The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

Estructura híbrida; Atrofia muscular espinal; Neurona motora de supervivencia 1Hybrid structure; Spinal muscular atrophy; Survival motor neuron 1Estructura híbrida; Atròfia muscular espinal; Neurona motora de supervivència 1After 26 years of discovery of the determinant survival motor neuron 1 and the modifier survival motor neuron 2 genes (SMN1 and SMN2, respectively), three SMN-dependent specific therapies are already approved by FDA and EMA and, as a consequence, worldwide SMA patients are currently under clinical investigation and treatment. Bi-allelic pathogenic variants (mostly deletions) in SMN1 should be detected in SMA patients to confirm the disease. Determination of SMN2 copy number has been historically employed to correlate with the phenotype, predict disease evolution, stratify patients for clinical trials and to define those eligible for treatment. In view that discordant genotype-phenotype correlations are present in SMA, besides technical issues with detection of SMN2 copy number, we have hypothesized that copy number determination is only the tip of the iceberg and that more deepen studies of variants, sequencing and structures of the SMN2 genes are necessary for a better understanding of the disease as well as to investigate possible influences in treatment responses. Here, we highlight the importance of a comprehensive approach of SMN1 and SMN2 genetics with the perspective to apply for better prediction of SMA in positive neonatal screening cases and early diagnosis to start treatments.This work was partially supported by Grants from Biogen and Roche (to E.F.T. supporting M.C.-R. and L.B.-P.), and from Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and cofunded with ERDF funds (Grant No. FIS PI18/000687) (to E.F.T.)

Recommendations for Interpreting and Reporting Silent Carrier and Disease-Modifying Variants in SMA Testing Workflows

Carrier screening; Diagnosis; Spinal muscular atrophyCribado de portadores; Diagnóstico; Atrofia muscular espinalCribratge de portadors; Diagnòstic; Atròfia muscular espinalGenetic testing for SMA diagnosis, newborn screening, and carrier screening has become a significant public health interest worldwide, driven largely by the development of novel and effective molecular therapies for the treatment of spinal muscular atrophy (SMA) and the corresponding updates to testing guidelines. Concurrently, understanding of the underlying genetics of SMA and their correlation with a broad range of phenotypes and risk factors has also advanced, particularly with respect to variants that modulate disease severity or impact residual carrier risks. While testing guidelines are beginning to emphasize the importance of these variants, there are no clear guidelines on how to utilize them in a real-world setting. Given the need for clarity in practice, this review summarizes several clinically relevant variants in the SMN1 and SMN2 genes, including how they inform outcomes for spinal muscular atrophy carrier risk and disease prognosis.This work was partially supported by Grants from Biogen ESP-SMG-17-11256 (to E.F.T. supporting L.B.-P.), Roche and Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co-funded with ERDF funds (Grant No. FIS PI18/000687) (to E.F.T.)

Morphological and cytochemical characterization of cell types of the adenohypophysis of Manjuba, Anchoviella lepidentostole (Fowler, 1911) (Osteichthyes, Engraulidae)

A hipófise de Anchoviella lepidentostole apresenta-se dividida em neuro-hipófise e adeno-hipófise, sendo que a caracterização morfológica e citoquímica dos tipos celulares desta região foi a proposta deste trabalho. A adeno-hipófise divide-se em pars intermedia (PI) e pars distalis (PD), sendo que esta última se divide em pars distalis rostralis (PDR) e pars distalis proximalis (PDP). As células da PDR organizam-se em folículos. No epitélio folicular foram caracterizados quatro tipos celulares: l-PDR (basófilo), ll-PDR (positivo à hematoxilina-chumbo/HPb+), lll-PDR (PAS+, AB pH2,5+ e AF+), e IV-PDR (acidófilas). A PDP possui dois tipos celulares: l-PDP (PAS+, AB pH2,5+ e AF+) e ll-PDP (acidófilas). Na PI também foram caracterizados dois tipos celulares: l-PI (HPb+) e ll-PI (cromófobo aos métodos empregados).The pituitary gland of Anchoviella lepidentostole consists of the neurohypophysis and the adenohypophysis, which is subdivided in pars intermedia and pars distalis. The pars distalis comprises pars distalis rostralis and pars distalis proximalis. The cell types of the pars distalis rostralis are arranged in follicles. In the follicular epithelium, four cell types were cytochemically characterized: l-PDR (basophilic), ll-PDR (lead haematoxylin+/HPb+), lll-PDR (PAS+, AB pH2.5+ and AF+), IV-PDR (acidophilic). Thepars distalis proximalis has two cell types: l-PDP (PAS+, AB pH 2.5+ and AF+) and ll-PDP (acidophilic). In the pars intermedia there are two cell types: l-PI (HPb+) and ll-PI (chromophobes)

Medidas de redução do contencioso tributário e o CPC/2015: contributos práticos para ressignificar o processo administrativo e judicial tributário

- Divulgação dos SUMÁRIOS das obras recentemente incorporadas ao acervo da Biblioteca Ministro Oscar Saraiva do STJ. Em respeito à Lei de Direitos Autorais, não disponibilizamos a obra na íntegra.- Localização na estante: 336.2:34(81) M489r- Coordenado por: Gisele Barra Bossa, Eduardo Perez Salusse, Tathiane Piscitelli e Juliana Furtado Costa Araujo

Deep Molecular Characterization of Milder Spinal Muscular Atrophy Patients Carrying the c.859G>C Variant in SMN2

Next-generation sequencing; Phenotype–genotype correlations; Spinal muscular atrophySeqüenciació de nova generació; Correlacions fenotip-genotip; Atròfia muscular espinalSecuenciación de nueva generación; Correlaciones fenotipo-genotipo; Atrofia muscular espinalSpinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by biallelic loss or pathogenic variants in the SMN1 gene. Copy number and modifier intragenic variants in SMN2, an almost identical paralog gene of SMN1, are known to influence the amount of complete SMN proteins. Therefore, SMN2 is considered the main phenotypic modifier of SMA, although genotype–phenotype correlation is not absolute. We present eleven unrelated SMA patients with milder phenotypes carrying the c.859G>C-positive modifier variant in SMN2. All were studied by a specific NGS method to allow a deep characterization of the entire SMN region. Analysis of two homozygous cases for the variant allowed us to identify a specific haplotype, Smn2-859C.1, in association with c.859G>C. Two other cases with the c.859G>C variant in their two SMN2 copies showed a second haplotype, Smn2-859C.2, in cis with Smn2-859C.1, assembling a more complex allele. We also identified a previously unreported variant in intron 2a exclusively linked to the Smn2-859C.1 haplotype (c.154-1141G>A), further suggesting that this region has been ancestrally conserved. The deep molecular characterization of SMN2 in our cohort highlights the importance of testing c.859G>C, as well as accurately assessing the SMN2 region in SMA patients to gain insight into the complex genotype–phenotype correlations and improve prognostic outcomes.This research was funded by grants from Biogen (ESP-SMG-17-11256), Roche, GaliciAME and Spanish Instituto de Salud Carlos III, Fondo de Investigaciones Sanitarias and co-funded with ERDF funds (grant no. FIS PI18/000687). A grant from Horizon 2020 IMI2 Screen4Care is acknowledged by E.B., and L.T., E.F.T., R.J., J.S., L.C.-C., F.M., E.B., and L.T. are members of the ERN NMD Network for Rare Diseases. E.F.T. is a member of the ERN ITHACA Network for Rare Diseases

Influência de diferentes extratos de levedura (insumos) no crescimento celular de Xanthomonas arboricola pv pruni cepa 101/ Influence of different yeast extracts (inputs) on the cell growth of Xanthomonas arboricola pv pruni strain 101

Xantana é um heteropolissacarídeo produzido por bactérias do gênero Xanthomonas. Esse biopolímero desempenha diversas funções de grande importância para indústrias de variados setores. O processo de produção de xantana é realizado em duas etapas: crescimento celular e produção do biopolímero, e ambas são importantes para a obtenção de xantana com rendimento e qualidade satisfatórios, os quais são influenciados por diferentes fatores, dentre eles os meios de cultivo utilizados. Objetivou-se avaliar o crescimento bacteriano de Xanthomonas arboricola pv pruni cepa 101 em meio de cultivo complexo YM adicionado de diferentes extratos de levedura, sendo um tradicional - controle (1) - e outros alternativos de menor custo - 560PW (2), 810PW (3), 845MG (4), 851MG (5), 861PW (6) - e relacionar com o teor de nitrogênio fornecido. Avaliou-se o crescimento celular (UFC.mL-1) e o teor de nitrogênio (mg.dL-1) nos tempos 24 h e em 0 e 24 h de crescimento celular, respectivamente. Não observou-se diferença estatística entre a concentração celular final obtida com extrato controle e os extratos alternativos. A concentração celular final variou entre 3,1 × 1010 a 5,2 × 1010 UFC.mL-1. O uso dos extratos de levedura 4, 6 e o controle resultaram em maior disponibilidade de nitrogênio no meio de cultivo no tempo inicial e ao final, e têm potencial para propiciar um maior crescimento celular. Observou-se aumento no teor de nitrogênio no tempo final, provavelmente devido à hidrólise celular parcial.  O teor inicial de nitrogênio variou de 9,11 a 12,04 e o final de 31,41 a 47,51 mg.dL-1, respectivamente. Os diferentes extratos de levedura avaliados são substitutos adequados para o crescimento celular da bactéria X. arboricola pv pruni cepa 101, e provavelmente para outras cepas da espécie, com resultados equivalentes ao obtido com o extrato controle