Search

See Karakaya and Wirth (doi:10.1093/brain/awz273) for a scientific commentary on this article. Neurofascin (NFASC) isoforms are immunoglobulin cell adhesion molecules involved in node of Ranvier assembly. Efthymiou et al. identify biallelic NFASC variants in ten unrelated patients with a neurodevelopmental disorder characterized by variable degrees of central and peripheral involvement. Abnormal expression of Nfasc155 is accompanied by severe loss of myelinated fibres., Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. © 2019, The Author(s).

A “Unidade de Estudo de Mastites em Pequenos Ruminantes”, formalmente constituída no âmbito do Programa Nacional de Re-equipamento Científico, da Fundação para a Ciência e a Tecnologia, vem dar corpo ao trabalho de colaboração de diversas equipas de investigação que se têm debruçado sobre a problemática das infecções intramamárias em pequenos ruminantes, nos seus aspectos de saúde animal, saúde pública veterinária e qualidade e segurança alimentar. Tem como principal objectivo criar condições para o desenvolvimento de trabalhos de investigação e divulgação científica que contribuam para reduzir a prevalência de mastites em pequenos ruminantes e assim melhorar a produção e a qualidade do leite, favorecendo produtores de leite, produtores de queijo e consumidores. Entre os trabalhos já realizados pela equipa científica, destacam-se o isolamento e identificação de agentes etiológicos de mastite em ovelhas, o estudo de factores de virulência nas bactérias mais relevantes, o estudo dos mecanismos de infecção e a resposta imunológica local e sistémica do hospedeiro e outros estudos na área da epidemiologia. O estudo da etiologia e da fisiopatologia da mastite ovina, com o objectivo de compreender a modulação da resposta imunitária da glândula mamária, poderá contribuir para o desenvolvimento de métodos de controlo com base na estimulação da resposta imunitária, alternativos ao uso de antibióticos., Revista de Ciências Agrárias, vol. 30 n.º 1 (2007)

4th Congress of the European-Academy-of-Neurology (EAN), Lisbon, PORTUGAL, JUN 16-19, 2018

BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

The ‘neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe−/− × Tfr2mut brain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P0.05). Overlap (P0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.

Submitted by Helena Donato (bibliotecahvfx@gmail.com) on 2016-03-27T17:45:14Z No. of bitstreams: 1 dIHEMOPHILUS.pdf: 3282934 bytes, checksum: 8e08105863ef6dcc9643ded109b2abea (MD5) Made available in DSpace on 2016-03-27T17:45:15Z (GMT). No. of bitstreams: 1 dIHEMOPHILUS.pdf: 3282934 bytes, checksum: 8e08105863ef6dcc9643ded109b2abea (MD5) Previous issue date: 2016

Introdução: Uma parceria Sociedade de Infecciologia Pediátrica / Instituto Nacional de Saúde Dr. Ricardo Jorge propôs-se avaliar a epidemiologia, fatores de risco, clínica, serotipos e suscetibilidade aos antibióticos da doença invasiva a Haemphilus influenzae nas crianças, em Portugal. Métodos: Estudo prospetivo descritivo multicêntrico, entre 1 de janeiro de 2010 e 30 de junho de 2014 (54 meses). Cada estirpe foi enviada ao Instituto Nacional de Saúde Dr. Ricardo Jorge acompanhada de inquérito clínico. Foi pesquisada produção de β-lactamase, resistência antibiótica, cápsula e serotipo. Resultados: Foram analisadas 38 estirpes (18 hospitais) isoladas em hemocultura (34), liquor (três) e líquido articular (uma). A incidência global foi 0,45/100000. Identificaram-se 25 (65,7%) Haemophilus influenzae não-capsulados, nove (23,7%) serotipo b (seis falências vacinais), duas (5,3%) serotipo a e duas (5,3%) serotipo f. As idades variaram entre 1 mês e 15 anos (lactentes 44,7%; 5 anos ou mais 26,3%); 23,7% tinham patologia prévia. As apresentações clínicas foram pneumonia (13), meningite (cinco), bacteriemia (cinco), infeção respiratória alta (quatro), bronquiolite (três) sépsis sem foco (três), artrite (duas), celulite periorbitária (uma), celulite (uma), epiglotite (uma). A meningite foi manifestação de 33,3% das infeções por serotipo b e de 4% das devidas a Haemophilus influenzae não-capsulados (p < 0,05). As infeções respiratórias altas bacteriémicas predominaram acima dos 5 anos (30% vs 3,6%; p < 0,05). Registaram-se sequelas neurológicas num caso (2,6%) e um óbito (2,6%). Verificou-se produção de β-lactamase em 7,9% e resistência à cefuroxima em 18,4%. Sem resistências a amoxicilina / clavulanato, cefotaxima, rifampicina. Discussão: A doença invasiva por Haemophilus influenzae atingiu diferentes grupos etários, predominando nos lactentes. As estirpes mais prevalentes foram de Haemophilus influenzae não-capsulados, causando maioritariamente bacteriemia e manifestações respiratórias. O serotipo b manteve-se em circulação sendo responsável por dois casos / ano.

Background: The homozygous missense mutation c.430G>T (p.G144W) in the GOSR2 gene has been repeatedly shown to cause progressive myoclonus epilepsy/ataxia. Thus far, no other disease associated GOSR2 mutation has been reported. Methods: From epilepsy, movement disorder and genetic clinics 43 patients suffering from progressive myoclonus epilepsy/ataxia were screened for defects in GOSR2, SCARB2 and CSTB. Results: A 61-year-old female patient suffering from progressive myoclonus epilepsy was found to be compound heterozygous for the known c.430G>T and a novel c.491_493delAGA (p.K164del) GOSR2 mutation. This is so far the oldest GOSR2 patient and her disease course seems overall milder. Conclusions: This finding further highlights the GOSR2 gene as a cause of progressive myoclonus epilepsy and expands the genotype for a potentially weaker disease allele.

Background. Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder of late onset, caused by a (CAG)n expansion at the ATXN3 gene (14q32.1). Variation in age-at-onset is partially explained by the size of the (CAG)n tract in expanded alleles. The remaining variation should be the product of other factors, namely modifier genes. The genotype at the APOE locus has been described as a possible modifier in different neurological disorders, namely Parkinson (PD) and Huntington disease (HD). In the CNS, apolipoprotein E constitutes an important mediator of cholesterol transport/metabolism, which is essential for synaptic integrity and neuronal function. Objective. To investigate a modulating effect of the APOE polymorphism on age-at-onset of MJD. Design and Subjects. The APOE polymorphism was typed in a series of 192 MJD patients. Results. Cases with the ε2/ε3 genotype presented an earlier onset, when compared with those with ε3/ε3 or ε3/ε4. In this series of patients, the presence of an APOE ε2 allele implies a decrease of nearly 5 years in the age-at-onset. When combining, in a general linear model, several other predictors, namely the presence/absence of the APOE ε2 allele, with the size of the (CAG)n in expanded alleles, the model was significantly improved and the explanation of onset variance was raised from 59.8% to 66.5%. Furthermore, the presence of the ε2 allele was associated with an onset below 39 years (OR=5.00; 95% CI: 1.18-21.14). Conclusions. These findings indicate that the polymorphism at the APOE gene plays a role as a genetic modifier of MJD phenotype., Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/63121/2009, SFRH/BPD/38659/2007, M3.1.3/F/004/2009, “Secretaria Regional da Ciência, Tecnologia e Equipamentos”., Fundação para a Ciência e a Tecnologia (FCT) - “Transcriptional variation of the ATXN3 gene as modulator of the clinical heterogeneity in Machado-Joseph disease (MJD)” (PIC/IC/83074/2007), Institute of Biotechnology and Biomedicine (IBBA) - “High prevalence diseases in the Azores Islands” (M2.1.2/I/026/2008

A síndrome de Ehlers-Danlos é uma entidade clínica caracterizada por hipermobilidade articular, lassidão e fragilidade cutânea resultante de alterações do tecido conjuntivo. São descritos seis tipos principais, com base em dados clínicos, no modo de transmissão hereditária e alterações bioquímicas e moleculares subjacentes. Os autores apresentam um caso clínico referente a uma doente do sexo feminino, de 44 anos de idade, internada por quadro de toracalgia direita com 2 meses de evolução, cujo estudo complementar revelou volumoso hemotórax. Foi estabelecido o diagnóstico de síndrome de Ehlers-Danlos do tipo IV. Ehlers-Danlos syndrome is a disease characterized by joint hypermobility, increased skin elasticity and fragility due to a connective tissue disorder. There are 6 main types, distinguished on the basis of clinical signs, mode of inheritance, biochemical abnormalities and underlying molecular abnormalities. The authors report the case of a female, 44 years-old, who presented with a 2- month chest pain, due to a spontaneous haemothorax. The clinical, laboratorial and imaging studies data allowed us to make the diagnosis of Ehlers-Danlos Syndrome type IV.

O queijo Serpa é um queijo curado, de pasta semimole, com Designação de Origem Protegida (DOP), obtido por esgotamento lento da coalhada após a coagulação do leite cru de ovelha, por acção de uma infusão de Cynara cardunculus L.. A avaliação sensorial, como o próprio nome nos induz, pode ser definida por uma trilogia que envolve o indivíduo, o produto e a avaliação propriamente dita. A relação estabelecida por estes três elementos e as possíveis combinações, originam nesta área uma metodologia extremamente diversificada. Metodologicamente a avaliação passa primeiro pela adopção do tipo de prova, seguidamente pela selecção do instrumento de avaliação, que na prática se traduz na escolha de uma escala e por último pela selecção dos indivíduos que são utilizados na avaliação, condicionando a resposta a obter. Pretendeu-se com este estudo avaliar a qualidade do queijo Serpa e definir os atributos de textura e olfacto-gustativos. Um painel de provadores treinado avaliou em 14 sessões 126 amostras de queijo Serpa com 60 dias de cura, estabelecendo-se para o efeito uma prova hedónica e uma prova quantitativa. O painel de provadores definiu o perfil das características de textura e olfacto gustativas do queijo Serpa e foram identificadas as associações entre os atributos e a qualidade do queijo. Serpa cheese is a soft cheese with an AOP designation, obtained from curdling of raw ewe’s milk, by the action of an infusion of Cynara cardunculus L. Sensory evaluation can be defined as a trilogy linking the panellists, the product and the assessment. The relation between them, makes it possible to determine different sensory methodology. According the main objective and the expected response, this methodology comprises the selection and training of panellists, the type of assessment and the type of scale. The aim of this study was to evaluate Serpa Cheese quality and define the sensory attributes of flavour and texture. A trained panel carried out the sensory evaluation of 126 Serpa cheese samples with sixty days of ripening, in fourteen sessions. The panellists also performed a quantitative and also a hedonic assessment. The trained panel defined the Serpa cheese sensory profile, as well as was established correlations between the sensory attributes and cheese ´ quality.