and the mechanisms of action of such therapies.
- Attention deficit disorder/hyperactivity: a scientific overview(2012) POLANCZYK, Guilherme V.; CASELLA, Erasmo Barbante; MIGUEL, Euripedes Constantino; REED, Umbertina Conti
- 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.