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    Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort
    (2020)
    Claudia Maccali
    ;
    Aline L. Chagas
    ;
    Ilka Boin
    ;
    Emilio Quiñonez
    ;
    Sebastián Marciano
      13Scopus© Citations 18
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    A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction
    (2020)
    Masamune Sakamoto
    ;
    Den Kouhei
    ;
    Muzhirah Haniffa
    ;
    Sebastián Silva
    ;
    Mónica Troncoso
      9Scopus© Citations 16
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    The gain of function <i>SCN1A</i> disorder spectrum: novel epilepsy phenotypes and therapeutic implications
    (2022)
    Andreas Brunklaus
    ;
    Tobias Brünger
    ;
    Tony Feng
    ;
    Carmen Fons
    ;
    Anni Lehikoinen
    <jats:title>Abstract</jats:title> <jats:p>Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals.</jats:p> <jats:p>Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants.</jats:p> <jats:p>We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4–69.3; P = 1.3 × 10−7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function.</jats:p> <jats:p>Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation.</jats:p> <jats:p>Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.</jats:p>
    Scopus© Citations 45  20
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    Epilepsy Genetics and Precision Medicine in Adults: A New Landscape for Developmental and Epileptic Encephalopathies
    (2022)
    Álvaro Beltrán-Corbellini
    ;
    Ángel Aledo-Serrano
    ;
    Rikke S. Møller
    ;
    Eduardo Pérez-Palma
    ;
    Irene García-Morales
    <jats:p>This review aims to provide an updated perspective of epilepsy genetics and precision medicine in adult patients, with special focus on developmental and epileptic encephalopathies (DEEs), covering relevant and controversial issues, such as defining candidates for genetic testing, which genetic tests to request and how to interpret them. A literature review was conducted, including findings in the discussion and recommendations. DEEs are wide and phenotypically heterogeneous electroclinical syndromes. They generally have a pediatric presentation, but patients frequently reach adulthood still undiagnosed. Identifying the etiology is essential, because there lies the key for precision medicine. Phenotypes modify according to age, and although deep phenotyping has allowed to outline certain entities, genotype-phenotype correlations are still poor, commonly leading to long-lasting diagnostic odysseys and ineffective therapies. Recent adult series show that the target patients to be identified for genetic testing are those with epilepsy and different risk factors. The clinician should take active part in the assessment of the pathogenicity of the variants detected, especially concerning variants of uncertain significance. An accurate diagnosis implies precision medicine, meaning genetic counseling, prognosis, possible future therapies, and a reduction of iatrogeny. Up to date, there are a few tens of gene mutations with additional concrete treatments, including those with restrictive/substitutive therapies, those with therapies modifying signaling pathways, and channelopathies, that are worth to be assessed in adults. Further research is needed regarding phenotyping of adult syndromes, early diagnosis, and the development of targeted therapies.</jats:p>
      36Scopus© Citations 24
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      3Scopus© Citations 46
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      7Scopus© Citations 28
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    Recommendations for the Nonpharmacological Treatment of Apathy in Brain Disorders
    (2020)
    Valeria Manera
    ;
    Sharon Abrahams
    ;
    Luis Agüera-Ortiz
    ;
    François Bremond
    ;
    Renaud David
      13  1Scopus© Citations 49