ADCY5-related dyskinesia - case series with literature review.

INTRODUCTION: ADCY5-related dyskinesia is a rare neurological disease caused by mutations in the gene encoding the adenylyl cyclase 5 (ADCY5) isoform, a protein that plays an important role in intracellular transmission. Variants in ADCY5 are associated with a spectrum of neurological disease encompassing dyskinesia, chorea, and dystonia. State of the-art. ADCY5 mutations result in clinically heterogeneous manifestations which comprise a range of core and less to highly variable symptoms. Due to the heterogeneous nature and difficulty in diagnosis of the disorder, available treatments are highly limited. CLINICAL IMPLICATIONS: ADCY5-related dyskinesia was reported in 52 individuals in the literature over a five-year period (January 2017 to January 2022). We have listed all the symptoms and their frequency. The most common symptom reported in these patients was dystonia. Over 50% of patients developed dyskinesia and chorea. We report two cases of familial occurrence of symptomatic ADCY5-related dyskinesia. A 45-year-old patient presented with involuntary movements which had been occurring since childhood. The proband's neurological examination revealed dysarthria, involuntary myoclonic twitches, and choreic movements. The patient's 9-year-old son had developed involuntary movements, mainly chorea and dystonia. FUTURE DIRECTIONS: This paper aims to summarise the recent literature on ADCY5-related neurological disorders and to present a new case of a Polish family with ADCY5 mutation. Genetic diagnostics are important in the context of possible future targeted treatments.

[A case of a pathological variant of the PRRT2 gene in twins with paroxysmal kinesiogenic dyskinesia]. / Sluchai patologicheskogo varianta gena PRRT2 u bliznetsov s paroksizmal'noi kineziogennoi diskineziei.

Paroxysmal dyskinesia is a clinically and etiologically polymorphic group of diseases, the main clinical manifestation of which is transient attacks of extrapyramidal movements, with different conditions of occurrence. Paroxysmal kinesigenic dyskinesia belongs to the group of primary dyskinesias, which also includes paroxysmal non-kinesigenic dyskinesia and exercise-induced paroxysmal dyskinesia. The most common cause of paroxysmal kinesiogenic dyskinesia is mutations in the PRRT2 gene; in cases of non-kinesiogenic dyskinesia, a mutation in the MR1 gene is detected. The diagnosis of primary dyskinesias causes significant difficulty for clinicians due to the rarity of occurrence, as well as the large spectrum of conditions occurring with paroxysmal motor disorders in childhood. The article describes the clinical observation of 16-year-old twin brothers with transient attacks of dystonic, choreic and ballistic hyperkinesis that suddenly arose during movement. Patients were treated for tics and epilepsy for 12 years. Taking into account the clinical picture - transient attacks of hyperkinesis, their connection with movement, as well as data from video-electroencephalographic monitoring, a diagnosis of paroxysmal kinesiogenic dyskinesia was established, which in a further diagnostic search was confirmed by targeted sequencing of the pathological variant of the PRRT2 gene previously described in patients with kinesiogenic dyskinesia. The administration of carbamazepine, which is the drug of choice in the treatment of this category of patients, has achieved significant control over hyperkinesis in twins. Thus, molecular genetic diagnosis helps confirm the diagnosis of paroxysmal dyskinesias, but careful analysis of the clinical picture, considering the provoking factor, remains the basis of diagnosis.

An insertion mutation of the MECP2 gene in severe neonatal encephalopathy and ocular and oropharyngeal dyskinesia: a case report.

BACKGROUND: Pathogenic variation of the MECP2 gene presents mostly as Rett syndrome in females and is extremely rare in males. Most male patients with MECP2 gene mutation show MECP2 duplication syndrome. CASE PRESENTATION: Here we report a rare case in a 10-month-old boy with a hemizygous insertion mutation in MECP2 as NM_001110792, c.799_c.800insAGGAAGC, which results in a frameshift mutation (p.R267fs*6). The patient presented with severe encephalopathy in the neonatal period, accompanied by severe development backwardness, hypotonia, and ocular and oropharyngeal dyskinesia. This is the first report of this mutation, which highlights the phenotype variability associated with MECP2 variants. CONCLUSIONS: This case helps to expand the clinical spectrum associated with MECP2 variants. Close attention should be paid to the growth and development of patients carrying a MECP2 variant or Xq28 duplication. Early interventions may help improve symptoms to some certain extent.

Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.

INTRODUCTION: Next generation sequencing technologies allow detection of very rare pathogenic gene variants and uncover cerebral palsy. Herein, we describe two siblings with cerebral palsy due to ELOVL1 splice site mutation in autosomal recessive manner. ELOVL1 catalyzes fatty acid elongation to produce very long-chain fatty acids (VLCFAs; ≥C21), most of which are components of sphingolipids such as ceramides and sphingomyelins. Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies (MIM: 618527) stem from ELOVL1 gene deficiency in human. METHODS: We have studied a consanguineous family with whole exome sequencing (WES) and performed in depth analysis of cryptic splicing on the molecular level using RNA. Comprehensive analysis of ceramides in the skin stratum corneum of patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS). ELOVL1 protein structure was computationally modelled. RESULTS: The novel c.376-2A > G (ENST00000372458.8) homozygous variant in the affected siblings causes exon skipping. Comprehensive analysis of ceramides in the skin stratum corneum of patients using LC-MS/MS demonstrated significant shortening of fatty acid moieties and severe reduction in the levels of acylceramides. DISCUSSION: It has recently been shown that disease associated variants of ELOVL1 segregate in an autosomal dominant manner. However, our study for the first time demonstrates an alternative autosomal recessive inheritance model for ELOVL1. In conclusion, we suggest that in ultra-rare diseases, being able to identify the inheritance patterns of the disease-associated gene or genes can be an important guide to identifying the molecular mechanism of genetic cerebral palsy.

Efficacy of Caffeine in ADCY5-Related Dyskinesia: A Retrospective Study.

BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.

Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia.

A growing number of gain-of-function (GOF) BK channelopathies have been identified in patients with epilepsy and movement disorders. Nevertheless, the underlying pathophysiology and corresponding therapeutics remain obscure. Here, we utilized a knock-in mouse model carrying human BK-D434G channelopathy to investigate the neuronal mechanism of BK GOF in the pathogenesis of epilepsy and dyskinesia. The BK-D434G mice manifest the clinical features of absence epilepsy and exhibit severe motor deficits and dyskinesia-like behaviors. The cortical pyramidal neurons and cerebellar Purkinje cells from the BK-D434G mice show hyperexcitability, which likely contributes to the pathogenesis of absence seizures and paroxysmal dyskinesia. A BK channel blocker, paxilline, potently suppresses BK-D434G­induced hyperexcitability and effectively mitigates absence seizures and locomotor deficits in mice. Our study thus uncovered a neuronal mechanism of BK GOF in absence epilepsy and dyskinesia. Our findings also suggest that BK inhibition is a promising therapeutic strategy for mitigating BK GOF-induced neurological disorders.

The Essential Role of Epigenetic Modifications in Neurodegenerative Diseases with Dyskinesia.

Epigenetics play an essential role in the occurrence and improvement of many diseases. Evidence shows that epigenetic modifications are crucial to the regulation of gene expression. DNA methylation is closely linked to embryonic development in mammalian. In recent years, epigenetic drugs have shown unexpected therapeutic effects on neurological diseases, leading to the study of the epigenetic mechanism in neurodegenerative diseases. Unlike genetics, epigenetics modify the genome without changing the DNA sequence. Research shows that epigenetics is involved in all aspects of neurodegenerative diseases. The study of epigenetic will provide valuable insights into the molecular mechanism of neurodegenerative diseases, which may lead to new treatments and diagnoses. This article reviews the role of epigenetic modifications neurodegenerative diseases with dyskinesia, and discusses the therapeutic potential of epigenetic drugs in neurodegenerative diseases.

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia.

Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.

The phenotypic spectrum of X-linked, infantile onset ALG13-related developmental and epileptic encephalopathy.

OBJECTIVE: Asparagine-linked glycosylation 13 (ALG13) deficiencies have been repeatedly described in the literature with the clinical phenotype of a developmental and epileptic encephalopathy (DEE). Most cases were females carrying the recurrent ALG13 de novo variant, p.(Asn107Ser), with normal transferrin electrophoresis. METHODS: We delineate the phenotypic spectrum of 38 individuals, 37 girls and one boy, 16 of them novel and 22 published, with the most common pathogenic ALG13 variant p.(Asn107Ser) and additionally report the phenotype of three individuals carrying other likely pathogenic ALG13 variants. RESULTS: The phenotypic spectrum often comprised pharmacoresistant epilepsy with epileptic spasms, mostly with onset within the first 6 months of life and with spasm persistence in one-half of the cases. Tonic seizures were the most prevalent additional seizure type. Electroencephalography showed hypsarrhythmia and at a later stage of the disease in one-third of all cases paroxysms of fast activity with electrodecrement. ALG13-related DEE was usually associated with severe to profound developmental delay; ambulation was acquired by one-third of the cases, whereas purposeful hand use was sparse or completely absent. Hand stereotypies and dyskinetic movements including dystonia or choreoathetosis were relatively frequent. Verbal communication skills were absent or poor, and eye contact and pursuit were often impaired. SIGNIFICANCE: X-linked ALG13-related DEE usually manifests as West syndrome with severe to profound developmental delay. It is predominantly caused by the recurrent de novo missense variant p.(Asn107Ser). Comprehensive functional studies will be able to prove or disprove an association with congenital disorder of glycosylation.

The BDNF Val66Met polymorphism (rs6265) enhances dopamine neuron graft efficacy and side-effect liability in rs6265 knock-in rats.

Prevalent in approximately 20% of the worldwide human population, the rs6265 (also called 'Val66Met') single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor (BDNF) is a common genetic variant that can alter therapeutic responses in individuals with Parkinson's disease (PD). Possession of the variant Met allele results in decreased activity-dependent release of BDNF. Given the resurgent worldwide interest in neural transplantation for PD and the biological relevance of BDNF, the current studies examined the effects of the rs6265 SNP on therapeutic efficacy and side-effect development following primary dopamine (DA) neuron transplantation. Considering the significant reduction in BDNF release associated with rs6265, we hypothesized that rs6265-mediated dysfunctional BDNF signaling contributes to the limited clinical benefit observed in a subpopulation of PD patients despite robust survival of grafted DA neurons, and further, that this mutation contributes to the development of aberrant graft-induced dyskinesias (GID). To this end, we generated a CRISPR knock-in rat model of the rs6265 BDNF SNP to examine for the first time the influence of a common genetic polymorphism on graft survival, functional efficacy, and side-effect liability, comparing these parameters between wild-type (Val/Val) rats and those homozygous for the variant Met allele (Met/Met). Counter to our hypothesis, the current research indicates that Met/Met rats show enhanced graft-associated therapeutic efficacy and a paradoxical enhancement of graft-derived neurite outgrowth compared to wild-type rats. However, consistent with our hypothesis, we demonstrate that the rs6265 genotype in the host rat is strongly linked to development of GID, and that this behavioral phenotype is significantly correlated with neurochemical signatures of atypical glutamatergic neurotransmission by grafted DA neurons.

GNAO1 mutation-related severe involuntary movements treated with gabapentin.

BACKGROUND: Mutations in GNAO1 typically result in neurodevelopmental disorders, including involuntary movements. They may be improved using calcium-channel modulators. CASE: The patient visited our hospital at age 2 years because of moderate global developmental delay. Her intermittent, generalized involuntary movements started at age 8 years. A de novo GNAO1 mutation, NM_020988.2:c.626G > A, (p.Arg209Cys), was identified by whole exome sequencing. At age 9 years, she experienced severe, intermittent involuntary movements, which led to rhabdomyolysis. She needed intensive care with administration of midazolam, dantrolene sodium hydrate, and plasma exchange. We started treating her with gabapentin (GBP), after which she recovered completely. At age 11 years, she developed continuous, generalized involuntary movements. This prompted us to increase the GBP dose, which again resolved the involuntary movements completely. CONCLUSION: In the case of movement disorders associated with GNAO1 mutations, GBP treatment may be attempted before more invasive procedures are performed.

Pharmacogenetic profile and the development of the dyskinesia induced by levodopa-therapy in Parkinson's disease patients: a population-based cohort study.

Levodopa-induced dyskinesia (LID) is an adverse effect that negatively impacts the quality of life of patients with Parkinson's disease (PD). Studies report that genetic variations in the genes of the pharmacogenetic pathway of the levodopa (L-DOPA) might be associated with LID development. The goal of the present study was to investigate a possible influence of functional genetic variants in the DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) genes with LID development. A total of 220 patients with idiopathic PD were enrolled. The genotyping for DRD1 (rs4532), DRD2 (rs1800497), DAT1 (rs28363170), and COMT (rs4680) polymorphisms were performed using Restriction Fragment Length Polymorphism (PCR-RFLP). Univariate and multivariate analyses were performed to assess the association of these polymorphisms and risk factors with LID development. Multivariate Cox regression analysis showed increased risk to LID development for both Levodopa Dose Equivalency (LED) (Hazard ratios (HR) = 1.001; 95% CI 1.00-1.01; p = 0.009) and individuals carrying the COMT L/L genotype (HR = 2.974; 95% CI 1.12-7.83; p = 0.010). Furthermore, when performed a Cox regression analysis adjusted for a total LED, we observed that the genotype COMT L/L had a 3.84-fold increased risk for LID development (HR = 3.841; 95% CI 1.29-11.37; p = 0.012). Our results suggest that before treating LID in PD patients, it is important to take into consideration genetic variant in the COMT gene, since COMT LL genotype may increase the risk for LID development.

Discinesia asociada a ADCY5 en la infancia: a propósito de una familia y revisión actualizada / ADCY5-associated dyskinesia in young children: a case report of a family and an updated review

INTRODUCCIÓN: La discinesia de la mutación ADCY5 es un raro trastorno del movimiento de inicio en la infancia. Se caracteriza por movimientos coreicos aislados o asociados a mioclonías y distonías que afectan a las extremidades, el cuello y la cara. El escaso número de pacientes y familias no permite aún una adecuada relación genotipo-fenotipo. OBJETIVOS: Presentar el caso de un niño con trastornos del movimiento de inicio precoz en el seno de una familia con tres generaciones de afectados, y realizar una revisión actualizada de la casuística y el tratamiento de esta rara enfermedad. CASO CLÍNICO: Varón de 6 años, remitido por retraso del lenguaje e hiperactividad. Tras seis meses de seguimiento, comenzó a presentar movimientos coreicos de predominio facial y de la raíz de los miembros, especialmente al despertar. Al año de seguimiento, se evidenció corea generalizado en reposo con afectación orofacial y torpeza en la marcha. Como antecedentes familiares destacaban su madre, abuelo, tío y prima maternos, que fueron diagnosticados de síndrome de Meige (distonía oromandibular y músculos periorbitarios) con trastornos del movimiento de tipo coreiforme sin filiar desde la infancia. El estudio cerebral por resonancia magnética no presentó alteraciones. Se realizó un exoma clínico dirigido a trastornos del movimiento que descubrió la mutación patógena en el gen ADCY5 causante de la discinesia familiar autosómica. CONCLUSIÓN: La mutación c.1126G > A p.A376T muestra una historia natural con un fenotipo clínico no progresivo en tres generaciones de afectados, con inicio en la infancia y respuesta al tratamiento con guanfacina

INTRODUCTION. Dyskinesia of the ADCY5 mutation is a rare movement-onset disorder in childhood. It is characterized by isolated chorea movements or associated with myoclonus and dystonia affecting the limbs, neck and face. The low number of patients and families still does not allow an adequate genotype-phenotype relationship. AIMS. The case of a child with movement disorders of early onset is presented in a family with three generations of affected members. An updated review of the casuistry and management of this rare disease is made. CASE REPORT: A 6-year-old boy referred for language delay and hyperactivity. After six months of follow-up he begins to show chorea movements of predominantly facial and limb roots, especially when waking up. At one year of follow-up, generalized chorea at rest with orofacial involvement and awkward gait begins to show. His family history includes his mother, grandfather, maternal uncle and cousin, who were diagnosed with Meige's syndrome (oromandibular dystonia and periorbital muscles) with choreiform-like movement disorders without affiliation since childhood. The brain study by MRI showed no alterations. A clinical exome targeting movement disorders was performed that discovered the pathogenic mutation in the ADCY5 gene causing autosomal familial dyskinesia. CONCLUSION: The c.1126G>A p.A376T mutation shows a natural history with a non-progressive clinical phenotype in three generations of affected members, with childhood debut and response to guanfacine treatment

Ampliando el fenotipo del síndrome FOXG1 / Expanding FOXG1 syndrome phenotype

No disponible

Treatment of Disorders of Tone and Other Considerations in Pediatric Movement Disorders.

Pediatric movement disorders (PMDs) consist of a heterogeneous group of signs and symptoms caused by numerous neurological diseases. Different neurological disorders in children also share overlapping movement disorders making a diagnosis of the underlying cause of the movement disorder challenging. The similarity of the symptoms across multiple disease types suggests that there may be a final common motor pathway causing the overlapping movement disorders. There are numerous disorders in children associated with disturbances in tone and involuntary movements. This chapter will focus primarily on those disorders that involve abnormalities of tone and other important considerations of pediatric movement disorders. This chapter will address rating scales and goals for treatment and will include a review of symptomatic treatment and, where possible, the treatment of the underlying disease processes. The chapter will review representative disorders, including an inborn error of metabolism, an autoimmune disorder, and a group of neurodegenerative disorders. These examples demonstrate how the disorder's underlying pathophysiology results in a specific approach to the underlying disease and the associated conditions of tone and involuntary movements. Finally, the multiple treatment options for cerebral palsy and considerations of cerebral palsy mimics will be discussed.

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia.

BACKGROUND: Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events. METHODS: A patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings. RESULTS: WES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures. CONCLUSION: This newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

Functional study and pathogenicity classification of PRRT2 missense variants in PRRT2-related disorders.

AIMS: PRRT2 variants are associated with various paroxysmal disorders. To date, more than 90 PRRT2 variants have been reported in PRRT2-related disorders. Lack of functional study in majority of missense variants makes their pathogenicity uncertain. We aim to evaluate the clinical significance of PRRT2 missense variants by performing in vitro experiments. METHODS: We systematically reviewed PRRT2-related disorders and summarized reported PRRT2 missense variants. Protein expression and subcellular localization of mutant PRRT2 were investigated in mammal cells. American College of Medical Genetics and Genomics (ACMG) guidelines were used to analyze the pathogenicity of PRRT2 missense variants. RESULTS: A total of 29 PRRT2 missense variants were identified in PRRT2-related disorders. Ten variants were observed to affect both subcellular localization and protein level, three variants only affect membrane localization, and two variants only affect protein level. According to ACMG guidelines, 15 variants were finally classified as "likely pathogenic", three as "benign", three as "likely benign", and eight as "uncertain significance" variants. The likely pathogenic variants were concentrated in the C-terminal of PRRT2. CONCLUSIONS: The pathogenicity of eight uncertain significance variants needs further investigation. C-terminal of PRRT2 is crucial for its physiological function.

Comparative gain-of-function effects of the KCNMA1-N999S mutation on human BK channel properties.

KCNMA1, encoding the voltage- and calcium-activated potassium channel, has a pivotal role in brain physiology. Mutations in KCNMA1 are associated with epilepsy and/or dyskinesia (PNKD3). Two KCNMA1 mutations correlated with these phenotypes, D434G and N999S, were previously identified as producing gain-of-function (GOF) effects on BK channel activity. Three new patients have been reported harboring N999S, one carrying a second mutation, R1128W, but the effects of these mutations have not yet been reported under physiological K+ conditions or compared to D434G. In this study, we characterize N999S, the novel N999S/R1128W double mutation, and D434G in a brain BK channel splice variant, comparing the effects on BK current properties under a physiological K+ gradient with action potential voltage commands. N999S, N999S/R1128W, and D434G cDNAs were expressed in HEK293T cells and characterized by patch-clamp electrophysiology. N999S BK currents were shifted to negative potentials, with faster activation and slower deactivation compared with wild type (WT) and D434G. The double mutation N999S/R1128W did not show any additional changes in current properties compared with N999S alone. The antiepileptic drug acetazolamide was assessed for its ability to directly modulate WT and N999S channels. Neither the WT nor N999S channels were sensitive to the antiepileptic drug acetazolamide, but both were sensitive to the inhibitor paxilline. We conclude that N999S is a strong GOF mutation that surpasses the D434G phenotype, without mitigation by R1128W. Acetazolamide has no direct modulatory action on either WT or N999S channels, indicating that its use may not be contraindicated in patients harboring GOF KCNMA1 mutations.NEW & NOTEWORTHYKCNMA1-linked channelopathy is a new neurological disorder characterized by mutations in the BK voltage- and calcium-activated potassium channel. The epilepsy- and dyskinesia-associated gain-of-function mutations N999S and D434G comprise the largest number of patients in the cohort. This study provides the first direct comparison between D434G and N999S BK channel properties as well as a novel double mutation, N999S/R1128W, from another patient, defining the functional effects during an action potential stimulus.