Luís Negrão
Hospitais da Universidade de Coimbra
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Publication
Featured researches published by Luís Negrão.
Laboratory Investigation | 2004
Mónica Mendes Sousa; José Ferrão; Rui Fernandes; António Guimarães; José B Geraldes; Rui Perdigoto; Luís Tomé; Oscar Mota; Luís Negrão; Alexandre Linhares Furtado; Maria João Saraiva
Familial amyloid polyneuropathy (FAP) is characterized by deposition of mutated transthyretin (TTR) in the peripheral nervous system. Prior to amyloid fibrils, nonfibrillar TTR aggregates are deposited inducing oxidative stress with increased nitration (3-NT). As the major source of TTR is the liver, liver transplantation (LT) is used to halt FAP. Given the shortage of liver donors, domino LT (DLT) using FAP livers is performed. The correlation between TTR deposition in the skin and nerve was tested in biopsies from normal individuals, asymptomatic carriers (FAP 0) and FAP patients; in FAP 0, nonfibrillar TTR was observed both in the skin and nerve in the same individuals; in patients, amyloid was detected in both tissues. The occurrence of amyloidosis in recipients of FAP livers was evaluated 1–7 years after DLT: TTR deposition occurred in the skin 3 years after transplantation either as amyloid or aggregates; in one of the recipients, fibrillar TTR was present in the epineurium 6 years after DLT. Deposits were scarce and 3-NT immunostaining was irrelevant. Nerve biopsies from DLT recipients had no FAP-related neuropathy. Our findings suggest that TTR amyloid formation occurs faster than predicted and that TTR of liver origin can cross the blood-nerve barrier. Recipients of FAP livers should be under surveillance for TTR deposition and tissue damage.
Journal of Human Genetics | 2015
Jorge Oliveira; Luís Negrão; Isabel Fineza; Ricardo Taipa; Manuel Melo-Pires; Ana Maria Fortuna; Ana Rita Gonçalves; Hugo Froufe; Conceição Egas; Rosário Santos; Mário Sousa
Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis.
Pediatric Neurology | 2014
Joana Serra Caetano; Carmen Costa; Jonathan Baets; Madgalena Zimon; Margarida Venâncio; Jorge M. Saraiva; Luís Negrão; Isabel Fineza
BACKGROUND Autosomal recessive axonal neuropathy with neuromyotonia is a recently described entity associated to the HINT1 gene, encoding histidine triad nucleotide-binding protein 1. PATIENT The authors report a Portuguese 16-year-old girl of Roma ethnicity, descendant of consanguineous parents, with progressive distal muscular atrophy and weakness, beginning at age 6. After several years of extensive investigation with inconclusive results, clinical myotonia was identified. Electrophysiologic studies revealed neuromyotonia associated with a severe chronic predominantly motor axonal neuropathy and homozygous mutation (c.334 C > A, p.H112 N) in HINT1 was detected. CONCLUSION This report emphasizes the late onset of clinical myotonia essential to the diagnosis.
Muscle & Nerve | 2016
Ernestina Santos; Ester Coutinho; Isabel Moreira; Ana Martins da Silva; Dina Lopes; Henrique Costa; Fernando Silveira; Goreti Nadais; Hugo Morais; João Martins; Maria Ceu Branco; Andreia Veiga; Rosa Santos Silva; Augusto Ferreira; Filipa Sousa; Marta Freijo; Ilda Matos; Rui André; Luís Negrão; Carla Fraga; Manuela Santos; Mafalda Sampaio; Carlos Lopes; Maria Isabel Leite; Guilherme Gonçalves
Introduction: In this study we estimated the prevalence, incidence, and mortality of myasthenia gravis (MG) in northern Portugal and characterized the clinical features of the patients identified. Methods: We used 2 data sources: clinical records from the hospitals and pyridostigmine prescription registers. Results: On December 31, 2013, we estimated a point prevalence of 111.7 patients per million population. The highest prevalence was observed in the group >65 years of age, especially in men (288.1 per million). During 2013, we estimated an incidence rate of 6.3 per million per year. Among women, the incidence rate was highest in the 15–49‐year age group; in men, incidence increased with age up to 22.1 per million in those >65 years old. The MG‐related mortality rate was 0.5 per million. Conclusions: These figures are in keeping with similar studies and emphasize the importance of diagnosis and management of MG in elderly populations. Muscle Nerve 54: 413–421, 2016
Neuromuscular Disorders | 2011
Luis Vernengo; Jorge Oliveira; Martin Krahn; Emília Vieira; Rosário Santos; Luisa Carrasco; Luís Negrão; Ana Panuncio; Véronique Labelle; Elsa Bronze-da-Rocha; Rosario Mesa; Carlos Pizzarossa; Nicolas Lévy; Maria-Mirta Rodriguez
Primary dysferlinopathies are a group of recessive heterogeneous muscular dystrophies. The most common clinical presentations are Miyoshi myopathy and LGMD2B. Additional presentations range from isolated hyperCKemia to severe functional disability. Symptomatology begins in the posterior muscle compartment of the calf and its clinical course progresses slowly in Miyoshi myopathy whereas LGMD2B involves predominantly the proximal muscles of the lower limbs. The age of onset ranges from 13 to 60years in Caucasians. We present five patients that carry a novel mutation in the exon12/intron12 boundary: c.1180_1180+7delAGTGCGTG (r.1054_1284del). We provide evidence of a founder effect due to a common ancestral origin of this mutation, detected in heterozygosity in four patients and in homozygosity in one patient.
Journal of Human Genetics | 2010
Rosário Santos; Jorge Oliveira; Emília Vieira; Teresa Coelho; António Leite Carneiro; Teresinha Evangelista; Cristina Dias; Ana Maria Fortuna; Argemiro Geraldo; Luís Negrão; A.A. Guimarães; Elsa Bronze-da-Rocha
The allelic muscle disorders known as limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy and distal anterior compartment myopathy result from defects in dysferlin—a sarcolemma-associated protein involved in membrane repair. Mutation screening in the dysferlin gene (DYSF) enabled the identification of seven Portuguese patients presenting the variant c.5492G>A, which was observed to promote skipping of exon 49 (p.Gly1802ValfsX17). Several residually expressed products of alternative splicing also involving exons 50 and 51 were detected in the leukocytes and muscle of both patients and normal controls. Quantitative transcript analysis confirmed these results and revealed that Δ49/Δ50 transcripts were predominant in blood. Although the patients were apparently unrelated, the c.5492G>A mutation was found in linkage disequilibrium with a particularly rare haplotype in the population, corroborating the hypothesis of a common origin. Despite the presence of the same mutation on the same haplotype background, onset of the disease was heterogeneous, with either proximal or distal muscle involvement.
Human Mutation | 2018
Jorge Oliveira; Angela Gruber; Márcio Cardoso; Ricardo Taipa; Isabel Fineza; Ana Gonçalves; Andreas Laner; Thomas L. Winder; Jocelyn Schroeder; Julie Rath; Márcia E. Oliveira; Emília Vieira; Ana Paula Sousa; José Pedro Vieira; Teresa Lourenço; Luciano Almendra; Luís Negrão; Manuela Santos; Manuel Melo-Pires; Teresa Coelho; Johan T. den Dunnen; Rosário Santos; Mário Sousa
Congenital muscular dystrophy type 1A (MDC1A) is one of the main subtypes of early‐onset muscle disease, caused by disease‐associated variants in the laminin‐α2 (LAMA2) gene. MDC1A usually presents as a severe neonatal hypotonia and failure to thrive. Muscle weakness compromises normal motor development, leading to the inability to sit unsupported or to walk independently. The phenotype associated with LAMA2 defects has been expanded to include milder and atypical cases, being now collectively known as LAMA2‐related muscular dystrophies (LAMA2‐MD). Through an international multicenter collaborative effort, 61 new LAMA2 disease‐associated variants were identified in 86 patients, representing the largest number of patients and new disease‐causing variants in a single report. The collaborative variant collection was supported by the LOVD‐powered LAMA2 gene variant database (https://www.LOVD.nl/LAMA2), updated as part of this work. As of December 2017, the database contains 486 unique LAMA2 variants (309 disease‐associated), obtained from direct submissions and literature reports. Database content was systematically reviewed and further insights concerning LAMA2‐MD are presented. We focus on the impact of missense changes, especially the c.2461A > C (p.Thr821Pro) variant and its association with late‐onset LAMA2‐MD. Finally, we report diagnostically challenging cases, highlighting the relevance of modern genetic analysis in the characterization of clinically heterogeneous muscle diseases.
Pediatric Dimensions | 2017
Joana Pimenta; Carmen Costa; Isabel Alonso; Ana Filipa Brandão; Jorge Sequeiros; Luís Negrão; Isabel Fineza
Introduction: Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disease characterized by cerebellar ataxia, peripheral neuropathy and pyramidal tract signs. Since its first report from Québec, more than 100 disease-causing variants have been reported in ARSACS, with variable clinical presentation. MRI imaging may help establishing the clinical diagnosis, especially if typical changes are present. Clinical case: A 7-year old boy presented an early-onset, progressive ataxia, with sensory-motor neuropathy, nystagmus, feet deformities and cognitive impairment. MRI findings showed cerebellar and cervical spine atrophy and linear areas of hypointensity in the pons. The finding of a novel homozygous mutation c.3066del(p. Asn1025Metfs*10) in the SACS gene, resulting in a frameshift and a premature stop codon, allowed the genetic confirmation of the clinical diagnosis. Correspondence to: Joana Filipa Marques Pimenta, Hospital Pediátrico de Coimbra-CHUC, Rua Dr. Afonso Romão, 3000-602 Coimbra, Portugal, Tel: +351 918519064, Fax: + 351 239 717 216, E-mail: [email protected]
Revista Portuguesa De Pneumologia | 2012
Fátima Saraiva; D Rodrigues; Helena Andrade; Luís Negrão; Lino Gonçalves; António Marinho; L.A. Providência
Emery-Dreifuss muscular dystrophy type 1 (EDMD1) is a familial disease with X-Linked recessive transmission, caused by a mutation in a nuclear envelope protein, emerin. Clinical manifestations usually occur in adolescence and include contractures, muscle atrophy and weakness, and cardiac conduction disturbances. We describe the case of a young male, aged 16, with first-degree atrioventricular (AV) block and limited extension of both forearms. He had elevated CK, and cardiac monitoring showed severe conduction tissue disease, with significant sinus pauses, chronotropic incompetence and periods of AV dissociation during exercise. Immunohistochemical staining using an emerin antibody showed absence of the protein in a fragment of muscle tissue and genetic study identified a mutation associated with EDMD1. Study of his brother, aged 21, also established a diagnosis of EDMD1. Both individuals received a permanent pacemaker but musculoskeletal manifestations at that time did not warrant any other intervention: Screening for certain genetic diseases, including muscular dystrophies, is mandatory following identification of conduction abnormalities in young people.
Journal of Parkinson's disease | 2016
Rui Araújo; Miguel Tábuas-Pereira; Luciano Almendra; Joana Ribeiro; Marta Arenga; Luís Negrão; A. Matos; Ana Morgadinho; Cristina Januário