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OBJECTIVE: We explored the efficacy and safety of lacosamide combined with inhibitors of fast-inactivated sodium channels or with other antiepileptic drugs, in patients with drug refractory focal epilepsy associated with intellectual or psychiatric disability. METHODS: Observational study of lacosamide including the monitoring of lacosamide trough plasma levels and of electroencephalograms. RESULTS: We followed up 44 patients from the start of lacosamide therapy for up to 3â¯years, with a clinical, electroencephalogram (EEG), and pharmacological follow-up. Median patients' age was 32.7â¯years, median age at epilepsy onset was 3.5â¯years. Intellectual disability was severe in 55.4% of the cohort and drug refractoriness was diagnosed in 88.6% of patients, who had predominantly focal seizures (80%). The severity of their epilepsy was suggested by the use of combined therapies with non-sodium blockers and sodium blockers in 75% of patients. Lacosamide was added to previous therapies and up-titrated to a median of 300â¯mg/d. Lacosamide add-on led to simplification of the previous drug regimen with a dose reduction in 87.9% of users of sodium blockers and in 66.7% of users of non-sodium blockers, and to withdrawal of previously administered sodium blockers in 48.5% users and non-sodium blockers in 47.6% users. Lacosamide was prescribed at lower doses in the presence of oxcarbazepine (pâ¯=â¯0.029), lamotrigine (pâ¯=â¯0.015), and topiramate (pâ¯<â¯0.001). Mean lacosamide plasma levels were 6.0⯱â¯2.4â¯mg/L; they were in linear correlation with the administered dose (R2â¯=â¯0.38, pâ¯<â¯0.001) and were influenced by the association with lamotrigine (pâ¯=â¯0.008), zonisamide (pâ¯=â¯0.012), and clobazam (pâ¯=â¯0.028). Lacosamide combination regimens led to an average reduction of 42% in baseline seizure frequency, with 50% patients reporting ≥50% seizure frequency reduction. Efficacy was directly correlated with lacosamide dose (R2â¯=â¯0.47, pâ¯<â¯0.001, Bâ¯=â¯0.53) and trough plasma levels (R2â¯=â¯0.31, pâ¯<â¯0.001, Bâ¯=â¯0.16). Electroencephalogram profiles were improved in 40.9% of patients and EEG improvement was not significantly correlated with seizure frequency reduction. Lacosamide safety was good, with 37 adverse reactions in 30 patients, of which 50% were attributed to lacosamide and led to lacosamide withdrawal in 18% of cases. The retention rate of lacosamide was of 88.6% at 1â¯year, 86.4% at 2â¯years, and 72.7% after three years. The severity of intellectual disability was directly correlated with increased possibility of lacosamide retention (ORâ¯=â¯0.46 per severity tier, pâ¯=â¯0.016). CONCLUSION: Lacosamide add-on allowed dose reduction of previous therapies and reduced the frequency of seizures, showing good tolerability even at high doses, without exceeding reference plasma levels.
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Epilepsia Refractaria , Epilepsia , Adulto , Anticonvulsivantes/efectos adversos , Epilepsia Refractaria/inducido químicamente , Epilepsia Refractaria/tratamiento farmacológico , Quimioterapia Combinada , Epilepsia/tratamiento farmacológico , Humanos , Lacosamida/uso terapéutico , Resultado del TratamientoRESUMEN
INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4â¯years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12â¯months of RFM therapy. METHODS: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58â¯years (meanâ¯=â¯22⯱â¯16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100â¯mg/week increments up to a dose of 300-2400â¯mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12â¯months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. RESULTS: After 12â¯months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. CONCLUSION: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1â¯year of follow-up.
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Síndrome de Lennox-Gastaut , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Niño , Cognición , Humanos , Síndrome de Lennox-Gastaut/tratamiento farmacológico , Persona de Mediana Edad , Estudios Prospectivos , Triazoles , Adulto JovenRESUMEN
INTRODUCTION: Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS. METHODS: Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism. RESULTS: WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu-elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20. WES failed to detect BPP-associated variants. CONCLUSIONS: Although we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient's NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.
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Trastornos de los Cromosomas/genética , Cromotripsis , Translocación Genética , Cesárea , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 22/genética , Hibridación Genómica Comparativa , Femenino , Genómica , Haploinsuficiencia/genética , Humanos , Lactante , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Embarazo , Cromosomas en Anillo , Factores de Transcripción/genéticaRESUMEN
Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG-fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra-striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG-informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra-striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247-2262, 2016. © 2016 Wiley Periodicals, Inc.
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Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Electroencefalografía , Imagen por Resonancia Magnética , Oxígeno/sangre , Percepción Visual/fisiología , Adulto , Encéfalo/diagnóstico por imagen , Mapeo Encefálico , Femenino , Humanos , Modelos Lineales , Masculino , Imagen Multimodal , Estimulación Luminosa , Análisis de OndículasRESUMEN
Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.
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Enfermedades del Sistema Nervioso Autónomo/etiología , Cardiopatías/etiología , Hemiplejía/complicaciones , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Electrocardiografía , Femenino , Cardiopatías/diagnóstico , Frecuencia Cardíaca/genética , Ventrículos Cardíacos/fisiopatología , Hemiplejía/genética , Humanos , Lactante , Recién Nacido , Cooperación Internacional , Masculino , Mutación/genética , ATPasa Intercambiadora de Sodio-Potasio/genética , Adulto JovenRESUMEN
Despite negative blood oxygenation level dependent (BOLD) responses to visual stimuli have recently gained considerable interest, the explanation for their underlying neuronal and vascular mechanisms is still controversial. In the present study, a multimodal experimental approach is presented to shed light on the negative BOLD phenomenon in the human brain. In particular, information from functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS) was integrated to confirm and gain insight into the phenomenon of negative BOLD responses (NBRs) to unpatterned intermittent photic stimulation (IPS) in healthy subjects. Eight healthy subjects participated in the study. Consistent findings emerged from the activation analysis of fMRI and NIRS data and the comparison of BOLD and hemoglobin responses at the single channel level showed that NBRs are related to a decrease in oxyhemoglobin (HbO) combined with a lower increase in deoxyhemoglobin (HHb), corresponding to a decrease in total hemoglobin (THb) and estimated cerebral blood volume (CBV). The HbO and HHb variations were significant in at least one channel in six subjects out of eight (p<0.05). The NIRS technique allowed obtaining valuable information on the vascular determinants of the NBRs, since the discrimination between HbO, HHb and THb information provided a more comprehensive view of the negative BOLD phenomenon. The within and between subject heterogeneous BOLD-Hb temporal relations pave the way to further investigations into the neurovascular properties of NBRs.
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Encéfalo/fisiología , Imagen por Resonancia Magnética , Oxígeno/sangre , Estimulación Luminosa , Espectroscopía Infrarroja Corta , Adulto , Femenino , Humanos , MasculinoRESUMEN
In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
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Deleción Cromosómica , Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 22/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Preescolar , Hibridación Genómica Comparativa , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Padres , Cromosomas en Anillo , Eliminación de Secuencia/genética , Translocación Genética , Adulto JovenRESUMEN
BACKGROUND: Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein, essential for cell polarity. Defects in neuronal cell polarity are associated with neurologic disorders. Only three patients with heterozygous MPP5 de novo variants have been reported so far, with global developmental delay, behavioral changes and in only one case epileptic seizures. OBJECTIVE: To describe a new patient with a novel truncating de novo mutation in MPP5 and to characterize in detail the epileptic phenotype and electroencephalographic features of the encephalopathy. METHODS: We identified a novel truncating de novo mutation in MPP5 in a 44 year old patient by exome sequencing (p.Ser498Phefs*15). We retrospectively analyzed his clinical and instrumental data along a thirty-year follow up. RESULT: Our patient presents with generalized tonic-clonic seizures, myoclonic and clonic seizures, non-epileptic myoclonus, tremor, severe intellectual disability, mild face dysmorphic traits, and psychosis. DISCUSSION AND CONCLUSION: We present a case of a childhood onset developmental encephalopathy with a likely-pathogenic variant in the MPP5 gene.. This represents the first complete description of the epileptic syndrome associated with the MPP5 gene.
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Encefalopatías , Epilepsia , Discapacidad Intelectual , Humanos , Niño , Adulto , Estudios Retrospectivos , Epilepsia/genética , Convulsiones/genética , Discapacidad Intelectual/genética , Fenotipo , Encefalopatías/genética , Proteínas de la Membrana/genética , Nucleósido-Fosfato Quinasa/genéticaRESUMEN
Copy number variants (CNVs) represent the genetic cause of about 15-20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband's lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband's LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.
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Glicina , Trastornos del Neurodesarrollo , Humanos , Femenino , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/metabolismo , Trastornos del Neurodesarrollo/patología , Glicina/metabolismo , Glicina/genética , Cromosomas Humanos Par 2/genética , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patología , Niño , Microcefalia/genética , Microcefalia/patología , Microcefalia/metabolismo , Deleción Cromosómica , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Discapacidad Intelectual/metabolismo , PreescolarRESUMEN
Childhood epilepsy can be frequently associated with impaired cognitive functioning. Previous research has suggested an increased risk of cognitive impairment that may be related to the etiology, the electro-clinical pattern and the load of anti-seizure medications (ASMs). The aim of this study was to evaluate the impact of different clinical features on the global intellectual functioning in a cohort of children and adolescents with epilepsy. We studied eighty patients diagnosed and followed in a tertiary care center. These factors were examined: 1. Etiology of epileptic syndrome; 2. Type of seizure; 3. Number of ASMs; 4. Seizure frequency; 5. Age at seizure onset; 6. Total duration of epilepsy; and 7. Active duration of epilepsy. Multiple regression analysis showed that the etiology and the total duration of epilepsy were the best indicators of intellectual functioning. The present data indicate that children with symptomatic epilepsy (SE) have lower IQ scores (M = 63.5), while children with self-limited focal epilepsy and generalized idiopathic epilepsy, i.e. age-related epileptic syndromes (ARES), have a higher IQ (M = 100.0; p < 0.01). Children with epilepsy of unknown etiology (UEE) (M = 75.1; p < 0.05) are positioned at an intermediate level between the SE and the ARES group (p < 0.01). Increased duration of epilepsy was associated with decreased intellectual functioning. In conclusion, knowledge about the risks associated with etiologic factors and the duration of the disease may guide the definition of optimal neuropsychological rehabilitation strategies.
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Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG recordings in children with these clinical pictures are abnormal, however the precise frequency of these abnormalities and their relationship with the pathogenic mechanisms and in particular with epileptic seizures are still unknown. We retrospectively reviewed 292 routine polysomnographic EEG tracings of preschool children (age < 6 years) who had received a first multidisciplinary diagnosis of ASD according to DSM-5 clinical criteria. Children (mean age: 34.6 months) were diagnosed at IRCCS E. Medea (Bosisio Parini, Italy). We evaluated: the background activity during wakefulness and sleep, the presence and the characteristics (focal or diffuse) of the slow-waves abnormalities and the interictal epileptiform discharges. In 78.0% of cases the EEG recordings were found to be abnormal, particularly during sleep. Paroxysmal slowing and epileptiform abnormalities were found in the 28.4% of the subjects, confirming the high percentage of abnormal polysomnographic EEG recordings in children with ASD. These alterations seem to be more correlated with the characteristics of the underlying pathology than with intellectual disability and epilepsy. In particular, we underline the possible significance of the prevalence of EEG abnormalities during sleep. Moreover, we analyzed the possibility that EEG data reduces the ASD clinical heterogeneity and suggests the exams to be carried out to clarify the etiology of the disorder.
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Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
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Cromosomas Humanos X/genética , Electroencefalografía , Duplicación de Gen , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Trastornos del Desarrollo del Lenguaje/complicaciones , Trastornos del Desarrollo del Lenguaje/genética , Femenino , Humanos , Masculino , LinajeRESUMEN
PURPOSE: Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern. METHODS: Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed. KEY FINDINGS: We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature. SIGNIFICANCE: Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients.
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Ondas Encefálicas/fisiología , Epilepsia/genética , Epilepsia/fisiopatología , Genes Duplicados/genética , Proteína 2 de Unión a Metil-CpG/genética , Adolescente , Adulto , Niño , Preescolar , Electroencefalografía , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Adulto JovenRESUMEN
Dynamin-1-like (DNM1L) is a gene located on chromosome 12p11.21 that encodes for dynamin-related protein (DRP1), a GTPase involved in mitochondrial and peroxisomal fusion, which plays a pivotal role in brain development. The missense variant, p.Arg403Cys, is clinically associated with childhood-onset super-refractory status epilepticus, with either subsequent poor neurological outcome or death (described in 13 patients). We present a 20-year-old girl carrying this mutation with a history of two episodes of super-refractory focal myoclonic status epilepticus which manifested as epilepsia partialis continua (EPC) with a 13-year interval, during which she displayed moderate intellectual disability, social and school reintegration, without complete control of myoclonic manifestations. The first status, which occurred at the age of six, was associated with transient left side thalamic involvement and the second episode with right side transient basal ganglia hyperintensity on MRI. After the second status, a persistent vegetative state with both drug-resistant epilepsia partialis continua and reticular myoclonus endured; the MRI showed progressive brain atrophy. In contrast to previous published cases, this new case of childhood-onset DNM1L encephalopathy demonstrated biphasic clinical progression. The main features of our patient were EPC, super-refractory status epilepticus, and transient and migrating subcortical thalamic hyperintensity on MRI at onset. The unusual clinical course is also noticeable, indicating possible epigenetic and/or protective factors, without underestimating the progressive and genetic basis of this encephalopathy. Precise characterization of seizures and whole-exome sequencing are crucial in order to establish early diagnosis.
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Dinaminas , Epilepsia Parcial Continua , Dinaminas/genética , Epilepsia Parcial Continua/diagnóstico , Epilepsia Parcial Continua/genética , Femenino , Humanos , Remisión Espontánea , Estado Epiléptico/etiología , Estado Epiléptico/genética , Adulto JovenRESUMEN
OBJECTIVE: Descriptions of electroencephalographic (EEG) patterns in Aicardi syndrome (AIC) have to date referred to small cohorts of up to six cases and indicated severe derangement of electrical activity in all cases. The present study was conducted to describe the long-term EEG evolution in a larger AIC cohort, followed for up to 23 years, and identify possible early predictors of the clinical and EEG outcomes. METHODS: In a retrospective study, two experienced clinical neurophysiologists systematically reviewed all EEG traces recorded in 12 AIC cases throughout their follow-up, from epilepsy onset to the present. Clinical outcome was assessed with standardized clinical outcome scales. RESULTS: Analysis of the data revealed two distinct AIC phenotypes. In addition to the "classical severe phenotype" already described in the literature, we identified a new "mild phenotype". The two phenotypes show completely different EEG features at onset of epilepsy and during its evolution, which correspond to different clinical outcomes. CONCLUSIONS: Data from our long-term EEG and clinical-neuroradiological study allowed us to describe two different phenotypes of AIC, with different imaging severity and, in particular, different EEG at onset, which tend to remain constant over time. SIGNIFICANCE: Together, these findings might help to predict long-term clinical outcomes.
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Síndrome de Aicardi , Epilepsia , Síndrome de Aicardi/diagnóstico por imagen , Electroencefalografía , Epilepsia/genética , Humanos , Imagen por Resonancia Magnética , Estudios RetrospectivosRESUMEN
A splice site variation (c.603-91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603-91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug-resistant and 401 patients with drug-responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603-91G>A genotypes was similar among drug-resistant and drug-responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603-91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response.
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Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Proteínas del Tejido Nervioso/genética , Polimorfismo Genético , Canales de Sodio/genética , Adulto , Anticonvulsivantes/farmacología , Carbamazepina/análogos & derivados , Carbamazepina/farmacología , Carbamazepina/uso terapéutico , Resistencia a Medicamentos , Epilepsias Parciales/genética , Femenino , Genotipo , Humanos , Italia/etnología , Masculino , Canal de Sodio Activado por Voltaje NAV1.1 , Oxcarbazepina , Farmacogenética , Población Blanca/genéticaRESUMEN
The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.
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Cromosomas Humanos X/genética , Duplicación de Gen , Enfermedades del Sistema Nervioso/genética , Adolescente , Adulto , Encéfalo/patología , Niño , Electrodiagnóstico , Electroencefalografía , Femenino , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/genética , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/patología , Enfermedades del Sistema Nervioso/psicología , Conducción Nerviosa/fisiología , Pruebas Neuropsicológicas , FenotipoRESUMEN
Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy.
RESUMEN
OBJECTIVE: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay. METHODS: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature. RESULTS: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy. CONCLUSIONS: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Guanilato-Quinasas/genética , Encefalopatías/genética , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Masculino , Mutación , Estudios RetrospectivosRESUMEN
Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort.