Form Of Progressive Myoclonus Epilepsy Research Articles

Glial alterations in the glutamatergic and GABAergic signaling pathways in a mouse model of Lafora disease, a severe form of progressive myoclonus epilepsy.

Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies (LBs), in the brain but also in peripheral tissues. It is assumed that the accumulation of LBs is related to the appearance of the characteristic pathological features of the disease. In mouse models of LD, we and others have reported an increase in the levels of reactive astrocytes and activated microglia, which triggers the expression of the different pro-inflammatory mediators. Recently, we have demonstrated that the TNF and IL-6 inflammatory signaling pathways are the main mediators of the neuroinflammatory phenotype associated with the disease. In this work, we present evidence that the activation of these pathways produces a dysregulation in the levels of different subunits of the excitatory ionotropic glutamatergic receptors (phopho-GluN2B, phospho-GluA2, GluK2) and also an increase in the levels of the GABA transporter GAT1 in the hippocampus of the Epm2b-/- mice. In addition, we present evidence of the presence of activated forms of the Src and Lyn protein kinases in this area. These effects may increase the excitatory glutamatergic signaling and decrease the inhibitory GABAergic tone, leading to hyper-excitability. More importantly, the enhanced production of these subunits occurs in non-neuronal cells such as activated microglia and reactive astrocytes, pointing out a key role of glia in the pathophysiology of LD.

Gene therapy for Lafora disease in the Epm2a−/− mouse model

Lafora disease is a rare and fatal form of progressive myoclonic epilepsy typically occurring early in adolescence. The disease results from mutations in the EPM2A gene, encoding laforin, or the EPM2B gene, encoding malin. Laforin and malin work together in a complex to control glycogen synthesis and prevent the toxicity produced by misfolded proteins via the ubiquitin-proteasome system. Disruptions in either protein cause alterations in this complex, leading to the formation of Lafora bodies containing abnormal, insoluble, and hyperphosphorylated forms of glycogen. We used the Epm2a-/- knock-out mouse model of Lafora disease to apply gene therapy by administering intracerebroventricular injections of a recombinant adeno-associated virus carrying the human EPM2A gene. We evaluated the effects of this treatment through neuropathological studies, behavioral tests, video-electroencephalography, electrophysiological recordings, and proteomic/phosphoproteomic analysis. Gene therapy ameliorated neurological and histopathological alterations, reduced epileptic activity and neuronal hyperexcitability, and decreased the formation of Lafora bodies. Moreover, differential quantitative proteomics and phosphoproteomics revealed beneficial changes in various molecular pathways altered in Lafora disease. Our results represent proof-of-principle for gene therapy with the coding region of the human EPM2A gene as a treatment for EPM2A related Lafora disease.

Retinal vascular pathology in a mouse model of Lafora progressive myoclonus epilepsy

Neurodegenerative diseases (ND) affect distinct populations of neurons and manifest various clinical and pathological symptoms. A subset of ND prognoses has been linked to vascular risk factors. Consequently, the current study investigated retinal vascular abnormalities in a murine model of Lafora neurodegenerative disease (LD), a fatal and genetic form of progressive myoclonus epilepsy that affects children. Here, arterial rigidity was evaluated by measuring pulse wave velocity and vasculature deformations in the retina. Our findings in the LD mouse model indicate altered pulse wave velocity, retinal vascular thinning, and convoluted retinal arteries.

CSTB gene replacement improves neuroinflammation, neurodegeneration and ataxia in murine type 1 progressive myoclonus epilepsy.

EPM1 is the most common form of Progressive Myoclonus Epilepsy characterized by late-childhood onset, ever-worsening and disabling myoclonus, seizures, ataxia, psychiatric disease, and shortened lifespan. EPM1 is caused by expansions of a dodecamer repeat sequence in the promoter of CSTB (cystatin B), which dramatically reduces, but does not eliminate, gene expression. The relatively late onset and consistent presence of a minimal amount of protein product makes EPM1 a favorable target for gene replacement therapy. If treated early, these children's normally developed brains could be rescued from the neurodegeneration that otherwise follows, and their cross-reactive immunological material (CRIM) positive status greatly reduces transgene related toxicity. We performed a proof-of-concept CSTB gene replacement study in Cstb knockout mice by introducing full-length human CSTB driven by the CBh promoter packaged in AAV9 and administered at postnatal days 21 and 60. Mice were sacrificed at 2 or 9 months of age, respectively. We observed significant improvements in expression levels of neuroinflammatory pathway genes and cerebellar granule cell layer apoptosis, as well as amelioration of motor impairment. The data suggest that gene replacement is a promising therapeutic modality for EPM1 and could spare affected children and families the ravages of this otherwise severe neurodegenerative disease.

Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes.

Lafora disease (LD; OMIM#254780) is a rare, devastating, and fatal form of progressive myoclonus epilepsy that affects young adolescents and has no treatment yet. One of the hallmarks of the disease is the accumulation of aberrant poorly branched forms of glycogen (polyglucosans, PGs) in the brain and peripheral tissues. The current hypothesis is that this accumulation is causative of the pathophysiology of the disease. Another hallmark of LD is the presence of neuroinflammation. We have recently reported the presence of reactive glia-derived neuroinflammation in LD mouse models and defined the main inflammatory pathways that operate in these mice, mainly TNF and IL-6 signaling pathways. In addition, we described the presence of infiltration of peripheral immune cells in the brain parenchyma, which could cooperate and aggravate the neuroinflammatory landscape of LD. In this work, we have checked the beneficial effect of two compounds with the capacity to ameliorate neuroinflammation and reduce leukocyte infiltration into the brain, namely fingolimod and dimethyl fumarate. Our results indicate a beneficial effect of fingolimod in reducing reactive astrogliosis-derived neuroinflammation and T-lymphocyte infiltration, which correlated with the improved behavioral performance of the treated Epm2b-/- mice. On the contrary, dimethyl fumarate, although it was able to reduce reactive astrogliosis, was less effective in preventing neuroinflammation and T-lymphocyte infiltration and in modifying behavioral tests.

Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data

BackgroundLafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype–phenotype correlations.MethodsWe collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy.Results250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23–6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75–5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration.ConclusionsThis study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.

Epm2aR240X knock-in mice present earlier cognitive decline and more epileptic activity than Epm2a−/− mice

Lafora disease is a rare recessive form of progressive myoclonic epilepsy, usually diagnosed during adolescence. Patients present with myoclonus, neurological deterioration, and generalized tonic-clonic, myoclonic, or absence seizures. Symptoms worsen until death, usually within the first ten years of clinical onset. The primary histopathological hallmark is the formation of aberrant polyglucosan aggregates called Lafora bodies in the brain and other tissues. Lafora disease is caused by mutations in either the EPM2A gene, encoding laforin, or the EPM2B gene, coding for malin. The most frequent EPM2A mutation is R241X, which is also the most prevalent in Spain. The Epm2a‐/− and Epm2b−/− mouse models of Lafora disease show neuropathological and behavioral abnormalities similar to those seen in patients, although with a milder phenotype. To obtain a more accurate animal model, we generated the Epm2aR240X knock-in mouse line with the R240X mutation in the Epm2a gene, using genetic engineering based on CRISPR-Cas9 technology. Epm2aR240X mice exhibit most of the alterations reported in patients, including the presence of LBs, neurodegeneration, neuroinflammation, interictal spikes, neuronal hyperexcitability, and cognitive decline, despite the absence of motor impairments. The Epm2aR240X knock-in mouse displays some symptoms that are more severe that those observed in the Epm2a−/− knock-out, including earlier and more pronounced memory loss, increased levels of neuroinflammation, more interictal spikes and increased neuronal hyperexcitability, symptoms that more precisely resemble those observed in patients. This new mouse model can therefore be specifically used to evaluate how new therapies affects these features with greater precision.

Age-Related microRNA Overexpression in Lafora Disease Male Mice Provides Links between Neuroinflammation and Oxidative Stress.

Lafora disease is a rare, fatal form of progressive myoclonus epilepsy characterized by continuous neurodegeneration with epileptic seizures, characterized by the intracellular accumulation of aberrant polyglucosan granules called Lafora bodies. Several works have provided numerous evidence of molecular and cellular alterations in neural tissue from experimental mouse models deficient in either laforin or malin, two proteins related to the disease. Oxidative stress, alterations in proteostasis, and deregulation of inflammatory signals are some of the molecular alterations underlying this condition in both KO animal models. Lafora bodies appear early in the animal's life, but many of the aforementioned molecular aberrant processes and the consequent neurological symptoms ensue only as animals age. Here, using small RNA-seq and quantitative PCR on brain extracts from laforin and malin KO male mice of different ages, we show that two different microRNA species, miR-155 and miR-146a, are overexpressed in an age-dependent manner. We also observed altered expression of putative target genes for each of the microRNAs studied in brain extracts. These results open the path for a detailed dissection of the molecular consequences of laforin and malin deficiency in brain tissue, as well as the potential role of miR-155 and miR-146a as specific biomarkers of disease progression in LD.

TNF and IL6/Jak2 signaling pathways are the main contributors of the glia-derived neuroinflammation present in Lafora disease, a fatal form of progressive myoclonus epilepsy

Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy (prevalence <1:1,000,000) characterized by the accumulation of insoluble deposits of aberrant glycogen (polyglucosans), named Lafora bodies, in the brain but also in peripheral tissues. LD is the most severe form of the group of progressive myoclonus epilepsies, since patients present a rapid deterioration and dementia with amplification of seizures, leading to death after a decade from the onset of the first symptoms. We have recently described that reactive glia-derived neuroinflammation should be considered a novel hallmark of LD since we observed a florid upregulation of differentially expressed genes in both LD mouse lines, which were mainly related to mediators of inflammatory response. In this work, we define an upregulation of the expression of mediators of the TNF and IL6/JAK2 signaling pathways in LD. In addition, we describe the activation of the non-canonical form of the inflammasome. Furthermore, we describe the infiltration of peripheral immune cells in the brain parenchyma, which could aggravate glia-derived neuroinflammation. Finally, we describe CXCL10 and S100b as blood biomarkers of the disease, which will allow the study of the progression of the disease using serum blood samples. We consider that the identification of these initial inflammatory changes in LD will be very important to implement possible anti-inflammatory therapeutic strategies to prevent the development of the disease.

Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2months at 10months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

Clinical case of neuronal ceroid lipofuscinosis type II in a child

Neuronal ceroid lipofuscinosis is a group of hereditary neurodegenerative diseases inherited by an autosomal recessive trait. This disease is the most common neurodegenerative pathology in children with a prevalence of 1:1,000,000 to 1:14,000 in the world. Currently, 14 genetically different forms of this pathology have been identified, which are characterized by the accumulation of abnormal lipofuscin-like material in the lysosomes of nerve cells, progressive and selective destruction of neurons. In neuronal ceroid lipofuscinosis, there is a defect in the gene that translates various lysosomal enzymes. Due to the insufficiency of the enzyme tripeptidyl peptidase 1, an accumulation of pathological autofluorescent lipopigment is observed in the central nervous system (CNS) of the patient, leading to violations of the normal function of neurons. Clinically, the disease manifests at the age of 34 years, in the form of progressive myoclonic epilepsy, mental and motor disorders, delays and stops in development. The article describes data on the prevalence, clinical features and therapy of this pathology, and also presents a clinical case with the onset of the disease in a child aged 2 years 11 months. The clinical case demonstrates the difficulties of diagnosing this pathology due to the rarity of this pathology, a wide range of differential diagnostics, the duration and high cost of molecular genetic studies. An early diagnosing would make it possible to explain the nature of epilepsy, to choose a rational therapy for this disease in a timely manner.

Age-Dependent Reduction in the Expression Levels of Genes Involved in Progressive Myoclonus Epilepsy Correlates with Increased Neuroinflammation and Seizure Susceptibility in Mouse Models.

Brain aging is characterized by a gradual decline in cellular homeostatic processes, thereby losing the ability to respond to physiological stress. At the anatomical level, the aged brain is characterized by degenerating neurons, proteinaceous plaques and tangles, intracellular deposition of glycogen, and elevated neuroinflammation. Intriguingly, such age-associated changes are also seen in neurodegenerative disorders suggesting that an accelerated aging process could be one of the contributory factors for the disease phenotype. Amongst these, the genetic forms of progressive myoclonus epilepsy (PME), resulting from loss-of-function mutations in genes, manifest symptoms that are common to age-associated disorders, and genes mutated in PME are involved in the cellular homeostatic processes. Intriguingly, the incidence and/or onset of epileptic seizures are known to increase with age, suggesting that physiological changes in the aged brain might contribute to increased susceptibility to seizures. We, therefore, hypothesized that the expression level of genes implicated in PME might decrease with age, thereby leading to a compromised neuronal response towards physiological stress and hence neuroinflammation in the aging brain. Using mice models, we demonstrate here that the expression level of PME genes shows an inverse correlation with age, neuroinflammation, and compromised heat shock response. We further show that the pharmacological suppression of neuroinflammation ameliorates seizure susceptibility in aged animals as well as in animal models for a PME. Taken together, our results indicate a functional role for the PME genes in normal brain aging and that neuroinflammation could be a major contributory player in susceptibility to seizures.

EP022: Action myoclonus-renal failure syndrome: An atypical storage disorder with a treatment dilemma

Action myoclonus-renal failure syndrome (AMRF) is a rare, autosomal recessive form of progressive myoclonic epilepsy associated with renal dysfunction, ranging from proteinuria to nephrotic syndrome and end stage renal disease, peripheral demyelinating polyneuropathy, and sensorineural hearing loss. SCARB2, the causative gene, encodes lysosomal-membrane type 2 protein (LIMP-2), a transmembrane protein responsible for trafficking of beta-glucocerebrosidase (GCase) to the lysosomes. LIMP-2 is particularly essential to GCase trafficking in neuronal cells, and in brains of LIMP-2 deficient mice, the significant reduction in GCase activity led to lipid storage, disturbed lysosomal function, and alpha-synuclein accumulation leading to neurotoxicity.

FDG-PET findings and alcohol-responsive myoclonus in a patient with Unverricht-Lundborg disease.

The aim of this report is to describe clinical, EEG, and neuroimaging findings in a patient with Unverricht-Lundborg disease (ULD), the most common form of progressive myoclonus epilepsy (PME). A 23-year-old male with genetically confirmed ULD had a phenotype consisting of myoclonus, generalized seizures, intellectual disability, ataxia, and dysarthria. Myoclonus and gait disturbance were strongly ameliorated by alcohol consumption. EEG revealed a posterior dominant rhythm with alpha variant, mild bilateral slowing, and anterior-predominant epileptiform abnormalities. Brain MRI showed mild cerebellar atrophy. FDG-PET revealed hypometabolism more prominent in the posterior brainstem, thalami, frontal and parietal lobes. This report confirms that alcohol may ameliorate myoclonus in a subset of patients with PME, including genetically confirmed ULD. In addition, the presence of FDG-PET hypometabolism predominant in the frontoparietal region and thalami has not been previously described in ULD, yet is consistent with previous brain morphometry studies showing motor cortex and thalamic atrophy in ULD, and brings into question the possibility of a shared metabolic pattern with other PMEs, notably Lafora disease.

Natural history of Lafora disease: a prognostic systematic review and individual participant data meta-analysis

BackgroundLafora disease (LD) is a rare fatal autosomal recessive form of progressive myoclonus epilepsy. It affects previously healthy children or adolescents, causing pharmacoresistant epilepsy, myoclonus and severe psychomotor deterioration. This work aims to describe the clinical course of LD and identify predictors of outcome by means of a prognostic systematic review with individual participant data meta-analysis.MethodsA search was conducted on MEDLINE and Embase with no restrictions on publication date. Only studies reporting genetically confirmed LD cases were included. Kaplan–Meier estimate was used to assess probability of death and loss of autonomy. Univariable and multivariable Cox regression models with mixed effects (clustered survival data) were performed to evaluate prognostic factors.ResultsSeventy-three papers describing 298 genetically confirmed LD cases were selected. Mean age at disease onset was 13.4 years (SD 3.7), with 9.1% aged ≥ 18 years. Overall survival rates in 272 cases were 93% [95% CI 89–96] at 5 years, 62% [95% CI 54–69] at 10 years and 57% [95% CI 49–65] at 15 years. Median survival time was 11 years. The probability of loss of autonomy in 110 cases was 45% [95% CI 36–55] at 5 years, 75% [95% CI 66–84] at 10 years, and 83% [95% CI 74–90] at 15 years. Median loss of autonomy time was 6 years. Asian origin and age at onset < 18 years emerged as negative prognostic factors, while type of mutated gene and symptoms at onset were not related to survival or disability.ConclusionsThis study documented that half of patients survived at least 11 years. The notion of actual survival rate and prognostic factors is crucial to design studies on the effectiveness of upcoming new disease-modifying therapies.

The rare rs769301934 variant in NHLRC1 is a common cause of Lafora disease in Turkey.

Lafora disease (LD) is a severe form of progressive myoclonus epilepsy inherited in an autosomal recessive fashion. It is associated with biallelic pathogenic variations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The disease usually starts with adolescent onset seizures followed by progressive dementia, refractory status epilepticus and eventually death within 10 years of onset. LD is generally accepted as having a homogenous clinical course with no considerable differences between EPM2A or NHLRC1 associated forms. Nevertheless, late-onset and slow progressing forms of the disease have also been reported. Herein, we have performed clinical and genetic analyses of 14 LD patients from 12 different families and identified 8 distinct biallelic variations in these patients. Five of these variations were novel and/or associated with the LD phenotype for the first time. Interestingly, almost half of the cases were homozygous for the rare rs769301934 (NM_198586.3(NHLRC1): c.436 G > A; p.(Asp146Asn)) allele in NHLRC1. A less severe phenotype with an onset at a later age may be the reason for the biased inflation of this variant, which is already present in the human gene pool and can hence arise in the homozygous form in populations with increased parental consanguinity.

Personalized Diagnosis of Lafora Disease through Biochemical Characterization of SNPs

Lafora disease (LD) is an autosomal recessive neurodegenerative disease. Patients develop normally as children, and are typically diagnosed during adolescence, when the disease presents as a form of progressive myoclonus epilepsy. The disease then progresses rapidly, with patients experiencing seizures of increasing severity and frequency, along with loss of muscle control and neurodegeneration, leading to death within 10 years. Multiple therapies are in development for LD patients, however, recent studies suggest that early detection will be critical for effective treatment of LD patients. It is known that patients with Lafora Disease have mutations in either Epilepsy, Progressive Mycolonus 2A (EPM2A), or Epilepsy, Progressive Mycolonus 2B (EPM2B), which code for the proteins laforin and malin, respectively. Laforin is the only known mammalian phosphatase that can remove phosphate from glycogen, and malin is an E3 ligase that has been shown to ubiquitinate enzymes involved in glycogen synthesis and degradation. Together, these proteins play critical roles in regulating glycogen metabolism. Disease causing mutations occur throughout each protein, suggesting multiple roles for both laforin and malin in glycogen regulation. Given the diversity of disease-causing mutations in these proteins, it is challenging to determine if a mutation will be deleterious prior to the onset of epilepsy in the patient. In order to effectively treat LD patients, disease-causing mutations will need to be identified prior to the onset of symptoms, while the patient still shows normal development. Therefore, physicians need a reliable method for determining mutation pathogenicity. Here, we present a biochemical pipeline for laforin to characterize newly identified SNPs and determine pathogenicity. Through the integration of multiple techniques including differential scanning fluorimetry, phosphatase activity assays, and HDX analysis, our lab has characterized the impact of SNPs on laforin function. This pipeline will allow physicians and patients to obtain personalized diagnoses of Lafora Disease prior to the onset of symptoms.

Generation of human induced pluripotent stem cell lines (UNIMGi003-A and UNIMGi004-A) from two Italian siblings affected by Unverricht-Lundborg disease

Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy caused by mutations in the gene encoding Cystatin B (CSTB), an inhibitor of lysosomal proteases. The most common mutation described in ULD patients is an unstable expansion of a dodecamer sequence located in the CSTB gene promoter. This expansion is causative of the downregulation of CSTB gene expression and, consequently, of its inhibitory activity. Here we report the generation of induced pluripotent stem cell (iPSC) lines from two Italian siblings having a family history of ULD and affected by different clinical and pathological phenotypes of the disease.

Report of two siblings with action myoclonus renal failure syndrome

Action myoclonus renal failure syndrome (AMRF) is a rare form of progressive myoclonic epilepsy (PME) associated with severe renal failure. AMRF is an autosomal recessive (AR) disease manifested by the development of neurologic and/or renal symptoms in the 2nd and 3rd decades. The disease occurs due to mutations in SCARB2, which encodes the lysosomal integral membrane type 2 (LIMP-2) protein [1].

Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy.

ObjectiveMutations in KCNC1 can cause severe neurological dysfunction, including intellectual disability, epilepsy, and ataxia. The Arg320His variant, which occurs in the voltage‐sensing domain of the channel, causes a highly penetrant and specific form of progressive myoclonus epilepsy with severe ataxia, designated myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK). KCNC1 encodes the voltage‐gated potassium channel KV3.1, a channel that is important for enabling high‐frequency firing in interneurons, raising the possibility that MEAK is associated with reduced interneuronal function.MethodsTo determine how this variant triggers MEAK, we expressed KV3.1bR320H in cortical interneurons in vitro and investigated the effects on neuronal function and morphology. We also performed electrophysiological recordings of oocytes expressing KV3.1b to determine whether the mutation introduces gating pore currents.ResultsExpression of the KV3.1bR320H variant profoundly reduced excitability of mature cortical interneurons, and cells expressing these channels were unable to support high‐frequency firing. The mutant channel also had an unexpected effect on morphology, severely impairing neurite development and interneuron viability, an effect that could not be rescued by blocking KV3 channels. Oocyte recordings confirmed that in the adult KV3.1b isoform, R320H confers a dominant negative loss‐of‐function effect by slowing channel activation, but does not introduce potentially toxic gating pore currents.SignificanceOverall, our data suggest that, in addition to the regulation of high‐frequency firing, KV3.1 channels play a hitherto unrecognized role in neuronal development. MEAK may be described as a developmental dendritopathy.