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Cells Jun 2023Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main... (Review)
Review
Familial adult myoclonus Epilepsy (FAME) is a non-coding repeat expansion disorder that has been reported under different acronyms and initially linked to four main loci: FAME1 (8q23.3-q24.1), FAME 2 (2p11.1-q12.1), FAME3 (5p15.31-p15.1), and FAME4 (3q26.32-3q28). To date, it is known that the genetic mechanism underlying FAME consists of the expansion of similar non-coding pentanucleotide repeats, TTTCA and TTTTA, in different genes. FAME is characterized by cortical tremor and myoclonus usually manifesting within the second decade of life, and infrequent seizures by the third or fourth decade. Cortical tremor is the core feature of FAME and is considered part of a spectrum of cortical myoclonus. Neurophysiological investigations as jerk-locked back averaging (JLBA) and corticomuscular coherence analysis, giant somatosensory evoked potentials (SEPs), and the presence of long-latency reflex I (or C reflex) at rest support cortical tremor as the result of the sensorimotor cortex hyperexcitability. Furthermore, the application of transcranial magnetic stimulation (TMS) protocols in FAME patients has recently shown that inhibitory circuits are also altered within the primary somatosensory cortex and the concomitant involvement of subcortical networks. Moreover, neuroimaging studies and postmortem autoptic studies indicate cerebellar alterations and abnormal functional connectivity between the cerebellum and cerebrum in FAME. Accordingly, the pathophysiological mechanism underlying FAME has been hypothesized to reside in decreased sensorimotor cortical inhibition through dysfunction of the cerebellar-thalamic-cortical loop, secondary to primary cerebellar pathology. In this context, the non-coding pentameric expansions have been proposed to cause cerebellar damage through an RNA-mediated toxicity mechanism. The elucidation of the underlying pathological mechanisms of FAME paves the way to novel therapeutic possibilities, such as RNA-targeting treatments, possibly applicable to other neurodegenerative non-coding disorders.
Topics: Humans; Adult; Myoclonus; Tremor; Epilepsies, Myoclonic; Reflex; Neurodegenerative Diseases
PubMed: 37371086
DOI: 10.3390/cells12121617 -
Epilepsia Jun 2021This study was undertaken to expand the phenotypic and genetic spectrum of CLCN4-related epilepsy and to investigate genotype-phenotype correlations.
OBJECTIVE
This study was undertaken to expand the phenotypic and genetic spectrum of CLCN4-related epilepsy and to investigate genotype-phenotype correlations.
METHODS
We systematically reviewed the phenotypic and genetic spectrum of newly diagnosed and previously reported patients with CLCN4-related epilepsy. Three novel variants identified in four patients reported in this study were evaluated through in silico prediction and functional analysis by Western blot, immunofluorescence, and electrophysiological measurements.
RESULTS
Epilepsy was diagnosed in 54.55% (24/44) of individuals with CLCN4-related disorders and was drug-resistant in most cases. Of 24 patients, 15 had epileptic encephalopathy and four died at an early age; 69.57% of patients had seizure onset within the first year of life. Myoclonic seizures are the most common seizure type, and 56.25% of patients presented multiple seizure types. Notably, seizure outcome was favorable in individuals with only one seizure type. All patients showed intellectual disability, which was severe in 65.22% of patients. Additional common features included language delay, behavioral disorders, and dysmorphic features. Five patients benefitted from treatment with lamotrigine. Most variants, which were mainly missense (79.17%), were inherited (70.83%). Whereas frameshift, intragenic deletion, or inherited variants were associated with milder phenotypes, missense or de novo variants led to more severe phenotypes. All evaluated CLCN4 variants resulted in loss of function with reduced ClC-4 currents. Nonetheless, genotype-phenotype relationships for CLCN4-related epilepsy are not straightforward, as phenotypic variability was observed in recurrent variants and within single families.
SIGNIFICANCE
Pathogenic CLCN4 variants contribute significantly to the genetic etiology of epilepsy. The phenotypic spectrum of CLCN4-related epilepsy includes drug-resistant seizures, cognitive and language impairment, behavioral disorders, and congenital anomalies. Notably, the mutation type and the number of seizure types correlate with the severity of the phenotype, suggesting its use for clinical prognosis. Lamotrigine can be considered a therapeutic option.
Topics: Adolescent; Adult; Aged; Anticonvulsants; Child; Child Behavior Disorders; Child, Preschool; Chloride Channels; Developmental Disabilities; Electroencephalography; Epilepsies, Myoclonic; Epilepsy; Female; Frameshift Mutation; Gene Deletion; Genetic Variation; Genotype; Humans; Lamotrigine; Language Disorders; Magnetic Resonance Imaging; Male; Mutation, Missense; Phenotype; Seizures
PubMed: 33951195
DOI: 10.1111/epi.16906 -
Seizure Apr 2021Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on... (Review)
Review
Dravet Syndrome (DS) is a rare and severe infantile-onset epileptic encephalopathy. DS research focuses mainly on children. We did a systematic review, completed on January 18, 2021, examining the number of clinical DS studies. We show that there are 208 studies on children exclusively, 28 studies on adults exclusively, and 116 studies involving adults and children combined. This 7:1 ratio of children to adult studies exclusively shows the dearth of research that addresses long-term natural history of DS into adulthood. Through this systematic review, we examine the most up-to-date information in DS adults as it pertains to seizures, electroencephalogram, imaging, treatment, motor abnormalities, cognitive and social behavior outcomes, cardiac abnormalities, sleep disturbances, diagnosis in adults, and mortality. Overall, the frequency of seizures increases in the first decade of life and then myoclonic, atypical absences and focal seizures with impaired awareness tend to decrease in frequency or even disappear in adulthood. Adults tend to have a notable reduction in status epilepticus, especially after 30 years of age. Parkinsonian features were seen in patients as young as 19 years old and are more severe in older patients, suggesting a progression of the parkinsonian symptoms. In adulthood, patients continue to present with behavior problems, associated with a lower health-related quality of life. The leading reported cause of death in DS adults is Sudden Unexpected Death in Epilepsy (SUDEP). Further studies in older adults are needed to understand the long-term outcomes of patients with DS.
Topics: Adult; Epilepsies, Myoclonic; Humans; Infant; Mutation; NAV1.1 Voltage-Gated Sodium Channel; Quality of Life; Spasms, Infantile; Young Adult
PubMed: 33677403
DOI: 10.1016/j.seizure.2021.02.025 -
Medicina Clinica Mar 2023Idiopathic generalized epilepsies (IGI) are an electroclinical syndrome that includes four subsyndromes according to the ILAE 2017 classification. The long-term...
INTRODUCTION
Idiopathic generalized epilepsies (IGI) are an electroclinical syndrome that includes four subsyndromes according to the ILAE 2017 classification. The long-term prognosis of these syndromes is uncertain due to the scarcity and heterogeneity of the studies. The objective of this study is to analyze the long-term prognosis of these syndromes, pharmacological treatment and the seizure recurrence.
METHOD
Observational and retrospective study of a serie of patients diagnosed with EGI. Epidemiological variables, pharmacological treatment, freedom of seizures and recurrence after withdrawal of treatment were collected.
RESULTS
We included 101 patients, the majority women (56.4%), with a median evolution of epilepsy of 17 years (interquartile range: 7-31). The most frequent syndrome was juvenile myoclonic epilepsy (46.5%), followed by epilepsy with generalized tonic-clonic seizures alone (25.7%), juvenile absence epilepsy (13.9%) and childhood absence epilepsy (13.9%). The 71.29% were on monotherapy and 20.79% on polytherapy, with significant differences between the different syndromes (P=.001). The most widely used drug was valproic acid. 39.6% presented seizure remission at 5 years, but we did not observe significant differences between the different syndromes (P=.982). The recurrence rate was 71.4% after withdrawal of treatment.
CONCLUSION
Juvenile myoclonic epilepsy was the most frequent subtype of IGE. We observed significant differences in terms of polytherapy in the different syndromes, although not in the rates of remission of seizures at one year and at five years. The majority of patients with treatment withdrawal relapsed.
Topics: Humans; Female; Child; Myoclonic Epilepsy, Juvenile; Retrospective Studies; Epilepsy, Generalized; Epilepsy, Absence; Seizures; Syndrome; Anticonvulsants; Electroencephalography
PubMed: 36030098
DOI: 10.1016/j.medcli.2022.06.019 -
Epilepsy & Behavior : E&B Aug 2023Epilepsy with eyelid myoclonia(EEM) or Jeavons syndrome is considered a genetic generalized epilepsy with a typical age of onset in childhood. Many types of seizures can... (Review)
Review
BACKGROUND
Epilepsy with eyelid myoclonia(EEM) or Jeavons syndrome is considered a genetic generalized epilepsy with a typical age of onset in childhood. Many types of seizures can be observed, including eyelid myoclonia, absence, generalized tonic-clonic, and myoclonic seizures. Seizures tend to be difficult to control requiring polypharmacy treatment or become drug-resistant. Dietary therapy, particularly with Modified Atkins Diet (MAD), as a treatment of seizures in this syndrome has rarely been studied. We report efficacy and tolerability of MAD in children with epilepsy with eyelid myoclonia.
METHODS
We reviewed medical records of children with EEM treated at the University of Chicago Ketogenic Diet program from 2017 to 2022. Patient's demography, seizure characteristics, EEG findings, response to treatment, and adverse effects were reviewed.
RESULT
Six patients with EEM were identified. Average age of seizure onset was 6 (2-11) years and an average age when the MAD started was 10.7 (6-15) years. All patients were started on MAD and completed at least 6 months on the diet at the time of report. An average of 4 (0-9) anti-seizure medications (ASM) had been tried prior to the MAD. All patients achieved ketosis with an average level of serum beta-hydroxybutyrate of 1.9 (1.03-3.61) mmol/L. At the 6-month follow-up visit, all patients (100%) experienced a greater than 50% seizure reduction, 3/6 patients (50%) had more than 90% seizure reduction, 1/6 patients (17%) became seizure-free. All seizure types demonstrated a greater than 80% reduction in frequency.Absence and myoclonic seizures showed the greatest reduction with 100% seizure reduction. Eyelid myoclonia and generalized tonic-clonic seizures showed more than 80% seizure reduction.Moreover, all patients reported improvement in alertness, mood, and concentration. Initial weight loss and mild gastrointestinal disturbances were reported in 2/6 patients (33%) and corrected with dietary adjustment.
CONCLUSION
The Modified Atkins Diet has shown to be effective and welltolerated for children with EEM in our study. Cognitive improvement has also been subjectively reported in all patients. Adverse effects are tolerable and correctable. The MAD, therefore, may be considered as a treatment option for patients with epilepsy with eyelid myoclonia.
Topics: Humans; Child; Adolescent; Diet, High-Protein Low-Carbohydrate; Retrospective Studies; Epilepsy, Generalized; Diet, Ketogenic; Epilepsy, Reflex; Epilepsies, Myoclonic; Myoclonus; Diet, Carbohydrate-Restricted; Seizures; Eye Diseases; Eyelids; Treatment Outcome
PubMed: 37459720
DOI: 10.1016/j.yebeh.2023.109347 -
Expert Review of Neurotherapeutics Apr 2020: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades.... (Review)
Review
: Progressive myoclonus epilepsies (PMEs) are a group of neurodegenerative diseases, invariably leading to severe disability or fatal outcome in a few years or decades. Nowadays, PMEs treatment remains challenging with a significant burden of disability for patients. Pharmacotherapy is primarily used to treat seizures, which impact patients' quality of life. However, new approaches have emerged in the last few years, which try to curb the neurological deterioration of PMEs through a better knowledge of the pathogenetic process. This is a review on the newest therapeutic options for the treatment of PMEs.: Experimental and clinical results on novel therapeutic approaches for the different forms of PME are reviewed and discussed. Special attention is primarily focused on the efficacy and tolerability outcomes, trying to infer the role novel approaches may have in the future.: The large heterogeneity of disease-causing mechanisms prevents researchers from identifying a single approach to treat PMEs. Understanding of pathophysiologic processes is leading the way to targeted therapies, which, through enzyme replacement or underlying gene defect correction have already proved to potentially strike on neurodegeneration.
Topics: Humans; Myoclonic Epilepsies, Progressive
PubMed: 32153206
DOI: 10.1080/14737175.2020.1741350 -
Epileptic Disorders : International... Feb 2023The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were...
The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike-wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike-waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Epilepsies, Myoclonic; Retrospective Studies; Seizures, Febrile; Electroencephalography; Epilepsy, Generalized
PubMed: 36946369
DOI: 10.1002/epd2.20052 -
Expert Opinion on Pharmacotherapy Oct 2022Dravet Syndrome (DS) is a developmental and epileptic encephalopathy carrying high-level psychobehavioral burdens. Although the disease has been known for almost 4... (Review)
Review
INTRODUCTION
Dravet Syndrome (DS) is a developmental and epileptic encephalopathy carrying high-level psychobehavioral burdens. Although the disease has been known for almost 4 decades, and despite significant progress in the understanding of its physiopathology and natural course, the pharmacological treatment leaves patients and caregivers with significant unmet needs. This review provides a summary of the current and promising therapeutic options for DS.
AREAS COVERED
PubMed and ClinicalTrials.gov were screened using 'Dravet Syndrome' OR 'DS,' AND 'pharmacotherapy,' AND 'treatments.' Randomized clinical trials, structured reviews, and meta-analyses were selected for in-human application of well-known anti-seizure medications; while experiments on models of DS were selected to evaluate the potential of new therapeutic strategies.
EXPERT OPINION
The search for new pharmacological treatment options is led by the need for care and defeat of the natural course of the disease, an aspect still largely neglected by the available therapeutic strategies. Yet, the last 6 years have led to a climate of increased interest and availability of clinical trials. Particularly, gene therapy could hopefully prevent DS evolution by directly relieving the specific genetic defect, although the possibility of off-target editing, and the uneasy administration route have still largely prevented its use.
Topics: Humans; Epilepsies, Myoclonic; Spasms, Infantile; Epileptic Syndromes
PubMed: 36124778
DOI: 10.1080/14656566.2022.2127089 -
Epilepsia Jul 2023Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are...
Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between -40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.
Topics: Cricetinae; Animals; Fluoxetine; Cricetulus; Precision Medicine; Gain of Function Mutation; Seizures; Epilepsies, Myoclonic; Seizures, Febrile
PubMed: 37203213
DOI: 10.1111/epi.17656 -
Epilepsia Apr 2024SCN1A variants are associated with epilepsy syndromes ranging from mild genetic epilepsy with febrile seizures plus (GEFS+) to severe Dravet syndrome (DS). Many variants...
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, χ = 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.
Topics: Humans; Retrospective Studies; NAV1.1 Voltage-Gated Sodium Channel; Epilepsy; Epilepsies, Myoclonic; Seizures, Febrile; Phenotype; Genetic Association Studies; Status Epilepticus; Mutation
PubMed: 38410936
DOI: 10.1111/epi.17882