ABSTRACT
Familial adult myoclonus epilepsy (FAME) is an autosomal dominant condition characterized by the association of myoclonic tremor and epilepsy mainly with onset in adulthood. The clinical course is non-progressive or slowly progressive, as epilepsy is commonly controlled with appropriate antiseizure medication and individuals have a normal life expectancy. However, the myoclonus severity increases with age and leads to some degree of disability in the elderly. Because the non-coding repeat expansions responsible for FAME are not detected by routine genetic tests being used at this time, a clinical diagnosis accompanied by neurophysiological testing remains essential to guide the geneticist on the selection of the specific genetic technique.
Subject(s)
Epilepsies, Myoclonic , Myoclonus , Humans , Adult , Aged , Myoclonus/diagnosis , Myoclonus/genetics , Myoclonus/complications , Epilepsies, Myoclonic/diagnosis , Epilepsies, Myoclonic/genetics , Epilepsies, Myoclonic/complications , Pedigree , Disease ProgressionABSTRACT
OBJECTIVE: Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of syndromes, including Lennox-Gastaut syndrome (LGS), which are refractory to multiple therapies. Perampanel efficacy has been reported in LGS but further real-world evidence is needed in DEEs. METHODS: A multicenter, retrospective, 1-year observational study in patients with DEEs on adjuvant perampanel treatment was conducted to assess perampanel safety and effectiveness in this type of patients in a real-world setting. Seizure types [focal onset seizures (FOS), generalized tonic-clonic seizures (GTCS), tonic seizures (TS), atonic seizures (AtS), atypical absences (AA), and myoclonic seizures (MS)] and seizure clusters were divided in different frequency groups: daily, weekly, and monthly seizures, and absent or seizure freedom. Patients could have more than one seizure type. For each frequency group, group change and seizure freedom were analyzed. RESULTS: Eighty-seven patients diagnosed with DEEs (45 males) of median age 22 [1-70] years were included. The most frequent DEEs were LGS (35.6%) and Lennox-like syndrome (37.9%). At baseline 20 patients had three to five types of seizures, 36 patients had two types of seizures and 31 patients had one predominant type of seizure. The mean number of seizure types per patient at baseline was 2.12 ± 0.97 which was reduced to 1.62 ± 0.91 at 12 months (p < 0.001). Overall, 51.7% of patients had a significant improvement in at least one seizure type. At baseline, 45 patients had GTCS, 42 FOS, 41 TS, 18 AA, 16 AtS, 11 MS, and 30 seizures clusters. Seizure freedom for each specific type at 12 months was significantly achieved by 35% of patients with GTCS (p < 0.001), 17% (p = 0.016) with TS and 37% with seizure clusters (p < 0.001). Patients achieved seizure freedom from other seizure types but with no statistical significance: 7% FOS-free, 28% AA-free, 6% Ats-free, and 18% MS-free. Regarding changes of group at 12 months, 22% of TS and 19% of FOS improved significantly to a group with lower seizure frequency (p = 0.004 and p = 0.02, respectively). In remaining groups (4% of GTCS, 11% of AA, 18% of Ats, 18% of MS, and 13% of seizure clusters), the improvement was not statistically significant. Twenty-nine patients discontinued perampanel: 18 (21%) due to AEs, 8 (9%) due to lack of efficacy, and 3 (3%) due to seizure worsening. Adverse events, mostly mild or moderate, were reported in 53% of patients, and irritability/mood changes (22%) and somnolence (17%) were the most frequent. CONCLUSION: This is the first large-scale real-world study with perampanel across different seizure types in patients with DEEs. Perampanel was effective, especially in GTCS, TS, and FOS, as well as in seizure clusters. Perampanel was generally well-tolerated without unexpected AEs.
Subject(s)
Epilepsies, Myoclonic , Epilepsy, Generalized , Lennox Gastaut Syndrome , Adult , Anticonvulsants , Humans , Male , Nitriles , Pyridones , Retrospective Studies , Seizures , Treatment Outcome , Young AdultABSTRACT
OBJECTIVE: To assess the effectiveness and tolerability of eslicarbazepine acetate (ESL) monotherapy in routine clinical practice for the treatment of focal-onset seizures. METHODS: Multicenter, retrospective, observational study conducted in patients older than 16 years treated with ESL as first-line monotherapy or converted to ESL monotherapy from polytherapy or other monotherapy. Outcomes included 1-year retention rate, seizure-free rates after 6 and 12 months of monotherapy treatment, and safety/tolerability issues. RESULTS: A total of 256 patients were included (106 first-line and 150 conversion to monotherapy; 56 patients aged >65 years). Overall, the 1-year retention rate was 79% (72.7% in the ≥65 years subgroup) and seizure-free rates at 6 and 12 months were 59.3% and 55.3% (72.2% and 67.3% in the ≥65 years subgroup), without significant differences when comparing first-line vs conversion-to-ESL monotherapy groups (P = .979). However, the conversion group was heterogeneous and included 43 (29.1%) patients that were seizure free the year prior ESL introduction. A substantially higher proportion of patients remained seizure free for the entire follow-up among those who initiated ESL due to tolerability problems compared with those treated due to inadequate seizure control (71.4% vs 37.3%). Overall, 62 of 256 (24.2%) patients reported AEs (39.3% in >65 years subgroup) and led to discontinuation in 20/256 (7.8%) patients (12.5% in >65 years subgroup). Commonly reported AEs were somnolence (6.6%), dizziness (6.3%), and headache (4.3%). Hyponatremia was recorded in five patients, the majority (4/5) of whom were older than 65 years. CONCLUSIONS: Eslicarbazepine acetate was effective and well-tolerated as first-line or conversion to monotherapy in a clinical setting in adult and elderly patients with focal-onset seizures.
Subject(s)
Anticonvulsants/therapeutic use , Dibenzazepines/therapeutic use , Seizures/drug therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
Subject(s)
Brain Diseases/diagnosis , Brain Diseases/genetics , Epilepsy/diagnosis , Kv1.2 Potassium Channel/genetics , Animals , Brain Diseases/complications , Epilepsy/complications , Epilepsy/genetics , Genetic Association Studies , Mutation , Oocytes/physiology , Phenotype , XenopusABSTRACT
Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.
Subject(s)
DNA-Binding Proteins/genetics , Epilepsies, Myoclonic/genetics , Animals , Child , Cognition Disorders/genetics , Cognition Disorders/pathology , Cohort Studies , Epilepsies, Myoclonic/pathology , Exome , Female , Gene Knockdown Techniques , Haploinsufficiency , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Larva/genetics , Male , NAV1.1 Voltage-Gated Sodium Channel/genetics , Phenotype , Seizures, Febrile/genetics , Seizures, Febrile/pathology , Young Adult , ZebrafishABSTRACT
Even though amygdalar lesions are a known epilepsy model in laboratory animals, the role of the amygdala in mesial temporal sclerosis is not well-known. To date, most interest has been paid to the role of the hippocampal formation. The aim of this article is to emphasize the role of the amygdala in order to render a patient seizure free. Two patients are presented who were 50 and 42 years old at the time of surgery. They suffered from seizures since childhood and were diagnosed with mesial temporal sclerosis. A temporal lobectomy with hippocampectomy and partial amygdalectomy was performed on both patients in the year 2000, with one patient operated on the right side and the other one on the left side. Both patients were seizure free after surgery for 6 years, but presented again with seizures after that time. They were evaluated again for surgery, and subdural grids were placed, together with a deep electrode in the remnants of the amygdala. The amygdalar electrode showed to be the seizure onset in the two cases, and its resection rendered both patients seizure free. These two patients show that a complete amygdalar resection is necessary to render some patients seizure free. It might be the amygdala has a greater role than previously thought.
Subject(s)
Amygdala/surgery , Epilepsy, Temporal Lobe/surgery , Adult , Female , Humans , Middle Aged , Neurosurgical ProceduresABSTRACT
Epileptic seizures are more common in patients with Alzheimer disease than in the general elderly population. Abnormal forms of hyperphosphorylated tau accumulate in Alzheimer disease and other tauopathies. Aggregates of tau are also found in patients with epilepsy and in experimental models of epilepsy. We report here the analysis of epileptic activity and neuropathological correlates of a transgenic line over-expressing human mutant tau, a model of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The FTDP-17 model displays spontaneous epileptic activity and seizures with spike-wave complexes in the EEG, and a higher sensitivity to the GABAA receptor antagonist pentylenetetrazol (PTZ) when compared to age-matched controls, showing a notably increased seizure length and a shorter latency to develop severe seizures. FTDP-17 human tau mutants also display lower convulsive thresholds and higher lethality after PTZ injections. Astrocytosis and activated microglia are prominent in the hippocampus and other brain regions of young FTDP-17 mice where the human mutant tau transgene is expressed, before the appearance of hyperphosphorylated tau aggregates in these structures. FTDP-17 human mutant tau over-expression produces epilepsy and increased GABAA receptor-mediated hyperexcitability in the absence of Aß pathology. Although aggregates of hyperphosphorylated tau have been observed in patients with epilepsy and in different chemically and electrically generated models of epilepsy, the FTDP-17 tau mutant analyzed here is the first model of genetically modified tau that presents with epilepsy. This model may represent a valuable tool to assay novel treatments in order to reduce tau pathology, a potential factor which may be involved in the development of epileptic seizures in dementia and other neurodegenerative diseases.
Subject(s)
Epilepsy/etiology , Frontotemporal Dementia/complications , Frontotemporal Dementia/genetics , tau Proteins/genetics , Animals , Brain/metabolism , Brain/pathology , Calcium-Binding Proteins/metabolism , Convulsants/toxicity , DNA-Binding Proteins , Disease Models, Animal , Electroencephalography , Epilepsy/chemically induced , Frontotemporal Dementia/pathology , Glial Fibrillary Acidic Protein/metabolism , Humans , Mice , Mice, Transgenic , Microfilament Proteins/metabolism , Pentylenetetrazole/toxicity , Polycomb-Group Proteins , Transcription Factors/metabolism , Video RecordingABSTRACT
Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2 months at 10 months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.
Subject(s)
Lafora Disease , Metformin , Animals , Mice , Lafora Disease/drug therapy , Lafora Disease/genetics , Metformin/therapeutic use , Gliosis , Follow-Up Studies , Ubiquitin-Protein Ligases/geneticsABSTRACT
INTRODUCTION: Experts agree that there is a need for protocols to guide health professionals on how to best manage psychiatric comorbidities in patients with epilepsy (PWE). We aimed to develop practical recommendations for key issues in the management of depression in PWE. METHODS: This was a qualitative study conducted in four steps: (1) development of a questionnaire on the management of depression in PWE to be answered; (2) literature review and, if evidence from guidelines/consensus or systematic reviews was available, drafting initial recommendations; (3) a nominal group methodology for reviewing initial recommendations and formulating new recommendations on those issues without available evidence; and (4) drafting and approving the final recommendations. A scientific committee (one neurologist and one psychiatrist) was responsible for the development of the project and its scientific integrity. The scientific committee selected a panel of experts (nine neurologists and nine psychiatrists with experience in this field) to be involved in the nominal group meetings and to formulate final recommendations. RESULTS: Fifteen recommendations were formulated. Four on the screening and diagnosis: screening and diagnosis of depression, evaluation of the risk of suicide, and diagnosis of depression secondary to epilepsy; nine on the management of depression: referral to a psychiatrist, selection of the antiseizure medication, change of antiseizure medication, antidepressant treatment initiation, selection of antidepressant, use of antidepressants during pregnancy, use of psychotherapy, antidepressant treatment duration, and discontinuation of antidepressant treatment; two on the follow-up: duration of the follow-up under usual conditions, and follow-up of patients at risk of suicide. CONCLUSION: We provide recommendations based on expert opinion consensus to help healthcare professionals assess depression in PWE. The detection and treatment of major depressive disorders are key factors in improving epilepsy outcomes and avoiding suicide risk.
ABSTRACT
OBJECTIVE: To investigate the clinical and EEG features of Encephalopathy with Status Epilepticus during slow Sleep (ESES) related to CNKSR2 pathogenic variants. METHODS: Detailed clinical history, repeated wakefulness/overnight sleep EEGs, brain MRI were collected in five patients, including one female, with CNKSR2-related ESES. RESULTS: Neurodevelopment in infancy was normal in two patients, delayed in three. Epilepsy onset (age range: 2-6 years) was associated with appearance or aggravation of cognitive impairment, language regression and/or behavioral disorders. Worsening of epilepsy and of cognitive/behavioral disturbances paralleled by enhancement of non-rapid eye movement (NREM) sleep-related, frontally predominant, EEG epileptic discharges [spike-wave-index (SWI): range 60-96%] was consistent with ESES. In three patients, episodes of absence status epilepticus or aggravation of atypical absences occurred, in this latter case associated with striking increment of awake SWI. Speech/oro-motor dyspraxia was diagnosed in four patients. In two patients, long-term follow-up showed epilepsy remission and persistence of mild/moderate cognitive disorders and behavioral disturbances into adulthood. CONCLUSIONS: Novel findings of our study are occurrence also in females, normal neurodevelopment before epilepsy onset, epilepsy aggravation associated with enhanced awake SWI, mild/moderate evolution in adulthood and language disorder due to speech/oro-motor dyspraxia. SIGNIFICANCE: Our findings expand the phenotypic spectrum of CNKSR2-related ESES.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Brain Diseases/genetics , Electroencephalography/methods , Genetic Variation/genetics , Sleep, Slow-Wave/genetics , Status Epilepticus/genetics , Adult , Brain Diseases/diagnostic imaging , Brain Diseases/physiopathology , Child , Child, Preschool , Female , Humans , Magnetic Resonance Imaging/methods , Male , Status Epilepticus/diagnostic imaging , Status Epilepticus/physiopathology , Young AdultABSTRACT
OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of zonisamide (ZNS) for the treatment of idiopathic generalized epilepsies (IGEs). METHODS: Thirteen patients with different types of IGEs who were treated with ZNS between the years 2006 and 2008 were identified. Efficacy and tolerability were assessed at months 6 and 12 post-treatment. Response was defined as a 50% or greater reduction in seizure frequency. RESULTS: Twelve patients (92.3%) continued with ZNS at month 6, and 11 (84.6%) at month 12. Mean daily dose was 319 mg (range 100-500 mg/d). Response was achieved at month 6 in eight of the 12 patients that continued with ZNS (66.6%), of which 7 were seizure-free (58.3%). At month 12, eight of the 11 patients that continued with ZNS were responders (72.7%) and 6 were seizure-free (63.6%). For different types of seizures, better responses were observed for absences and generalized tonic-clonic seizures. Four out of 13 patients (30.7%) experienced adverse events and in two (15.3%), these led to withdrawal. CONCLUSION: In this retrospective study, ZNS showed efficacy and tolerability for the treatment of different types of IGEs. Limitations include a small sample size and a relatively short period of follow-up. Our results are promising and justify the need for prospective controlled trials in IGE.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy, Generalized/drug therapy , Isoxazoles/therapeutic use , Adolescent , Adult , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Child , Dose-Response Relationship, Drug , Electroencephalography , Epilepsy, Generalized/classification , Epilepsy, Generalized/diagnosis , Female , Follow-Up Studies , Humans , Isoxazoles/administration & dosage , Isoxazoles/adverse effects , Male , Middle Aged , Retrospective Studies , Spain , Treatment Outcome , Young Adult , ZonisamideABSTRACT
PURPOSE: External trigeminal nerve stimulation is an emerging noninvasive therapy for drug resistant epilepsy (DRE). The aim of this study is to describe the long-term outcome of a series of patients treated with eTNS. METHODS: We present a retrospective observational study of patients with DRE who received eTNS treatment, comparing the monthly seizure frequency during the 3-months period before eTNS initiation with the monthly seizure frequency at 6, 12, 24, 36 and 48 months after eTNS. We analyze the responder rate, the retention rate and the tolerability. RESULTS: 17 patients with highly drug-resistant epilepsy were included. Mean follow-up was 2194 [6-56] months. The responder rate was 35% at 6 months and 12 months, 23% at 24 months, 19% at 36 months, and 14% at 48 months. Retention rates at the same periods were 88%, 53%, 41%, 37.5% and 28.5%. There were no reports of serious adverse events. Four patients reported improvement in sleep and better mood. CONCLUSION: The effectivity of eTNS is similar to some of the new treatments available, with a retention rate of 52% in the first year and 285% at 4 years. Tolerability is excellent with only mild effects reported by a minority of patients.
Subject(s)
Drug Resistant Epilepsy/therapy , Electric Stimulation Therapy , Adolescent , Adult , Child , Drug Resistant Epilepsy/complications , Electric Stimulation Therapy/methods , Follow-Up Studies , Humans , Middle Aged , Patient Compliance , Retrospective Studies , Seizures/etiology , Seizures/therapy , Treatment Outcome , Trigeminal Nerve , Young AdultABSTRACT
Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare genetic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose uptake through the blood-brain barrier. Our objective is to analyze the frequency of GLUT1-DS in patients with absences with atypical features. Sequencing analysis and detection of copy number variation of the SLC2A1 gene was carried out in patients with atypical absences including: early-onset absence, intellectual disability, additional seizure types, refractory epilepsy, associated movement disorders, as well as those who have first-degree relatives with absence epilepsy or atypical EEG ictal discharges. Of the 43 patients analyzed, pathogenic variations were found in 2 (4.6%). Six atypical characteristics were found in these 2 patients. The greater the number of atypical characteristics presenting in patients with absence seizures, the more likely they have a SLC2A1 mutation. Although GLUT1-DS is an infrequent cause of absence epilepsy, recognizing this disorder is important, since initiation of a ketogenic diet can reduce the frequency of seizures, the severity of the movement disorder, and also improve the quality of life of the patients and their families.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/complications , Carbohydrate Metabolism, Inborn Errors/genetics , Epilepsy, Absence/etiology , Epilepsy, Absence/genetics , Genetic Variation/genetics , Glucose Transporter Type 1/genetics , Monosaccharide Transport Proteins/deficiency , Adolescent , Adult , Carbohydrate Metabolism, Inborn Errors/diet therapy , Child , Child, Preschool , Cohort Studies , Diet, Ketogenic/methods , Epilepsy, Absence/diet therapy , Female , Humans , Male , Middle Aged , Monosaccharide Transport Proteins/genetics , Treatment Outcome , Young AdultSubject(s)
Lysosomal Membrane Proteins/genetics , Mutation/genetics , Myoclonic Epilepsies, Progressive/genetics , Myoclonus/genetics , Receptors, Scavenger/genetics , Renal Insufficiency/complications , Adult , Ataxia/genetics , Female , Humans , Myoclonus/diagnosis , Renal Insufficiency/genetics , Sequence Analysis, DNA/methodsABSTRACT
Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel). Using this gene panel, we were able to identify disease-causing variants in 17 out of 87 (19.5%) analyzed patients, all found in known epilepsy-associated genes (KCNQ2, CDKL5, STXBP1, SCN1A, PCDH19, POLG, SLC2A1, ARX, ALG13, CHD2, SYNGAP1, and GRIN1). Twelve of 18 variants arose de novo and 6 were novel. The highest yield was found in patients with onset in the first years of life, especially in patients classified as having early-onset epileptic encephalopathy. Knowledge of the underlying genetic cause provides essential information on prognosis and could be used to avoid unnecessary studies, which may result in a greater diagnostic cost-effectiveness.
Subject(s)
Developmental Disabilities/diagnosis , Epilepsy/diagnosis , Genetic Predisposition to Disease , Child, Preschool , Developmental Disabilities/genetics , Epilepsy/genetics , Female , Humans , Infant, Newborn , MaleABSTRACT
BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.
ABSTRACT
PURPOSE: The goal of this study is to report the efficacy and tolerability of lacosamide (LCM) monotherapy, as first-line and conversion regimens, in the treatment of patients with partial-onset seizures. METHODS: We retrospectively reviewed the charts of patients with focal epilepsy on LCM monotherapy from six centers in Spain. Efficacy and tolerability were evaluated in the overall group and in subgroups of patients who were naive to antiepileptic drug (AED) therapy (Group 1) and those who had previously been treated with AEDs (Group 2). RESULTS: Sixty-six patients were identified including 18 patients in Group 1 and 48 patients in Group 2. Patients were followed up for 0.5-54 months in monotherapy (mean 15.5 months). Forty-two (63.6%) patients remained seizure-free during all the follow-up. At 6 and 12 months, seizure-free rates were 77.6% and 72.3%, respectively. The drug was withdrawn in 10 (15%) patients (3 side effects, 6 lack of efficacy, 1 other reason). Fifteen (22.7%) patients reported mild to moderate side effects with the use of LCM. No differences were found between Groups 1 and 2 regarding efficacy outcomes or tolerability issues. CONCLUSIONS: In our series more than two-thirds of the patients remained seizure-free on LCM monotherapy. Side effects were generally mild and led to discontinuation in only 3/66 (4.5%) patients. Our experience suggests that LCM monotherapy, either as first-line or after conversion, may be a valuable option for patients with focal epilepsy.
Subject(s)
Acetamides/therapeutic use , Anticonvulsants/therapeutic use , Epilepsies, Partial/drug therapy , Seizures/drug therapy , Acetamides/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Anticonvulsants/adverse effects , Female , Follow-Up Studies , Humans , Lacosamide , Male , Middle Aged , Retrospective Studies , Spain , Time Factors , Treatment Outcome , Young AdultABSTRACT
Spinal muscular atrophy and progressive myoclonic epilepsy (SMAPME, OMIM#159950) is a rare autosomal recessive disorder characterized by the combination of progressive myoclonic epilepsy and muscular weakness due to lower motor neuron disease. Mutations in ASAH1, previously associated only to Farber disease, have been recently described in seven patients with SMAPME. A homozygous c.125C>T mutation was initially found in six patients with a clinical homogeneous phenotype. A heterozygous compound mutation found in an additional patient has broadened the clinical and genetic spectrum of clinical SMAPME. We report a new case of a 13-year-old girl with SMAPME with the homozygous ASAH1 c.125C>T mutation, unique in that it is due to paternal uniparental disomy. She experienced muscle weakness from the age of three due to lower motor neuron involvement that lead to severe handicap and onset in late childhood of a progressive myoclonic epilepsy. This clinical picture fully overlaps with that of previously reported patients with this mutation and supports our view that the clinical phenotype associated with the homozygous c.125C>T mutation constitutes a clinically homogenous and recognizable disease.
Subject(s)
Acid Ceramidase/genetics , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/physiopathology , Myoclonic Epilepsies, Progressive/genetics , Myoclonic Epilepsies, Progressive/physiopathology , Uniparental Disomy , Adolescent , Chromosomes, Human, Pair 8 , Female , Haplotypes , Homozygote , Humans , Muscular Atrophy, Spinal/etiology , Mutation , Myoclonic Epilepsies, Progressive/etiology , PhenotypeABSTRACT
No disponible
Subject(s)
Humans , Female , Infant , Hypoxia/complications , Seizures/diagnosis , Seizures/etiology , Seizures/drug therapy , Anticonvulsants/administration & dosage , Valproic Acid/administration & dosage , Levetiracetam/administration & dosageABSTRACT
A benign prognosis has been claimed in benign familial infantile seizures (BFIS). However, few studies have assessed the long-term evolution of these patients. The objective of this study is to describe atypical courses and presentations in BFIS families with mutations in PRRT2 gene. We studied clinically affected individuals from five BFIS Spanish families. We found mutations in PRRT2 in all 5 families. A non-BFIS phenotype or an atypical BFIS course was found in 9/25 (36%) patients harbouring a PRRT2 mutation. Atypical features included neonatal onset, mild hemiparesis, learning difficulties or mental retardation, and recurrent seizures during adulthood. We also report a novel PRRT2 mutation (c.121_122delGT). In BFIS families an atypical phenotype was present in a high percentage of the patients. These findings expand the clinical spectrum of PRRT2 mutations including non-benign epileptic phenotypes.