RESUMO
Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.
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Glicosilfosfatidilinositóis , Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Estudos Retrospectivos , Lactente , Adulto , Glicosilfosfatidilinositóis/deficiência , Glicosilfosfatidilinositóis/genética , Deficiência Intelectual/genética , Deficiências do Desenvolvimento/genética , Adulto Jovem , Defeitos Congênitos da Glicosilação/genética , Fenótipo , Convulsões/genéticaRESUMO
Developmental and epileptic encephalopathies (DEEs) are characterized by pharmacoresistant seizures and developmental delay. Patients with DEEs experience multiple seizure types, including tonic-clonic seizures (TCS) that can be generalized tonic-clonic (GTCS) or focal evolving to bilateral tonic-clonic (FBTCS). Fenfluramine (FFA) has demonstrated efficacy in reduction of TCS in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and other DEEs. Using the PRISMA-ScR (Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Review) guidelines, we performed a scoping review to describe changes in TCS in patients treated with FFA. A comprehensive search of five literature databases was conducted up to February 14, 2023. Studies were included if they reported change in GTCS or TCS (but not FBTCS) after treatment with FFA in patients with DEEs. Duplicate patients and studies with unclear efficacy data were excluded. Fourteen of 422 studies met the eligibility criteria. Data extracted and evaluated by expert clinicians identified 421 unique patients with DS (in nine studies), CDKL5 deficiency disorder, SCN8A-related disorder, LGS, SCN1B-related disorder, and other DEEs. The median percent reduction in GTCS or TCS from baseline was available in 10 studies (n = 328) and ranged from 47.2% to 100%. Following FFA treatment, 10 studies (n = 144) reported ≥50% reduction in GTCS or TCS from baseline in 72% of patients; in nine of those (n = 112), 54% and 29% of patients achieved ≥75% and 100% reduction in GTCS or TCS from baseline, respectively. Overall, this analysis highlighted improvements in GTCS or TCS frequency when patients were treated with FFA regardless of the DEE evaluated. Future studies may confirm the impact of FFA on TCS reduction and on decreased premature mortality risk (including sudden unexpected death in epilepsy), improvement in comorbidities and everyday executive function, decreased health care costs, and improvement in quality of life.
Assuntos
Fenfluramina , Síndrome de Lennox-Gastaut , Humanos , Fenfluramina/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsias Mioclônicas/complicações , Convulsões/tratamento farmacológico , Espasmos Infantis/tratamento farmacológico , Anticonvulsivantes/uso terapêuticoRESUMO
OBJECTIVE: SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants are de novo, making early phenotype prediction difficult, and genotype-phenotype associations remain poorly understood. METHODS: We assessed data from a retrospective cohort of 1018 individuals with SCN1A-related epilepsies. We explored relationships between variant characteristics (position, in silico prediction scores: Combined Annotation Dependent Depletion (CADD), Rare Exome Variant Ensemble Learner (REVEL), SCN1A genetic score), seizure characteristics, and epilepsy phenotype. RESULTS: DS had earlier seizure onset than other GEFS+ phenotypes (5.3 vs. 12.0 months, p < .001). In silico variant scores were higher in DS versus GEFS+ (p < .001). Patients with missense variants in functionally important regions (conserved N-terminus, S4-S6) exhibited earlier seizure onset (6.0 vs. 7.0 months, p = .003) and were more likely to have DS (280/340); those with missense variants in nonconserved regions had later onset (10.0 vs. 7.0 months, p = .036) and were more likely to have GEFS+ (15/29, χ2 = 19.16, p < .001). A minority of protein-truncating variants were associated with GEFS+ (10/393) and more likely to be located in the proximal first and last exon coding regions than elsewhere in the gene (9.7% vs. 1.0%, p < .001). Carriers of the same missense variant exhibited less variability in age at seizure onset compared with carriers of different missense variants for both DS (1.9 vs. 2.9 months, p = .001) and GEFS+ (8.0 vs. 11.0 months, p = .043). Status epilepticus as presenting seizure type is a highly specific (95.2%) but nonsensitive (32.7%) feature of DS. SIGNIFICANCE: Understanding genotype-phenotype associations in SCN1A-related epilepsies is critical for early diagnosis and management. We demonstrate an earlier disease onset in patients with missense variants in important functional regions, the occurrence of GEFS+ truncating variants, and the value of in silico prediction scores. Status epilepticus as initial seizure type is a highly specific, but not sensitive, early feature of DS.
Assuntos
Epilepsias Mioclônicas , Epilepsia , Convulsões Febris , Estado Epiléptico , Humanos , Estudos Retrospectivos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Epilepsia/genética , Epilepsia/diagnóstico , Epilepsias Mioclônicas/genética , Convulsões Febris/genética , Fenótipo , Estudos de Associação Genética , Mutação/genéticaRESUMO
BACKGROUND: Dravet syndrome (DS) is a rare and severe form of epilepsy that begins in infancy, which is primarily caused by pathogenic variants in the SCN1A gene. DS is characterized by prolonged and frequent drug-resistant seizures, as well as developmental delays and behavioral problems. The identification of these comorbidities is based on clinical interview and relies on healthcare professionals (HCPs) experience. METHODS: We assembled a group of expert HCPs and caregivers to create a screening checklist for assessing DS-Associated Neuropsychiatric Comorbidities (DANC). The checklist includes questions related to cognitive and psychiatric domains, motor skills, and the impact of DS on families' daily lives. We administered the checklist to 24 caregivers of DS patients from Belgium, France, and Spain. After piloting, we obtained feedback from expert HCPs and caregivers to refine the checklist. RESULTS: DS patients showed a wide array of neuropsychiatric symptoms related to DS. The most common cognitive domains reported were attention difficulties and multitasking problems (18/24 caregivers), and impulsivity (17/24), while the most common psychiatric symptoms were temper tantrums (14/24), mood swings (13/24) and autism spectrum disorder (12/24). Balance and coordination problem have been reported in almost all patients with a statement of only 4/23 with complete mobility. Most patients were dependent on others for self-care and eating, and presented sleeping disturbances. Caregivers reported high levels of stress in the family unit, both between siblings and parents. Results show that the main concerns of parents were the behavior and the cognition of the person with DS. The quantitative feedback results showed good-to-very good scores on usefulness, ease of completion, clarity and comprehensiveness of the checklist. CONCLUSIONS: This pilot study suggests that the DANCE checklist could be a useful screening tool in daily practice for neuropsychiatric comorbidities facilitating their diagnosis and treatment, and empowering both caregivers and patients.
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AIM: This cohort study aimed to describe functional mobility in Dravet syndrome, a developmental and epileptic encephalopathy. METHOD: Functional mobility was assessed in individuals (aged 3-25 years), diagnosed with Dravet syndrome, using the Functional Mobility Scale (FMS), Mobility Questionnaire 28 (MobQues28), and estimated walking distance. Secondary outcome variables were Gait Profile Score (GPS), walking velocity, age at independent walking, intellectual disability, seizure frequency, genetic variant type, and body mass index (BMI). RESULTS: Forty participants aged 3 years to 24 years 2 months (mean = 12 years 2 months) had a median MobQues28 of 79%, median scores of 5, 5, and 4 for the FMS 5 m, 50 m, and 500 m and a median estimated walking distance of 1 km to 3 km. Most difficulties were seen in walking up and down the stairs, walking over obstacles, kicking a ball, and running. MobQues28 scores showed a significant decrease (-6.6%, p = 0.016) in the age category of young adults (≥18 years). After correcting for age, MobQues28 was correlated to age at independent walking (-0.485, p = 0.002), GPS (-0.460, p = 0.003), and walking velocity (0.334, p = 0.038). Analysis of variance showed a significant effect of intellectual disability and BMI on MobQues28 (p = 0.029, p = 0.049). No effect of seizure frequency or genetic variant was found (p = 0.579, p = 0.337). INTERPRETATION: Functional mobility limitations were observed mainly in dual tasks and activities requiring stability, with limitations increasing from the age of 18 years. Age at independent walking, gait impairments, intellectual disability, and BMI can impact functional mobility in Dravet syndrome. WHAT THIS PAPER ADDS: Most limitations were seen in dual task activities and activities that required more stability. Deterioration in functional mobility occurred in young adults. The more gait impairments, the more functional mobility limitations. Age at independent walking, intellectual disability, and body mass index can impact functional mobility.
Assuntos
Epilepsias Mioclônicas , Deficiência Intelectual , Humanos , Criança , Adulto Jovem , Estudos de Coortes , Deficiência Intelectual/genética , Limitação da Mobilidade , Epilepsias Mioclônicas/genética , Caminhada , Marcha , ConvulsõesRESUMO
OBJECTIVE: This study was undertaken to determine the plasma concentration and pharmacokinetic variability of fenfluramine (FFA) and its main active metabolite norfenfluramine (norFFA) in relation to the prevalence of adverse effects in patients with refractory epilepsy treated with FFA. In addition, the interaction with concomitant antiseizure medications including stiripentol (STP) is studied. METHODS: Patients were recruited at our center from two open-label sources, an investigator-initiated observational study and an international multicenter extension study. Venous blood samples were collected between June 2015 and December 2020. Plasma FFA and norFFA concentrations were determined by liquid chromatography tandem spectrometric analysis. Clinical data were collected retrospectively. Intrapatient coefficient of variation was calculated for all patients with at least three samples. Interpatient variability was calculated based on the concentration to weight-adjusted dose ratio (C/D) of all patients. RESULTS: We collected 321 samples from 61 patients (49 with Dravet syndrome, seven with Lennox-Gastaut syndrome, and five with a developmental and epileptic encephalopathy). With a mean daily dose of .33 mg/kg/day (SD = ±.16), the median FFA plasma concentration was 41.4 µg/L (range = 5.1-712.5) and median norFFA concentration 28.1 µg/L (range = 2.6-149.6). The FFA plasma concentration was linearly related to the daily dose (p < .001) and norFFA levels (p < .001). The C/D of FFA increased with age (p < .001). Median FFA C/D was 428% higher (p < .001), norFFA C/D 83% lower (p < .001), and norFFA/FFA 23% lower (p < .001) in patients treated with STP comedication. Higher FFA concentration was associated with fatigue (p = .001) and somnolence (p < .001), but not anorexia (p = .0619) or reduction in seizure frequency (p = .772). Gender and other ASMs were not associated with significant variations in (nor)FFA C/D ratio. SIGNIFICANCE: Most FFA levels are in the lower range (<50 µg/L), although a high interpatient and intrapatient variability is present. In combination with STP, the dose of FFA should be reduced.
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Epilepsias Mioclônicas , Fenfluramina , Anticonvulsivantes/farmacocinética , Monitoramento de Medicamentos , Epilepsias Mioclônicas/complicações , Fenfluramina/uso terapêutico , Humanos , Estudos RetrospectivosRESUMO
Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in â¼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.
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Epilepsia/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio Ativados por Sódio/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Adulto JovemRESUMO
AIM: To investigate the relation between cognitive and motor development in preschool aged children with Dravet syndrome, in particular between the age of independent walking and cognitive development. METHOD: Results of cognitive and motor developmental assessments and the age of independent walking were retrieved retrospectively from the medical records of 33 children (17 males, 16 females; mean age at last evaluation 33.2mo, SD 8.2mo, range 9-48mo) diagnosed with Dravet syndrome. Cognitive and motor developmental age, derived from the Bayley Scales of Infant Development or through standardized neurodevelopmental assessment, were converted into cognitive and motor developmental quotients. Multiple test scores per child were included. RESULTS: A strong positive relation was found between cognitive and motor developmental quotient (Pearson r=0.854; p<0.001) in 20 children (slope=0.75; 95% CI: 0.54-0.95). A later age of independent walking was associated with a lower cognitive developmental quotient (28 children; p<0.001; slope=-1.01; 95% CI: -1.53 to -0.49). A higher cognitive developmental quotient was seen in children with an age at testing younger than 24 months. The cognitive developmental quotient of children with a delay in independent walking (>17.6mo) was significantly lower than those without a delay (p=0.006). INTERPRETATION: A strong relation exists between cognitive and motor development. Furthermore, the age of independent walking might be an important indicator of the development of children with Dravet syndrome. WHAT THIS PAPER ADDS: Cognitive and motor development are strongly related in children with Dravet syndrome. Later age of independent walking is associated with worse cognitive development in children with Dravet syndrome.
Assuntos
Desenvolvimento Infantil/fisiologia , Cognição/fisiologia , Epilepsias Mioclônicas/psicologia , Caminhada/fisiologia , Pré-Escolar , Epilepsias Mioclônicas/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Estudos RetrospectivosRESUMO
N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
Assuntos
Epilepsia Generalizada/genética , Receptores de N-Metil-D-Aspartato/genética , Adulto , Sequência de Aminoácidos/genética , Animais , Criança , Pré-Escolar , Epilepsia Generalizada/fisiopatologia , Feminino , Regulação da Expressão Gênica/genética , Ácido Glutâmico/metabolismo , Células HEK293 , Humanos , Masculino , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/genéticaRESUMO
OBJECTIVE: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. METHODS: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. RESULTS: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. SIGNIFICANCE: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Assuntos
Epilepsia/genética , Comorbidade , Variações do Número de Cópias de DNA , Epilepsia/complicações , Predisposição Genética para Doença , Genótipo , Humanos , FenótipoRESUMO
AIM: The aim of this study is to describe the course of motor development in children with Dravet syndrome. METHOD: Forty-three participants (21 males, 22 females; mean age at last assessment 53.89mo±42.50mo) met the inclusion criteria of having a confirmed diagnosis of Dravet syndrome and presence of data on motor development. All data between 1985 and 2018 were derived retrospectively from their medical records. Gross motor milestones and motor age equivalents were used to describe motor development. Standardized neurodevelopmental assessment and the Bayley Scales of Infant Development defined the overall motor development. Peabody Developmental Motor Scales, Bruininks-Oseretsky Test of Motor Proficiency, and the Beery-Buktenica Developmental Test of Visual-Motor Integration were used to describe development in specific motor domains. RESULTS: Children with Dravet syndrome showed a delay in both sitting (seven out of 14) and walking independently (11 out of 25). Overall motor age equivalents revealed a delay in 29 out of 38 assessments (age 9-115mo). All assessments of children older than 2 years (16 out of 16) showed a delay. Gross motor delay was present in seven out of seven and fine motor delay in 10 out of 13 assessments (age 19-167mo). INTERPRETATION: Motor development is delayed in the majority of children with Dravet syndrome older than 2 years and increases with age. WHAT THIS PAPER ADDS: A delay in motor development is present in most children with Dravet syndrome older than 2 years. Large diversity in early gross motor milestones confirms heterogeneity in Dravet syndrome.
Desarrollo motor en niños con el síndrome de Dravet OBJETIVO: El objetivo de este estudio es describir el curso del desarrollo motor en los niños con síndrome de Dravet. METODOLOGÍA: Cuarenta y tres participantes (21 niños, 22 niñas; con edad promedio en la última evaluación de 53,89 meses ± 42,50 meses) cumplieron los criterios de inclusión: tener un diagnóstico confirmado de síndrome de Dravet y presentar datos de desarrollo motor. Todos los datos recogidos entre 1,985 y 2,018 fueron extraídos retrospectivamente de las historias clínicas. Los hitos de motricidad gruesa y las equivalencias de edad motora se utilizaron para describir el desarrollo motor. Evaluaciones del neurodesarrollo estandarizadas y la escala de desarrollo infantil Bayley definieron el desarrollo motor global. La escala de desarrollo motor Peabody, el test de competencia motora Bruininks-Oseretsky y el test de desarrollo de la integración visomotora Beery-Buktenica se utilizaron para describir el desarrollo en los dominios motores específicos. RESULTADOS: Los niños con el síndrome de Dravet mostraron un retraso tanto en sentarse (7 de 14) como en caminar de manera independiente (11 de 25). En conjunto, las edades motoras equivalentes revelaron un retraso en 29 de las 38 evaluaciones (edad de 9-115 meses). Todas las evaluaciones de niños mayores de 2 años (16 de 16) mostraron un retraso. El retraso de la motricidad gruesa estuvo presente en 7 de 7 evaluaciones y el retraso de la motricidad fina en 10 de 13 evaluaciones (edad 19-167 meses). INTERPRETACIÓN: El desarrollo motor está retrasado en la mayoría de los niños con síndrome de Dravet mayores de dos años y aumenta con la edad.
Desenvolvimento motor em crianças com síndrome de Dravet OBJETIVO: O objetivo deste estudo é descrever o curso do desenvolvimento motor em crianças com síndrome de Dravet. MÉTODO: Quarenta e três participantes (21 do sexo masculino, 22 do sexo feminino; média de idade na última avaliação 53,89m ± 42,50m) atenderam aos critérios de inclusão de ter um diagnóstico confirmado de síndrome de Dravet e a presença de dados sobre o desenvolvimento motor. Todos os dados entre 1985 e 2018 foram derivados retrospectivamente de seus registros médicos. Marcos motores globais e idade motora equivalente foram usados para descrever o desenvolvimento motor. Avaliação padronizada do neurodesenvolvimento e a Escala Bayley de Desenvolvimento Infantil definiram o desenvolvimento global. A Escala Peabody de Desenvolvimento Motor, o Teste de Proficiência Motora de Bruininks-Oseretsky, e o Teste Desenvolvimental de Beery-Buktenica para Integração Visuo-motora foram usados para descrever o desenvolvimento em domínios motores específicos. RESULTADOS: Crianças com síndrome de Dravet mostraram atraso no sentar (sete em 14) e no andar independente (11 em 25). A idade motora global equivalente revelou atraso em 29 de 38 avaliações (idade 9-115m). Todas as avaliações de crianças com mais de 2 anos (16 de 16) mostraram atraso. O atraso motor global estava presente em sete de sete, e motor fino em 10 de 13 avaliações (idade 19-167m). INTERPRETAÇÃO: O desenvolvimento motor é atrasado na maioria das crianças com síndrome de Dravet maiores do que 2 anos, e aumenta com a idade.
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Desenvolvimento Infantil/fisiologia , Epilepsias Mioclônicas/fisiopatologia , Transtornos das Habilidades Motoras/fisiopatologia , Destreza Motora/fisiologia , Movimento/fisiologia , Criança , Pré-Escolar , Epilepsias Mioclônicas/complicações , Feminino , Humanos , Lactente , Masculino , Transtornos das Habilidades Motoras/complicações , Estudos RetrospectivosRESUMO
OBJECTIVE: Lennox-Gastaut syndrome (LGS) is a drug-resistant, childhood onset electroclinical epilepsy syndrome with multiple seizure types and diagnostic electroencephalogram findings. ZX008 (fenfluramine HCl oral solution) was well tolerated and reduced seizure frequency in Dravet syndrome, prompting this phase 2, open-label, dose-finding study of add-on ZX008 in patients with LGS (NCT02655198). METHODS: Eligible treatment-refractory patients with LGS aged 3-18 years with ≥4 documented convulsive seizures (CS) in the prior 4 weeks were administered adjunctive ZX008 twice daily at an initial dose of 0.2 mg/kg/d, with incremental dose escalations up to 0.8 mg/kg/d or 30 mg/d (maximum dose) every 4 weeks in nonresponders (<50% reduction in CS frequency). After 20 weeks (core study), responders were offered entry into a long-term extension study. Seizures were captured via diary. Cardiac safety was monitored by Doppler echocardiography and electrocardiogram. RESULTS: Thirteen patients were enrolled (mean age = 11.7 years, range = 3-17). Ten (77%) patients completed 20 weeks of ZX008 treatment. During the core study, there was a 53% median reduction (N = 13) in CS; median reduction was 60% in the 10 completers. Eight patients (62%) had a ≥50% CS reduction; three (23%) patients had a ≥75% reduction. Nine (69%) patients entered the long-term extension study. At 15 months (n = 9), median reduction in CS was 58%; six (67%) patients had a ≥50% reduction, and three (33%) patients had a ≥75% reduction. The most common adverse events were decreased appetite (n = 4, 31%) and decreased alertness (n = 2, 15%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. SIGNIFICANCE: ZX008 provided clinically meaningful reduction (≥50%) in CS frequency in the majority of patients with LGS in this pilot study and was generally well tolerated. A phase 3, randomized, controlled study is ongoing.
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Anticonvulsivantes/uso terapêutico , Fenfluramina/uso terapêutico , Síndrome de Lennox-Gastaut/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Projetos Piloto , Resultado do TratamentoRESUMO
BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Transtorno do Espectro Autista/genética , Face/anormalidades , Feminino , Fatores de Transcrição Forkhead/química , Fatores de Transcrição Forkhead/metabolismo , Humanos , Transtornos da Linguagem/genética , Masculino , Transtornos das Habilidades Motoras/genética , Mutação , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Estabilidade Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Síndrome , Transcrição GênicaRESUMO
Dravet syndrome (DS) is a rare and therapy-resistant epilepsy syndrome. A retrospective analysis of add-on fenfluramine treatment in 12 patients with DS was published in 2012 and provided evidence of a meaningful long-term response. Herein we present the results of a subsequent 5-year prospective observation of this original cohort. Ten patients with a mean current age of 24 years were followed prospectively from 2010 until 2014. The mean current dose of fenfluramine was 0.27 mg/kg/day, with a mean treatment duration of 16.1 years. Seizure frequency was derived from a seizure diary. Cardiac examinations and assessments of clinical effectiveness and adverse events were performed at least annually. Three patients were seizure-free for the entire 5 years, and an additional four patients experienced seizure-free intervals of at least 2 years. Fenfluramine was generally well-tolerated. Two patients had mild (stable) valve thickening on the last echocardiography that was deemed clinically insignificant. No patient had any clinical or echocardiographic signs of pulmonary hypertension. These findings support the long-term control of convulsive seizures by low-dose fenfluramine while being well tolerated in this cohort of patients with DS. After up to 27 years of treatment, no patient has developed any clinical signs or symptoms of cardiac valvulopathy or pulmonary hypertension.
Assuntos
Epilepsias Mioclônicas/tratamento farmacológico , Fenfluramina/uso terapêutico , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Adolescente , Adulto , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified in patients with benign (familial) infantile convulsions (B(F)IC), infantile convulsions with choreoathetosis (ICCA) and paroxysmal dyskinesias (PDs). However it remains unknown whether PRRT2 mutations are causal in other epilepsy syndromes. After we discovered a PRRT2 mutation in a large family with ICCA containing one individual with febrile seizures (FS) and one individual with West syndrome, we analysed PRRT2 in a heterogeneous cohort of patients with different types of infantile epilepsy. METHODS: We screened a cohort of 460 patients with B(F)IC or ICCA, fever related seizures or infantile epileptic encephalopathies. All patients were tested for point mutations using direct sequencing. RESULTS: We identified heterozygous mutations in 16 individuals: 10 familial and 6 sporadic cases. All patients were diagnosed with B(F)IC, ICCA or PD. We were not able to detect mutations in any of the other epilepsy syndromes. Several mutation carriers had learning disabilities and/or impaired fine motor skills later in life. CONCLUSIONS: PRRT2 mutations do not seem to be involved in the aetiology of FS or infantile epileptic encephalopathies. Therefore B(F)IC, ICCA and PD remain the core phenotypes associated with PRRT2 mutations. The presence of learning disabilities or neuropsychiatric problems in several mutation carriers calls for additional clinical studies addressing this developmental aspect in more detail.
Assuntos
Epilepsia/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Mutação Puntual/genética , Epilepsia/complicações , Epilepsia/diagnóstico , Feminino , Humanos , Deficiências da Aprendizagem/complicações , Deficiências da Aprendizagem/genética , Masculino , Transtornos das Habilidades Motoras/complicações , Transtornos das Habilidades Motoras/genética , Linhagem , FenótipoRESUMO
Mixta calida, previously known as Pantoea calida, was initially isolated from powdered infant milk in 2010. It falls within the Erwiniaceae family (class: Enterobacterales). While Mixta calida was traditionally regarded as non-pathogenic, we now present a case of Mixta calida bacteraemia and meningitis in a 5-week-old child, successfully treated with cefotaxime. This case, in contrast to prior reports with potential contamination issues, is the first to offer compelling evidence of Mixta calida's pathogenicity in humans.
RESUMO
The implementation of whole exome sequencing (WES) has had a major impact on the diagnostic yield of genetic testing in individuals with epilepsy. The identification of a genetic etiology paves the way to precision medicine: an individualized treatment approach, based on the disease pathophysiology. The aim of this retrospective cohort study was to: (1) determine the diagnostic yield of WES in a heterogeneous cohort of individuals with epilepsy referred for genetic testing in a real-world clinical setting, (2) investigate the influence of epilepsy characteristics on the diagnostic yield, (3) determine the theoretical yield of treatment changes based on genetic diagnosis and (4) explore the barriers to implementation of precision medicine. WES was performed in 247 individuals with epilepsy, aged between 7 months and 68 years. In 34/247 (14 %) a (likely) pathogenic variant was identified. In 7/34 (21 %) of these individuals the variant was found using a HPO-based filtering. Diagnostic yield was highest for individuals with an early onset of epilepsy (39 %) or in those with a developmental and epileptic encephalopathy (34 %). Precision medicine was a theoretical possibility in 20/34 (59 %) of the individuals with a (likely) pathogenic variant but implemented in only 11/34 (32 %). The major barrier to implementation of precision treatment was the limited availability or reimbursement of a given drug. These results confirm the potential impact of genetic analysis on treatment choices, but also highlight the hurdles to the implementation of precision medicine. To optimize precision medicine in real-world practice, additional endeavors are needed: unifying definitions of precision medicine, establishment of publicly accessible databases that include data on the functional effect of gene variants, increasing availability and reimbursement of precision therapeutics, and broadening access to innovative clinical trials.
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Epilepsia Generalizada , Epilepsia , Humanos , Lactente , Medicina de Precisão , Estudos Retrospectivos , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Epilepsia/genética , Testes Genéticos/métodos , Epilepsia Generalizada/genéticaRESUMO
INTRODUCTION: Dravet Syndrome (DS) is a severe developmental and epileptic encephalopathy. Fenfluramine recently demonstrated to be a highly efficacious and safe treatment option for DS patients. Fenfluramine has been recently approved by the FDA and EMA and is marketed as Fintepla®. AREAS COVERED: DS and the need for additional anticonvulsive treatment options is discussed. The results of three placebo-controlled phase III studies (1 with and 2 without stiripentol) and 2 open label (extension) studies are reviewed. All studies demonstrate a consistent and impressive seizure reduction, confirming the results of two smaller investigator-initiated trials. The mechanism of action of fenfluramine is discussed. Finally, the place of fenfluramine in the future treatment of DS is outlined. EXPERT OPINION: Fenfluramine has a potent anticonvulsive effect in DS. Although not yet fully elucidated, the anticonvulsive mechanism of fenfluramine seems to be mainly serotonergic. Fenfluramine is generally well tolerated. A dose reduction is necessary in combination with stiripentol. Considering new competitors, efficacy seems lower for cannabidiol and is comparable with stiripentol. Preclinical studies indicate a disease specific action and possible disease modification in DS. The latter would support the use of fenfluramine above its anticonvulsive effect and needs to be further elaborated.
Assuntos
Epilepsias Mioclônicas , Espasmos Infantis , Anticonvulsivantes/uso terapêutico , Epilepsias Mioclônicas/tratamento farmacológico , Síndromes Epilépticas , Fenfluramina/uso terapêutico , Humanos , Convulsões/tratamento farmacológico , Espasmos Infantis/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVES: Pathogenic variants in the neuronal sodium channel α1 subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies. METHODS: We performed a retrospective multicenter cohort study comprising data from patients with SCN1A-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using 2 independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome vs other GEFS+ phenotypes. RESULTS: A total of 1,018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1, and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score (133.4 [SD 78.5] vs 52.0 [SD 57.5]; p < 0.001) and young age at onset (6.0 [SD 3.0] vs 14.8 [SD 11.8] months; p < 0.001) were each associated with Dravet syndrome vs GEFS+. A combined SCN1A genetic score and seizure onset model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC] 0.89 [95% CI 0.86-0.92]) and outperformed all other models (AUC 0.79-0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC 0.94 [95% CI 0.91-0.97]) and 2 (AUC 0.92 [95% CI 0.82-1.00]). DISCUSSION: The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/). CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.