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GABAA receptor β3 subunit mutation D120N causes Lennox-Gastaut syndrome in knock-in mice.

ABSTRACT: The Lennox-Gastaut syndrome is a devastating early-onset epileptic encephalopathy, associated with severe behavioural abnormalities. Its pathophysiology, however, is largely unknown. A de novo mutation (c.G358A, p.D120N) in the human GABA type-A receptor β3 subunit gene (GABRB3) has been identified in a patient with Lennox-Gastaut syndrome. To determine whether the mutation causes Lennox-Gastaut syndrome in vivo in mice and to elucidate its mechanistic effects, we generated the heterozygous Gabrb3+/D120N knock-in mouse and found that it had frequent spontaneous atypical absence seizures, as well as less frequent tonic, myoclonic, atonic and generalized tonic-clonic seizures. Each of these seizure types had a unique and characteristic ictal EEG. In addition, knock-in mice displayed abnormal behaviours seen in patients with Lennox-Gastaut syndrome including impaired learning and memory, hyperactivity, impaired social interactions and increased anxiety. This Gabrb3 mutation did not alter GABA type-A receptor trafficking or expression in knock-in mice. However, cortical neurons in thalamocortical slices from knock-in mice had reduced miniature inhibitory post-synaptic current amplitude and prolonged spontaneous thalamocortical oscillations. Thus, the Gabrb3+/D120N knock-in mouse recapitulated human Lennox-Gastaut syndrome seizure types and behavioural abnormalities and was caused by impaired inhibitory GABAergic signalling in the thalamocortical loop. In addition, treatment with antiepileptic drugs and cannabinoids ameliorated atypical absence seizures in knock-in mice. This congenic knock-in mouse demonstrates that a single-point mutation in a single gene can cause development of multiple types of seizures and multiple behavioural abnormalities. The knock-in mouse will be useful for further investigation of the mechanisms of Lennox-Gastaut syndrome development and for the development of new antiepileptic drugs and treatments.

SUBMITTER: Qu S

PROVIDER: S-EPMC7238755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesThis study aimed to investigate the functional network effects of corpus callosotomy (CC), a well-recognized palliative surgical therapy for patients with Lennox-Gastaut syndrome (LGS). Specifically, we sought to gain insight into the effects of CC on LGS remission, based on brain networks in LGS by calculating network metrics and evaluating by network measures before and after surgery.MethodsElectroencephalographic recordings made during preoperative and 3-month postoperative states in 14 patients with LGS who had undergone successful CC were retrospectively analyzed. First, undirected correlation matrices were constituted for the mathematical expression of functional networks. Then, we plotted these networks to analyze the effects of CC on connectivity. In addition, conventional local and global network measures were applied to evaluate differences in network topology between preoperative and postoperative states.ResultsIn the preoperative state, hubs were mainly distributed around the paramedian regions. After CC, the hubs moved from the paramedian regions to the dual-hemisphere and even the lateral regions. Thus, the general connectivity state became more homogeneous, which was verified by network plots and statistical analysis of local measures. The results of global network measures indicated a decreased clustering coefficient in the delta band, decreased characteristic path length in both the delta and gamma bands, and increased global efficiency in the gamma band.ConclusionOur results showed a consistent variation in the global brain network that converted to a small-world topology with an optimal balance of functional integration and segregation of the network. Such changes were positively correlated with satisfactory surgery results, which could be interpreted as being indicative of LGS recovery process after CC. For patients with refractory LGS along with no focal epileptogenic zone findings, which were not suitable for the resective surgical therapy, our results verified that CC could work as an effective surgical treatment option.

Project description:Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient's lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%-68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%-78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat-OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a 'one size fits all' approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.

Project description:BackgroundLennox-Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant epilepsy with multiple seizure types starting in childhood, a typical slow spike-wave pattern on electroencephalogram, and cognitive dysfunction.MethodsWe performed a systematic literature review according to the PRISMA guidelines to identify, synthesize and appraise the burden of illness in LGS (including "probable" LGS). Studies were identified by searching MEDLINE, Embase and APA PsychInfo, Cochrane's database of systematic reviews, and Epistemonikos. The outcomes were epidemiology (incidence, prevalence or mortality), direct and indirect costs, healthcare resource utilization, and patient and caregiver health-related quality of life (HRQoL).ResultsThe search identified 22 publications evaluating the epidemiology (n = 10), direct costs and resource (n = 10) and/or HRQoL (n = 5). No studies reporting on indirect costs were identified. With no specific ICD code for LGS in many regions, several studies had to rely upon indirect methods to identify their patient populations (e.g., algorithms to search insurance claims databases to identify "probable" LGS). There was heterogeneity between studies in how LGS was defined, the size of the populations, ages of the patients and length of the follow-up period. The prevalence varied from 4.2 to 60.8 per 100,000 people across studies for probable LGS and 2.9-28 per 100,000 for a confirmed/narrow definition of LGS. LGS was associated with high mortality rates compared to the general population and epilepsy population. Healthcare resource utilization and direct costs were substantial across all studies. Mean annual direct costs per person varied from $24,048 to $80,545 across studies, and home-based care and inpatient care were significant cost drivers. Studies showed that the HRQoL of patients and caregivers was adversely affected, although only a few studies were identified. In addition, studies suggested that seizure events were associated with higher costs and worse HRQoL. The risk of bias was low or moderate in most studies.ConclusionsLGS is associated with a significant burden of illness featuring resistant seizures associated with higher costs and worse HRQoL. More research is needed, especially in evaluating indirect costs and caregiver burden, where there is a notable lack of studies.

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GABAA receptor β3 subunit mutation D120N causes Lennox-Gastaut syndrome in knock-in mice.

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