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Scientific Reports Feb 2022Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we...
Juvenile myoclonic epilepsy (JME) is a common idiopathic generalised epilepsy with variable seizure prognosis and sex differences in disease presentation. Here, we investigate the combined epidemiology of sex, seizure types and precipitants, and their influence on prognosis in JME, through cross-sectional data collected by The Biology of Juvenile Myoclonic Epilepsy (BIOJUME) consortium. 765 individuals met strict inclusion criteria for JME (female:male, 1.8:1). 59% of females and 50% of males reported triggered seizures, and in females only, this was associated with experiencing absence seizures (OR = 2.0, p < 0.001). Absence seizures significantly predicted drug resistance in both males (OR = 3.0, p = 0.001) and females (OR = 3.0, p < 0.001) in univariate analysis. In multivariable analysis in females, catamenial seizures (OR = 14.7, p = 0.001), absence seizures (OR = 6.0, p < 0.001) and stress-precipitated seizures (OR = 5.3, p = 0.02) were associated with drug resistance, while a photoparoxysmal response predicted seizure freedom (OR = 0.47, p = 0.03). Females with both absence seizures and stress-related precipitants constitute the prognostic subgroup in JME with the highest prevalence of drug resistance (49%) compared to females with neither (15%) and males (29%), highlighting the unmet need for effective, targeted interventions for this subgroup. We propose a new prognostic stratification for JME and suggest a role for circuit-based risk of seizure control as an avenue for further investigation.
Topics: Adolescent; Adult; Child; Cross-Sectional Studies; Drug Resistance; Epilepsies, Myoclonic; Epilepsy, Absence; Female; Humans; Male; Middle Aged; Myoclonic Epilepsy, Juvenile; Photosensitivity Disorders; Prognosis; Seizures; Sex Characteristics; Young Adult
PubMed: 35190554
DOI: 10.1038/s41598-022-06324-2 -
Epilepsia Aug 2023The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is...
The progressive myoclonus epilepsies (PMEs) are a heterogeneous group of neurodegenerative disorders, typically presenting in late childhood. An etiologic diagnosis is achieved in about 80% of patients with PME, and genome-wide molecular studies on remaining, well-selected, undiagnosed cases can further dissect the underlying genetic heterogeneity. Through whole-exome sequencing (WES), we identified pathogenic truncating variants in the IRF2BPL gene in two, unrelated patients presenting with PME. IRF2BPL belongs to the transcriptional regulators family and it is expressed in multiple human tissues, including the brain. Recently missense and nonsense mutations in IRF2BPL were found in patients presenting with developmental delay and epileptic encephalopathy, ataxia, and movement disorders, but none with clear PME. We identified 13 other patients in the literature with myoclonic seizures and IRF2BPL variants. There was no clear genotype-phenotype correlation. With the description of these cases, the IRF2BPL gene should be considered in the list of genes to be tested in the presence of PME, in addition to patients with neurodevelopmental or movement disorders.
Topics: Humans; Child; Myoclonic Epilepsies, Progressive; Seizures; Epilepsies, Myoclonic; Genotype; Movement Disorders; Carrier Proteins; Nuclear Proteins
PubMed: 36810721
DOI: 10.1111/epi.17557 -
CNS Drugs Apr 2018Dravet syndrome (DS) is a medically refractory epilepsy that onsets in the first year of life with prolonged seizures, often triggered by fever. Over time, patients... (Review)
Review
Dravet syndrome (DS) is a medically refractory epilepsy that onsets in the first year of life with prolonged seizures, often triggered by fever. Over time, patients develop other seizure types (myoclonic, atypical absences, drops), intellectual disability, crouch gait and other co-morbidities (sleep problems, autonomic dysfunction). Complete seizure control is generally not achievable with current therapies, and the goals of treatment are to balance reduction of seizure burden with adverse effects of therapies. Treatment of co-morbidities must also be addressed, as they have a significant impact on the quality of life of patients with DS. Seizures are typically worsened with sodium-channel agents. Accepted first-line agents include clobazam and valproic acid, although these rarely provide adequate seizure control. Benefit has also been noted with stiripentol, topiramate, levetiracetam, the ketogenic diet and vagal nerve stimulation. Several agents presently in development, specifically fenfluramine and cannabidiol, have shown efficacy in clinical trials. Status epilepticus is a recurring problem for patients with DS, particularly in their early childhood years. All patients should be prescribed a home rescue therapy (usually a benzodiazepine) but should also have a written seizure action plan that outlines when rescue should be given and further steps to take in the local hospital if the seizure persists despite home rescue therapy.
Topics: Animals; Epilepsies, Myoclonic; Humans
PubMed: 29594870
DOI: 10.1007/s40263-018-0511-y -
Clinical Dysmorphology Jan 2022Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM# 611726) is a rare autosomal recessive condition associated with pathogenic variants in... (Review)
Review
Epilepsy, progressive myoclonic 3, with or without intracellular inclusions (MIM# 611726) is a rare autosomal recessive condition associated with pathogenic variants in KCTD7, which encodes the BR-C,ttk and bab/pox virus and zinc finger domain-containing KCTD7 protein. We report four individuals from three Indian families presenting with an initial period of normal development, progressive myoclonic seizures followed by neuroregression and an abnormal electroencephalogram. We identified two novel missense variants, c.458G>C p.(Arg153Pro) and c.205C>G p.(Leu69Val) and one known disease-causing variant, c.280C>T p.(Arg94Trp) in KCTD7 by exome sequencing. We review the literature of 67 individuals with variants in KCTD7. Our study expands the molecular spectrum of KCTD7-related progressive myoclonic epilepsy.
Topics: Humans; Mutation, Missense; Myoclonic Epilepsies, Progressive; Potassium Channels; Exome Sequencing
PubMed: 34866617
DOI: 10.1097/MCD.0000000000000394 -
Epileptic Disorders : International... Sep 2016The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential... (Review)
Review
The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.
Topics: Epilepsies, Myoclonic; Humans
PubMed: 27618961
DOI: 10.1684/epd.2016.0860 -
Revue Neurologique Apr 2024The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy... (Review)
Review
The ILAE's Task Force on Nosology and Definitions revised in 2022 its definition of juvenile myoclonic epilepsy (JME), the most common idiopathic generalized epilepsy disorder, but this definition may well change again in the future. Although good drug response could almost be a diagnostic criterion for JME, drug resistance (DR) is observed in up to a third of patients. It is important to distinguish this from pseudoresistance, which is often linked to psychosocial problems or psychiatric comorbidities. After summarizing these aspects and the various definitions applied to JME, the present review lists the risk factors for DR-JME that have been identified in numerous studies and meta-analyses. The factors most often cited are absence seizures, young age at onset, and catamenial seizures. By contrast, photosensitivity seems to favor good treatment response, at least in female patients. Current hypotheses on DR mechanisms in JME are based on studies of either simple (e.g., cortical excitability) or more complex (e.g., anatomical and functional connectivity) neurophysiological markers, bearing in mind that JME is regarded as a neural network disease. This research has revealed correlations between the intensity of some markers and DR, and above all shed light on the role of these markers in associated neurocognitive and neuropsychiatric disorders in both patients and their siblings. Studies of neurotransmission have mainly pointed to impaired GABAergic inhibition. Genetic studies have generally been inconclusive. Increasing restrictions have been placed on the use of valproate, the standard antiseizure medication for this syndrome, owing to its teratogenic and developmental risks. Levetiracetam and lamotrigine are prescribed as alternatives, as is vagal nerve stimulation, and there are several other promising antiseizure drugs and neuromodulation methods. The development of better alternative treatments is continuing to take place alongside advances in our knowledge of JME, as we still have much to learn and understand.
Topics: Humans; Myoclonic Epilepsy, Juvenile; Anticonvulsants; Drug Resistant Epilepsy; Female; Risk Factors
PubMed: 38461125
DOI: 10.1016/j.neurol.2024.02.385 -
Acta Neurologica Belgica Apr 2024Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant... (Review)
Review
Familial Adult Myoclonus Epilepsy (FAME), with a prevalence of < 1/35 000, is known under different acronyms. The disease is transmitted in an autosomal dominant manner and is characterized by the occurrence of cortical myoclonic tremor, overt myoclonus, and rare bilateral tonic-clonic seizures. FAME is considered neurodegenerative, although it is relatively slow in progression. Diagnosis is based on specific neurophysiological testing, namely jerk-locked back-averaging, somatosensory evoked potentials, long latency reflex, and motor evoked potentials, among others. Imaging data, including functional magnetic resonance imaging, indicate a cortical origin of the cortical myoclonic tremor and decreased cerebellar activation. Cerebellar changes in Purkinje cells have been noted, from few neuropathology reports, in patients from isolated pedigrees. The differential diagnosis includes essential tremor, some forms of genetic generalized epilepsy, and progressive myoclonus epilepsies. Treatment is mainly symptomatic.
Topics: Adult; Humans; Myoclonus; Tremor; Epilepsies, Myoclonic; Evoked Potentials, Somatosensory; Reflex; Electroencephalography
PubMed: 38114875
DOI: 10.1007/s13760-023-02432-6 -
Practical Neurology Jun 2015Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a... (Review)
Review
Progressive myoclonic epilepsies are a group of disorders characterised by a relentlessly progressive disease course until death; treatment-resistant epilepsy is just a part of the phenotype. This umbrella term encompasses many diverse conditions, ranging from Lafora body disease to Gaucher's disease. These diseases as a group are important because of a generally poor response to antiepileptic medication, an overall poor prognosis and inheritance risks to siblings or offspring (where there is a proven genetic cause). A correct diagnosis also helps patients and their families to accept and understand the nature of their disease, even if incurable. Here, we discuss the phenotypes of these disorders and summarise the relevant specific investigations to identify the underlying cause.
Topics: Humans; Myoclonic Epilepsies, Progressive
PubMed: 25720773
DOI: 10.1136/practneurol-2014-000994 -
Seizure Apr 2019Familial adult myoclonic epilepsy (FAME), also described with different acronyms (ADCME, BAFME, FEME, FCTE and others), is a high-penetrant autosomal dominant condition... (Review)
Review
Familial adult myoclonic epilepsy (FAME), also described with different acronyms (ADCME, BAFME, FEME, FCTE and others), is a high-penetrant autosomal dominant condition featuring cortical hand tremors, myoclonic jerks, and occasional/rare convulsive seizures. Prevalence is unknown since this condition is often under-recognized, but it is estimated to be less than 1/35,000. The disease usually starts in the second decade of life and has been genetically associated with at least 4 different loci (8q24, 2p11.1-q12.2, 5p15.31-p15 and 3q26.32-3q28). Recently, the expansion of non coding TTTTA and TTTCA repeats has been identified as the causative mutation in Japanese families linked to the 8q24. The diagnosis is supported by clinical features and electrophysiological investigations as jerk-locked back averaging, C-reflex, and somatosensory-evoked potential. Photic stimulation, emotional stress, and sleep deprivation may trigger both tonic-clonic and myoclonic seizures. FAME has a slow but progressive clinical course occurring with intellectual disability and worsening of both tremor and myoclonus although with a less severe decline compared to other progressive myoclonic epilepsies. Valproate, levetiracetam, and benzodiazepines are considered the first-line treatments.
Topics: DNA Repeat Expansion; Epilepsies, Myoclonic; Humans
PubMed: 30928698
DOI: 10.1016/j.seizure.2019.03.009 -
Epilepsia Jun 2023Familial adult myoclonic epilepsy (FAME) is an under-recognized disorder characterized by cortical myoclonus, generalized tonic-clonic seizures, and additional clinical...
OBJECTIVE
Familial adult myoclonic epilepsy (FAME) is an under-recognized disorder characterized by cortical myoclonus, generalized tonic-clonic seizures, and additional clinical symptoms, which vary depending on the FAME subtype. FAME is caused by pentanucleotide repeat expansions of intronic TTTCA/TTTTA in different genes. FAME should be distinguished from a range of differential diagnoses.
METHODS
The differential diagnoses and frequent presentations leading to misdiagnosis of FAME were investigated from the available literature and reported based on an expert opinion survey.
RESULTS
The phenotypic features of FAME, including generalized tonic-clonic and myoclonic seizures, are also seen in other epilepsy syndromes, such as juvenile myoclonic epilepsy, with a resultant risk of misdiagnosis and lack of identification of the underlying cause. Cortical myoclonus may mimic essential tremor or drug-induced tremor. In younger individuals, the differential diagnosis includes progressive myoclonus epilepsies (PMEs), such as Unverricht-Lundborg disease, whereas, in adulthood, late-onset variants of PMEs, such as sialidoses, myoclonus epilepsy, and ataxia due to potassium channel pathogenic variants should be considered. PMEs may also be suggested by cognitive impairment, cerebellar signs, or psychiatric disorders. Electroencephalography (EEG) may show similarities to other idiopathic generalized epilepsies or PMEs, with generalized spike-wave activity. Signs of cortical hyperexcitability may be seen, such as an increased amplitude of somatosensory evoked potentials or enhanced cortical reflex to sensory stimuli, together with the neurophysiological pattern of the movement disorder.
SIGNIFICANCE
Recognition of FAME will inform prognostic and genetic counseling and diagnosis of the insidious progression, which may occur in older individuals who show mild cognitive deterioration. Distinguishing FAME from other disorders in individuals or families with this constellation of symptoms is essential to allow the identification of underlying etiology.
Topics: Humans; Adult; Aged; Diagnosis, Differential; Myoclonus; Epilepsies, Myoclonic; Epilepsy, Generalized; Electroencephalography; Myoclonic Epilepsies, Progressive; Myoclonic Epilepsy, Juvenile; Seizures
PubMed: 36751956
DOI: 10.1111/epi.17536