The Spectrum of KCNQ2- and KCNQ3-Related Epilepsy

2021 ◽  
Author(s):  
Anna Portale ◽  
Mattia Comella ◽  
Giulia Salomone ◽  
Alessandra Di Nora ◽  
Lidia Marino ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Response To Treatment ◽  
Psychomotor Development ◽  
K Channel ◽  
Loss Of Function ◽  
M Current ◽  
Wide Range ◽  
Cortical Visual Impairment ◽  
Infantile Epilepsy

Abstract KCNQ genes encode for a family of six transmembrane domains, single pore-loop, and K+ channel α-subunits that have a wide range of physiological correlates. In the brain, KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current which is essential in raising the threshold for firing an action potential; mutations in these genes may cause several types of infantile epilepsies. KCNQ2-related disorders represent a continuum of overlapping neonatal epileptic phenotypes that range from KCNQ2 benign familial neonatal epilepsy (BFNE), a seizure disorder that occur in children who typically have a normal psychomotor development and are inherited as an autosomal dominant trait, to KCNQ2 early-onset epileptic encephalopathy (EOEE) as the result of a de novo pathogenic variant. KCNQ3-related disorders are rarer and include BFNE, benign familial infantile epilepsy and KCNQ3-related epileptic encephalopathy with intellectual disability with or without seizures and/or cortical visual impairment. For both KCNQ2- and KCNQ3-related disorders, it is possible to use several drugs for different classes of mutations (i.e., gain of function vs. loss of function), and usually their effects vary in relation to the clinical presentation and the phenotype of the patient. However, KCNQ2-EOEE patients have a worse response to treatment than KCNQ2-BFNE patients and usually become drug resistant with multiple daily seizures.

scholarly journals Loss–of–function variants in the KCNQ5 gene are associated with genetic generalized epilepsies

2021 ◽  
Author(s):  
Johanna Krueger ◽  
Julian Schubert ◽  
Josua Kegele ◽  
Audrey Labalme ◽  
Miaomiao Mao ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
De Novo ◽  
Surface Expression ◽  
Epileptic Encephalopathy ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
K Channel ◽  
Loss Of Function ◽  
Normal Surface ◽  
Missense Variants

Objective: De novo missense variants in KCNQ5, encoding the voltage–gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease–related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. Methods: 1292 families with GGE were studied by next-generation sequencing. Whole–cell patch–clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling. Results: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss–of–function (LOF). When mutant channels were co–expressed with wild–type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant–negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The p.Arg359Cys variant altered PI(4,5)P2–interaction, presumably in the non–conducting preopen–closed state. Interpretation: Our study indicates that specific deleterious KCNQ5 variants are associated with GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant–negative effects through functional, rather than trafficking deficits. LOF of KV7.5 channels will reduce the M–current, likely resulting in increased excitability of KV7.5–expressing neurons. Further studies on a network level are necessary to understand which circuits are affected and how the variants induce generalized seizures.

scholarly journals KCNMA1-linked channelopathy

2019 ◽  
Vol 151 (10) ◽  
pp. 1173-1189 ◽  
Author(s):  
Cole S. Bailey ◽  
Hans J. Moldenhauer ◽  
Su Mi Park ◽  
Sotirios Keros ◽  
Andrea L. Meredith
Keyword(s):  
De Novo ◽  
Phenotypic Variability ◽  
Bk Channels ◽  
Bk Channel ◽  
K Channel ◽  
Loss Of Function ◽  
Current Standard ◽  
Α Subunit ◽  
Specific Patient ◽  
Organ Systems

KCNMA1 encodes the pore-forming α subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1−/−) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as “KCNMA1-linked channelopathy.” These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

scholarly journals GNAO1 encephalopathy

2017 ◽  
Vol 3 (2) ◽  
pp. e143 ◽  
Author(s):  
Federica Rachele Danti ◽  
Serena Galosi ◽  
Marta Romani ◽  
Martino Montomoli ◽  
Keren J. Carss ◽  
...  
Keyword(s):  
Hospital Admissions ◽  
De Novo ◽  
Clinical Symptoms ◽  
Molecular Genetic ◽  
Cerebral Atrophy ◽  
Epileptic Encephalopathy ◽  
Causative Role ◽  
Diffuse Astrocytoma ◽  
Who Grade ◽  
Wide Range

Objective:To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease.Methods:We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques.Results:Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.Conclusions:Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.

scholarly journals Impaired M-current in KCNQ2 Encephalopathy Evokes Dyshomeostatic Modulation of Excitability

2019 ◽  
Author(s):  
Dina Simkin ◽  
Timothy J. Searl ◽  
Brandon N. Piyevsky ◽  
Marc Forrest ◽  
Luis A. Williams ◽  
...  
Keyword(s):  
Disease Model ◽  
Epileptic Encephalopathy ◽  
Bk Channels ◽  
Disease Stage ◽  
Loss Of Function ◽  
Therapeutic Implications ◽  
M Current ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
And Function

ABSTRACTMutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells and gene editing to establish a disease model, and measured the functional properties of patient-derived neurons using electrophysiological and optical approaches. We find that while patient-derived excitatory neurons exhibit reduced M-current early, they develop intrinsic and network hyperexcitability progressively. This hyperexcitability is associated with faster action potential repolarization, larger afterhyperpolarization, and a functional enhancement of large conductance Ca2+-activated K+ (BK) channels. These properties facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Importantly, we were able to phenocopy these excitability features in control neurons only by chronic but not acute pharmacological inhibition of M-current. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function and lead to alterations in the neurodevelopmental trajectory of patient-derived neurons. Our work has therapeutic implications in explaining why KCNQ2 agonists are not beneficial unless started at an early disease stage.

scholarly journals Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Dina Simkin ◽  
Kelly A Marshall ◽  
Carlos G Vanoye ◽  
Reshma R Desai ◽  
Bernabe I Bustos ◽  
...  
Keyword(s):  
Disease Model ◽  
Neuronal Model ◽  
Epileptic Encephalopathy ◽  
Loss Of Function ◽  
M Current ◽  
Complex Disorder ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
And Function ◽  
Action Potential Repolarization

Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.

scholarly journals Early Infantile Epileptic Encephalopathy in anSTXBP1Patient with Lactic Acidemia and Normal Mitochondrial Respiratory Chain Function

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Dong Li ◽  
Elizabeth Bhoj ◽  
Elizabeth McCormick ◽  
Fengxiang Wang ◽  
James Snyder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Respiratory Chain ◽  
Mitochondrial Disease ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Epileptic Encephalopathy ◽  
Skeletal Muscle Biopsy ◽  
Wide Range ◽  
Lactic Acidemia

A wide range of clinical findings have been associated with mutations in Syntaxin Binding Protein 1 (STXBP1), including multiple forms of epilepsy, nonsyndromic intellectual disability, and movement disorders.STXBP1mutations have recently been associated with mitochondrial pathology, although it remains unclear if this phenotype is a part of the core feature for this gene disorder. We report a 7-year-old boy who presented for diagnostic evaluation of intractable epilepsy, episodic ataxia, resting tremor, and speech regression following a period of apparently normal early development. Mild lactic acidemia was detected on one occasion at the time of an intercurrent illness. Due to the concern for mitochondrial disease, ophthalmologic evaluation was performed that revealed bilateral midperiphery pigmentary mottling. Optical coherence tomography (OCT) testing demonstrated a bilaterally thickened ganglion cell layer in the perifovea. Skeletal muscle biopsy analysis showed no mitochondrial abnormalities or respiratory chain dysfunction. Exome sequencing identified ade novoc.1651C>T (p.R551C) mutation inSTXBP1.Although mitochondrial dysfunction has been reported in some individuals, our proband had only mild lactic acidemia and no skeletal muscle tissue evidence of mitochondrial disease pathology. Thus, mitochondrial dysfunction is not an obligate feature ofSTXBP1disease.

A Review of Some of the Rheumatological Problems and Engineering Capabilities

1987 ◽  
Vol 16 (4) ◽  
pp. 191-193
Author(s):  
H A Bird
Keyword(s):  
Musculoskeletal System ◽  
Response To Treatment ◽  
Functional Evaluation ◽  
Loss Of Function ◽  
The United Kingdom ◽  
Joint Pathology ◽  
Wide Range ◽  
Repetitive Stress ◽  
The Individual ◽  
Cardinal Symptoms

Up to 150 different diseases can affect the joints and musculoskeletal system. These range from musculoskeletal rheumatism, which is self-limiting and causes no demonstrable joint pathology, through metabolic and degenerative joint diseases to the chronic auto-immune disorders of inflammation of which rheumatoid arthritis is the most common in the United Kingdom, and the most severe. Many of these conditions are characterised by inflammation which has the cardinal symptoms of heat, swelling, pain, erythema, and loss of function. Rheumatologists require accurate and objective methods of measuring all these parameters at a large number of joints, each of different anatomical structure, in order to adequately monitor the course of the disease and its response to treatment. Complementary information is required on the function of muscles, ligaments, tendons, and bone, as well as the joints. Although the individual analysis of each of these components is likely to provide the most information on disease pathogenesis, functional evaluation which integrates many of these variables simultaneously is likely to provide most information on the patient's progress. Both are needed. In the realm of therapeutics, a wide range of prostheses, all of sound bioengineering design, are available. Greater problems arise in the matching of different prostheses to an individual patients needs and in their fixation in a patient whose disease is constantly altering the joint contour. The attention of bioengineers is now being directed towards the design of replacements for other parts of the joint and musculoskeletal system, for example, ligaments. Adequate methods of testing these under repetitive stress and of measuring the improvement they provide will be increasingly required.

Biallelic Mutations in SLC1A2; an Additional Mode of Inheritance for SLC1A2-Related Epilepsy

2017 ◽  
Vol 49 (01) ◽  
pp. 059-062 ◽  
Author(s):  
Mirjana Gusic ◽  
Roman Günthner ◽  
Bader Alhaddad ◽  
Reka Kovacs-Nagy ◽  
Christine Makowski ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Genetic Mechanism ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Functional Studies ◽  
Additional Mode ◽  
Biallelic Mutations ◽  
Mode Of Inheritance

AbstractRecently, heterozygous de novo mutations in SCL1A2 have been reported to underlie severe early-onset epileptic encephalopathy. In one male presenting with epileptic seizures and visual impairment, we identified a novel homozygous splicing variant in SCL1A2 (c.1421 + 1G > C) by using exome sequencing. Functional studies on cDNA level confirmed a consecutive loss of function. Our findings suggest that not only de novo mutations but also biallelic variants in SLC1A2 can cause epilepsy and that there is an additional autosomal recessive mode of inheritance. These findings also contribute to the understanding of the genetic mechanism of autosomal dominant SLC1A2-related epileptic encephalopathy as they exclude haploinsufficiency as exclusive genetic mechanism.

scholarly journals Case Report: Causative De novo Variants of KCNT2 for Developmental and Epileptic Encephalopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Pan Gong ◽  
Xianru Jiao ◽  
Dan Yu ◽  
Zhixian Yang
Keyword(s):  
De Novo ◽  
Gene Mutations ◽  
Epileptic Encephalopathy ◽  
Infantile Spasms ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Ohtahara Syndrome ◽  
Whole Exome

Objective:KCNT2 gene mutations had been described to cause developmental and epileptic encephalopathies (DEEs). In this study, we presented the detailed clinical features and genetic analysis of two unrelated patients carrying two de novo variants in KCNT2 and reviewed eight different cases available in publications.Methods: Likely pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Results: Our two unrelated patients were diagnosed with Ohtahara syndrome followed by infantile spasms (IS) and possibly the epilepsy of infancy with migrating focal seizures (EIMFS), respectively. They both manifested dysmorphic features with hirsute arms, thick hair, prominent eyebrows, long and thick eyelashes, a broad nasal tip, and short and smooth philtrum. In the eight patients reported previously, two was diagnosed with IS carrying a ‘change-of-function' mutation and a gain-of-function mutation, respectively, two with EIMFS-like carrying a gain-of-function mutation and a loss-of-function mutation, respectively, one with EIMFS carrying a loss-of-function mutation, three with DEE without functional analysis. Among them, two patients with gain-of-function mutations both exhibited dysmorphic features and presented epilepsy phenotype, which was similar to our patients.Conclusion: Overall, the most common phenotypes associated with KCNT2 mutation were IS and EIMFS. Epilepsy phenotype associated with gain- and loss-of-function mutations could overlap. Additional KCNT2 cases will help to make genotype-phenotype correlations clearer.

scholarly journals The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Laura B. Jones ◽  
Colin H. Peters ◽  
Richard E. Rosch ◽  
Maxine Owers ◽  
Elaine Hughes ◽  
...  
Keyword(s):  
De Novo ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Channel Function ◽  
Biophysical Analysis ◽  
Gain And Loss ◽  
Patients With Epilepsy

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

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