Use of lacosamide in children: experience of a tertiary medical care center in Brazil

Background Lacosamide (LCM) is a third-generation anti-seizure drug approved in Europe and the United States, either as a monotherapy or adjunctive therapy, to treat partial-onset seizures in adults, adolescents, and children. In Brazil, LCM is licensed for treatment only in patients older than 16 years of age. Objective To evaluate a cohort of children presenting with refractory epilepsy who received LCM as an add-on therapy and observe the response and tolerability to the LCM treatment. Methods A retrospective cohort study conducted in a tertiary health care facility, which included 26 children, aged up to 16 years, who presented with refractory epilepsy and received LCM as an add-on treatment. The follow-up visits were scheduled every 3 months until 9 months of treatment with LCM. Results After 3 months of LCM administration, in 73.1% of the children, there was a reduction of > 50% in the frequency of seizures, and this clinical improvement was maintained in most patients (73.9%) for the following 9 months. Mild (such as, somnolence and behavioral changes) or severe (seizure worsening) adverse effects were observed in two and three children respectively. Among responders to LCM, there was a higher prevalence of males, fewer concomitant anti-seizure drugs, and lower percentage of patients using sodium channel blockers. Conclusions Lacosamide should be considered as an early treatment option in pediatric patients with refractory epilepsy, mainly focal seizures

Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by the development of multiple hamartomas in many organs and tissues. It occurs due to inactivating mutations in either of the two genes, TSC1 and TSC2, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the TSC1 and TSC2 loci has been performed in several cohorts of patients and a broad spectrum of pathogenic mutations have been described. In Brazil, there is no data regarding incidence and prevalence of tuberous sclerosis and mutations in TSC1 and TSC2. We analyzed both genes in 53 patients with high suspicion of tuberous sclerosis using multiplex-ligation dependent probe amplification and a customized next generation sequencing panel. Confirmation of all variants was done by the Sanger method. We identified 50 distinct variants in 47 (89%) of the patients. Five were large rearrangements and 45 were point mutations. The symptoms presented by our series of patients were not different between male and female individuals, except for the more common occurrence of shagreen patch in women (p = 0.028). In our series, consistent with other studies, TSC2 mutations were associated with a more severe phenotypic spectrum than TSC1 mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis1210CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFundo de Incentivo a Pesquisa e Eventos (FIPE) of Hospital de Clinicas de Porto Alegre; Institute do Cancer Infantil (ICI

Families with a likely benign or variant of uncertain significance in <i>TSC1</i> and <i>TSC</i>.

<p>Families with a likely benign or variant of uncertain significance in <i>TSC1</i> and <i>TSC</i>.</p

Molecular analysis of <i>TSC1</i> and <i>TSC2</i> genes and phenotypic correlations in Brazilian families with tuberous sclerosis

<div><p>Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by the development of multiple hamartomas in many organs and tissues. It occurs due to inactivating mutations in either of the two genes, <i>TSC1</i> and <i>TSC2</i>, following a second hit in a tumor suppressor gene in most hamartomas. Comprehensive screening for mutations in both the <i>TSC1</i> and <i>TSC2</i> loci has been performed in several cohorts of patients and a broad spectrum of pathogenic mutations have been described. In Brazil, there is no data regarding incidence and prevalence of tuberous sclerosis and mutations in <i>TSC1</i> and <i>TSC2</i>. We analyzed both genes in 53 patients with high suspicion of tuberous sclerosis using multiplex-ligation dependent probe amplification and a customized next generation sequencing panel. Confirmation of all variants was done by the Sanger method. We identified 50 distinct variants in 47 (89%) of the patients. Five were large rearrangements and 45 were point mutations. The symptoms presented by our series of patients were not different between male and female individuals, except for the more common occurrence of shagreen patch in women (p = 0.028). In our series, consistent with other studies, <i>TSC2</i> mutations were associated with a more severe phenotypic spectrum than <i>TSC1</i> mutations. This is the first study that sought to characterize the molecular spectrum of Brazilian individuals with tuberous sclerosis.</p></div

Phenotypic comparison between male and female individuals with TSC.

<p>Phenotypic comparison between male and female individuals with TSC.</p

Assessing the landscape of STXBP1-related disorders in 534 individuals

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches

Assessing the landscape of STXBP1-related disorders in 534 individuals.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches

NEOTROPICAL ALIEN MAMMALS: a data set of occurrence and abundance of alien mammals in the Neotropics

Biological invasion is one of the main threats to native biodiversity. For a species to become invasive, it must be voluntarily or involuntarily introduced by humans into a nonnative habitat. Mammals were among first taxa to be introduced worldwide for game, meat, and labor, yet the number of species introduced in the Neotropics remains unknown. In this data set, we make available occurrence and abundance data on mammal species that (1) transposed a geographical barrier and (2) were voluntarily or involuntarily introduced by humans into the Neotropics. Our data set is composed of 73,738 historical and current georeferenced records on alien mammal species of which around 96% correspond to occurrence data on 77 species belonging to eight orders and 26 families. Data cover 26 continental countries in the Neotropics, ranging from Mexico and its frontier regions (southern Florida and coastal-central Florida in the southeast United States) to Argentina, Paraguay, Chile, and Uruguay, and the 13 countries of Caribbean islands. Our data set also includes neotropical species (e.g., Callithrix sp., Myocastor coypus, Nasua nasua) considered alien in particular areas of Neotropics. The most numerous species in terms of records are from Bos sp. (n = 37,782), Sus scrofa (n = 6,730), and Canis familiaris (n = 10,084); 17 species were represented by only one record (e.g., Syncerus caffer, Cervus timorensis, Cervus unicolor, Canis latrans). Primates have the highest number of species in the data set (n = 20 species), partly because of uncertainties regarding taxonomic identification of the genera Callithrix, which includes the species Callithrix aurita, Callithrix flaviceps, Callithrix geoffroyi, Callithrix jacchus, Callithrix kuhlii, Callithrix penicillata, and their hybrids. This unique data set will be a valuable source of information on invasion risk assessments, biodiversity redistribution and conservation-related research. There are no copyright restrictions. Please cite this data paper when using the data in publications. We also request that researchers and teachers inform us on how they are using the data