Sleep-related hypermotor epilepsy in a patient with mucopolysaccharidosis type III.
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ABSTRACT:
SUBMITTER: Abramova AA
PROVIDER: S-EPMC8663726 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectivesTo evaluate functional connectivity (FC) in patients with sleep-related hypermotor epilepsy (SHE) compared to healthy controls.MethodsResting state fMRI was performed in 13 patients with a clinical diagnosis of SHE (age = 38.3 ± 11.8 years, 6 M) and 13 matched healthy controls (age = 38.5 ± 10.8 years, 6 M).Data were first analysed using probabilistic independent component analysis (ICA), then a graph theoretical approach was applied to assess topological and organizational properties at the whole brain level. We evaluated node degree (ND), betweenness centrality (BC), clustering coefficient (CC), local efficiency (LE) and global efficiency (GE). The differences between the two groups were evaluated non-parametrically.ResultsAt the group level, we distinguished 16 RSNs (Resting State Networks). Patients showed a significantly higher FC in sensorimotor and thalamic regions (p < 0.05 corrected). Compared to controls, SHE patients showed no significant differences in network global efficiency, while ND and BC were higher in regions of the limbic system and lower in the occipital cortex, while CC and LE were higher in regions of basal ganglia and lower in limbic areas (p < 0.05 uncorrected).Discussion and conclusionsThe higher FC of the sensorimotor cortex and thalamus might be in agreement with the hypothesis of a peculiar excitability of the motor cortex during thalamic K-complexes. This sensorimotor-thalamic hyperconnection might be regarded as a consequence of an alteration of the arousal regulatory system in SHE. An altered topology has been found in structures like basal ganglia and limbic system, hypothesized to be involved in the pathophysiology of the disease as suggested by the dystonic-dyskinetic features and primitive behaviours observed during the seizures.
| S-EPMC5842749 | biostudies-literature
Project description:The syndrome known as nocturnal frontal lobe epilepsy is recognized worldwide and has been studied in a wide range of clinical and scientific settings (epilepsy, sleep medicine, neurosurgery, pediatric neurology, epidemiology, genetics). Though uncommon, it is of considerable interest to practicing neurologists because of complexity in differential diagnosis from more common, benign sleep disorders such as parasomnias, or other disorders like psychogenic nonepileptic seizures. Moreover, misdiagnosis can have substantial adverse consequences on patients' lives. At present, there is no consensus definition of this disorder and disagreement persists about its core electroclinical features and the spectrum of etiologies involved. To improve the definition of the disorder and establish diagnostic criteria with levels of certainty, a consensus conference using formal recommended methodology was held in Bologna in September 2014. It was recommended that the name be changed to sleep-related hypermotor epilepsy (SHE), reflecting evidence that the attacks are associated with sleep rather than time of day, the seizures may arise from extrafrontal sites, and the motor aspects of the seizures are characteristic. The etiology may be genetic or due to structural pathology, but in most cases remains unknown. Diagnostic criteria were developed with 3 levels of certainty: witnessed (possible) SHE, video-documented (clinical) SHE, and video-EEG-documented (confirmed) SHE. The main research gaps involve epidemiology, pathophysiology, treatment, and prognosis.
| S-EPMC4862248 | biostudies-literature
Project description:To assess the long-term outcome of sleep-related hypermotor epilepsy (SHE).We retrospectively reconstructed a representative cohort of patients diagnosed with SHE according to international diagnostic criteria, sleep-related seizures ?75% and follow-up ?5 years. Terminal remission (TR) was defined as a period of ?5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimates to calculate the cumulative time-dependent probability of TR and to generate survival curves. Univariate and multivariate Cox regression analyses were performed.We included 139 patients with a 16-year median follow-up (2,414 person-years). The mean age at onset was 13 ± 10 years. SHE was sporadic in 86% of cases and familial in 14%; 16% of patients had underlying brain abnormalities. Forty-five percent of patients had at least 1 seizure in wakefulness lifetime and 55% had seizures only in sleep (typical SHE). At the last assessment, 31 patients achieved TR (TR group, 22.3%), while 108 (NTR group, 77.7%) still had seizures or had been in remission for <5 years. The cumulative TR rate was 20.4%, 23.5%, and 28.4% by 10, 20, and 30 years from inclusion. At univariate analysis, any underlying brain disorder (any combination of intellectual disability, perinatal insult, pathologic neurologic examination, and brain structural abnormalities) and seizures in wakefulness were more frequent among the NTR group (p = 0.028; p = 0.043). Absence of any underlying brain disorder (hazard ratio 4.21, 95% confidence interval 1.26-14.05, p = 0.020) and typical SHE (hazard ratio 2.76, 95% confidence interval 1.31-5.85, p = 0.008) were associated with TR.Our data show a poor prognosis of SHE after a long-term follow-up. Its outcome is primarily a function of the underlying etiology.
| S-EPMC5200852 | biostudies-other
Project description:Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is characterized by severe sleep-related rigid hypermotor seizures. The pathogenic genes of ADSHE include genes encoding subunits of the neuronal nicotinic acetylcholine receptor, KCNT1, DEPDC5, NPRL2/3, CABP4, and CRH. Individuals with KCNT1-related ADSHE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems. In this study, a 12-year-old Chinese girl was referred for genetic evaluation of grand mal seizures. She had paroxysmal convulsions of the limbs and loss of consciousness just after falling asleep without obvious triggers. A novel heterozygous missense mutation c.2797C > T (p.Arg933Cys) in exon 24 of the KCNT1 was identified in the proband by whole-exome sequencing and Sanger sequencing, and the clinical symptoms were compatible with ADSHE. The proband's father has been showing similar symptoms for more than 20 years and had the same site mutation. Her mother and sister were physically and genetically normal. The study revealed a novel variant in the KCNT1 and expanded the mutation spectrum for this clinical condition. Our results provide further evidence supporting a causative role in KCNT1 variants in ADSHE.
| S-EPMC9438967 | biostudies-literature
Project description:Sleep-related hypermotor epilepsy (SHE) (previously frontal lobe epilepsy) is a rare seizure disorder commonly misdiagnosed or unrecognized, causing negative patient sequelae. While usually reported in familial studies, it is more commonly acquired. Diagnosis is a challenge due to its low incidence in comparison with the more common sleep disorders or psychogenic etiologies in the differential diagnosis. Diagnosis is scaled on degree of certainty based on described or clinically documented semiology, with video EEG as a helpful, but not necessary, adjunct. Current treatment is similar to other focal epilepsies. We studied a 36-year-old active duty male soldier who presented with 2?years of predominantly sleep related, abrupt, short, and anamnestic hyperkinetic movements with unstructured vocalizations. Prior workup included non-contributory video electroencephalograph (EEG) and polysomnography as well as normal brain magnetic resonance imaging (MRI). Treatments for presumed psychiatric and parasomnia disturbances were not effective in establishing diagnosis or relief. Evaluation at our tertiary, multidisciplinary care institution recorded events consistent with the diagnosis of clinical SHE. He was enrolled in an advanced multishell diffusion-weighted imaging MRI research study to evaluate white matter tracts, given his history of mild, repetitive, non-penetrating traumatic brain injury, not otherwise requiring hospitalization. Multishell diffusion MRI tractography found changes not previously described in the right frontal lobe white matter tracts. These changes were consistent with neurological localization and serve as a potential nidus for this patient's seizure disorder. Misdiagnosis of SHE can result in detrimental biopsychosocial sequelae of untreated epilepsy, unnecessary or harmful intervention, or the stigmata of a behavioral disorder. Further investigation into diagnosis and etiology of acquired SHE is needed. Assessment for white matter abnormalities can potentially provide information into pathogenesis of epilepsy disorders.
| S-EPMC5786569 | biostudies-literature
Project description:IntroductionSleep-related hypermotor epilepsy (SHE) is characterized by asymmetric tonic/dystonic posturing and/or complex hyperkinetic seizures occurring mostly during sleep. Experts agree that SHE should be considered a unique syndrome.PurposeWe present 8 cases of SHE for which a genetic diagnosis was carried out using a multigene epilepsy panel.MethodsWe retrospectively screened familial and isolated cases of SHE in current follow-ups in our center.ResultsWe included 8 (5F/3M) patients, 5 of whom had a positive familial history of epilepsy. We identified a pathogenic mutation in CHRNA4, CHRNB2, and 3 different pathogenic changes in DEPDC5.ConclusionsAwareness of SHE needs to be raised, given its implications for finding an appropriate treatment, its relationship to cognitive and psychiatric comorbidities, and the opportunity to prevent the disorder in the descendants. We present our series with their clinical, radiological, electroencephalographic, and genetic characteristics, in which we found 3 pathogenic mutations in the DEPDC5 gene but not previously reported in the literature. Identifying new pathogenic mutations or new genes responsible for SHE will facilitate a better understanding of the disease and a correct genetic counseling.
| S-EPMC8844731 | biostudies-literature
Project description:Sleep-related hypermotor epilepsy (SHE) is a group of seizure disorders prominently associated with mutations in nicotinic acetylcholine receptors (nAChR). The most prevalent central nervous system nAChR subtype contains ?4 and ?2 subunits, in two ratios. (?4?2)2?2-nAChR have high agonist sensitivity (HS-isoform), whereas (?4?2)2?4-nAChR agonist responses exhibit a small high-sensitivity, and a predominant low-sensitivity, phase of function (LS-isoform). Multiple non-synonymous mutations in the second and third transmembrane domains of ?4 and ?2 subunits are associated with SHE. We recently demonstrated that two additional, SHE-associated, missense mutations in the major cytoplasmic loops of these subunits [?4(R336H) and ?2(V337G)] cause increased macroscopic function-per receptor. Here, we use single-channel patch-clamp electrophysiology to show that these mutations influence single-channel amplitudes and open- and closed-state kinetics. Pure populations of HS- or LS-isoform ?4?2-nAChR were expressed by injecting either 1:10 or 30:1 ?4:?2 cRNA ratios, respectively, into Xenopus laevis oocytes. Functional properties of the resulting mutant ?4?2-nAChR isoforms were compared to their wildtype counterparts. ?4(R336H) subunit incorporation minimally affected single-channel amplitudes, whereas ?2(V337G) subunit incorporation reduced them significantly in both isoforms. However, for both mutant subunits, increased function-per-receptor was predominantly caused by altered single channel kinetics. The ?4(R336H) mutation primarily destabilizes desensitized states between openings. By contrast, the ?2(V337G) mutation principally stabilizes receptor open states. The use of naturally-occurring and physiologically-impactful mutations has allowed us to define valuable new insights regarding the functional roles of nAChR intracellular domains. Further mechanistic context is provided by intracellular-domain structures recently published for other members of the Cys-loop receptor superfamily (?3?4-nAChR and 5-HT3AR).
| S-EPMC7928491 | biostudies-literature
Project description:Nocturnal frontal lobe epilepsy (NFLE) is a syndrome characterized by the occurrence of sleep related seizures of variable complexity and duration. Hypermotor seizures (HMS) represent a classic manifestation of this syndrome, associated with a perturbation of the ventromesial frontal cortex and anterior cingulate gyrus regions. Nevertheless, in recent years, reports have showed that the seizure onset zone (SOZ) need not be of frontal origin to generate HMS. Here we report an unusual case of a patient presenting with a seven-year history of drug-resistant sleep related HMS arising from the mesial parietal region. The presence of an infrequent feeling of levitation before the HMS was key to suspecting a subtle focal cortical dysplasia in the right precuneus region. A stereo-EEG investigation confirmed the extra-frontal seizure onset of the HMS and highlighted the interrelationship between unstable sleep and seizure precipitation.
| S-EPMC4513272 | biostudies-literature
Project description:Background and purposeThe mechanisms causing spontaneous epileptic seizures, including carbamazepine-resistant/zonisamide -sensitive seizures and comorbidity in autosomal dominant sleep-related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L-mutant CHRNA4.Experimental approachEffects of carbamazepine and zonisamide on epileptic discharges of S286L-TG rat were measured using telemetry electrocorticogram. Transmission abnormalities of L-glutamate and GABA in thalamocortical pathway of S286L-TG rats were investigated using multiprobe microdialysis and ultra-high-performance liquid-chromatography.Key resultsEpileptic discharges in S286L-TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L-ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L-TG rats. However, zonisamide was able to compensate for the attenuated S286L-mutant nAChR induced GABA release in frontal-cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L-mutant nAChR on thalamocortical transmission were attenuated compared with those of wild-type nAChR. Loss-of-function of S286L-nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission.Conclusion and implicationsOur results suggest that functional abnormalities of S286L-nAChR are associated with intra-frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE-seizure and comorbidity of S284L-ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine-resistant ADSHE-seizure of S284L-ADSHE patients.
| S-EPMC7161548 | biostudies-literature
Project description:Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile-onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease-modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno-associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first-in-man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease-modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.
| S-EPMC8436764 | biostudies-literature