A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation

Genetic variation in SLC12A5 which encodes KCC2, the neuron‐specific cation‐chloride cotransporter that is essential for hyperpolarizing GABAergic signaling and formation of cortical dendritic spines, has not been reported in human disease. Screening of SLC12A5 revealed a co‐segregating variant (KCC2‐R952H) in an Australian family with febrile seizures. We show that KCC2‐R952H reduces neuronal Cl− extrusion and has a compromised ability to induce dendritic spines in vivo and in vitro. Biochemical analyses indicate a reduced surface expression of KCC2‐R952H which likely contributes to the functional deficits. Our data suggest that KCC2‐R952H is a bona fide susceptibility variant for febrile seizures.Peer reviewe

Idiopathic Generalized Epilepsy: Misunderstandings, Challenges, and Opportunities

The idiopathic generalized epilepsies (IGE) make up a fifth of all epilepsies, but <1% of epilepsy research. This skew reflects misperceptions: diagnosis is straightforward, pathophysiology is understood, seizures are easily controlled, epilepsy is outgrown, morbidity and mortality are low, and surgical interventions are impossible. Emerging evidence reveals that patients with IGE may go undiagnosed or misdiagnosed with focal epilepsy if EEG or semiology have asymmetric or focal features. Genetic, electrophysiologic, and neuroimaging studies provide insights into pathophysiology, including overlaps and differences from focal epilepsies. IGE can begin in adulthood and patients have chronic and drug-resistant seizures. Neuromodulatory interventions for drug-resistant IGE are emerging. Rates of psychiatric and other comorbidities, including sudden unexpected death in epilepsy, parallel those in focal epilepsy. IGE is an understudied spectrum for which our diagnostic sensitivity and specificity, scientific understanding, and therapies remain inadequate

Developmental and epileptic encephalopathies

Developmental and epileptic encephalopathies, the most severe group of epilepsies, are characterized by seizures and frequent epileptiform activity associated with developmental slowing or regression. Onset typically occurs in infancy or childhood and includes many well-defined epilepsy syndromes. Patients have wide-ranging comorbidities including intellectual disability, psychiatric features, such as autism spectrum disorder and behavioural problems, movement and musculoskeletal disorders, gastrointestinal and sleep problems, together with an increased mortality rate. Problems change with age and patients require substantial support throughout life, placing a high psychosocial burden on parents, carers and the community. In many patients, the aetiology can be identified, and a genetic cause is found in >50% of patients using next-generation sequencing technologies. More than 900 genes have been identified as monogenic causes of developmental and epileptic encephalopathies and many cell components and processes have been implicated in their pathophysiology, including ion channels and transporters, synaptic proteins, cell signalling and metabolism and epigenetic regulation. Polygenic risk score analyses have shown that common variants also contribute to phenotypic variability. Holistic management, which encompasses antiseizure therapies and care for multimorbidities, is determined both by epilepsy syndrome and aetiology. Identification of the underlying aetiology enables the development of precision medicines to improve the long-term outcome of patients with these devastating diseases

Building on Progress Towards Fair Access : annual report 2019

Supplementary Table 3: Anti-epileptic drug use in patients with SYNGAP1 mutations or deletion

Clinical profile of patients with ATP1A3 mutations in alternating hemiplegia of childhood-a study of 155 patients.

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials

Quantifying resilience of humans and other animals

All life requires the capacity to recover from challenges that are as inevitable as they are unpredictable. Understanding this resilience is essential for managing the health of humans and their livestock. It has long been difficult to quantify resilience directly, forcing practitioners to rely on indirect static indicators of health. However, measurements from wearable electronics and other sources now allow us to analyze the dynamics of physiology and behavior with unsurpassed resolution. The resulting flood of data coincides with the emergence of novel analytical tools for estimating resilience from the pattern of micro-recoveries observed in natural time series. Such dynamic indicators of resilience (DIORs) may be used to monitor the risk of systemic failure across systems ranging from organs to entire organisms. These tools invite a fundamental rethink of our approach to the adaptive management of health and resilience

The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. One hypothesis proposes that sudden death is mediated by post-ictal central respiratory depression, which could relate to underlying pathology in key respiratory nuclei and/or their neuromodulators. Our aim was to investigate neuronal populations in the ventrolateral medulla (which includes the putative human pre-Bötzinger complex) and the medullary raphe. Forty brainstems were studied comprising four groups: 14 SUDEP, six epilepsy controls, seven Dravet syndrome cases and 13 non-epilepsy controls. Serial sections through the medulla (from obex 1 to 10 mm) were stained for Nissl, somatostatin, neurokinin 1 receptor (for pre-Bötzinger complex neurons) and galanin, tryptophan hydroxylase and serotonin transporter (neuromodulatory systems). Using stereology total neuronal number and densities, with respect to obex level, were measured. Whole slide scanning image analysis was used to quantify immunolabelling indices as well as co-localization between markers. Significant findings included reduction in somatostatin neurons and neurokinin 1 receptor labelling in the ventrolateral medulla in sudden death in epilepsy compared to controls (P < 0.05). Galanin and tryptophan hydroxylase labelling was also reduced in sudden death cases and more significantly in the ventrolateral medulla region than the raphe (P < 0.005 and P < 0.05). With serotonin transporter, reduction in labelling in cases of sudden death in epilepsy was noted only in the raphe (P ≤ 0.01); however, co-localization with tryptophan hydroxylase was significantly reduced in the ventrolateral medulla. Epilepsy controls and cases with Dravet syndrome showed less significant alterations with differences from non-epilepsy controls noted only for somatostatin in the ventrolateral medulla (P < 0.05). Variations in labelling with respect to obex level were noted of potential relevance to the rostro-caudal organization of respiratory nuclear groups, including tryptophan hydroxylase, where the greatest statistical difference noted between all epilepsy cases and controls was at obex 9-10 mm (P = 0.034), the putative level of the pre-Bötzinger complex. Furthermore, there was evidence for variation with duration of epilepsy for somatostatin and neurokinin 1 receptor. Our findings suggest alteration to neuronal populations in the medulla in SUDEP with evidence for greater reduction in neuromodulatory neuropeptidergic and mono-aminergic systems, including for galanin, and serotonin. Other nuclei need to be investigated to evaluate if this is part of more widespread brainstem pathology. Our findings could be a result of previous seizures and may represent a pathological risk factor for SUDEP through impaired respiratory homeostasis during a seizure