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Molecular Genetics & Genomic Medicine Oct 2020Pathogenic KCNA1 variants have been linked to episodic ataxia type 1 (EA1), a rare neurological syndrome characterized by continuous myokymia and attacks of generalized...
BACKGROUND
Pathogenic KCNA1 variants have been linked to episodic ataxia type 1 (EA1), a rare neurological syndrome characterized by continuous myokymia and attacks of generalized ataxia that can be triggered by fever, abrupt movements, emotional stress, and fatigue. Currently, over 40 KCNA1 variants have been identified in individuals with EA1.
METHODS
A male patient displayed partial seizures in addition to EA1 symptoms, often triggered by fever. A sibling presented with typical EA1 symptoms, seizures, and learning difficulties. In addition, the older brother displayed cognitive impairment, developmental delay, and slurred speech, which were absent in his younger sister. Whole-exome sequencing was performed for the patients.
RESULTS
A novel de novo missense variant in KCNA1 (p.Ala261Thr) was identified in the male patient, which is located in a base of the 3rd transmembrane domain (S3). The other novel KCNA1 variant (p.Gly376Ser) was identified in the sibling and was inherited from an unaffected father with low-level mosaicism. The variant was located in the S5-S6 extracellular linker of the voltage sensor domain of the Kv channel. Next, we systematically reviewed the available clinical phenotypes of individuals with EA1 and observed that individuals with KCNA1 variants at the C-terminus were more likely to suffer from seizures and neurodevelopmental disorders than those with variants at the N-terminus.
CONCLUSION
Our study expands the mutation spectrum of KCNA1 and improves our understanding of the genotype-phenotype correlations of KCNA1. Definitive genetic diagnosis is beneficial for the genetic counseling and clinical management of individuals with EA1.
Topics: Ataxia; Child, Preschool; Developmental Disabilities; Female; Humans; Infant; Kv1.1 Potassium Channel; Male; Mosaicism; Mutation, Missense; Myokymia; Phenotype; Protein Domains
PubMed: 32705822
DOI: 10.1002/mgg3.1434 -
Acta Myologica : Myopathies and... Mar 2020Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders....
Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in , previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.
Topics: Adult; Brain; Calcium; Calcium-Regulating Hormones and Agents; Diagnosis, Differential; Female; Humans; Hypocalcemia; Kv1.1 Potassium Channel; Magnesium; Magnetic Resonance Imaging; Mutation; Myokymia; Neurologic Examination; Tetany
PubMed: 32607479
DOI: 10.36185/2532-1900-007 -
Annals of Indian Academy of Neurology 2020
PubMed: 32606527
DOI: 10.4103/aian.AIAN_590_19 -
Neuro-ophthalmology (Aeolus Press) Apr 2020Herein, we describe a novel manifestation of facial nerve synkinesis, swallow-induced eyelid myokymia, and hypothesise that this phenomenon is due to synkinetic facial...
Herein, we describe a novel manifestation of facial nerve synkinesis, swallow-induced eyelid myokymia, and hypothesise that this phenomenon is due to synkinetic facial nerve innervations of the stylohyoid-posterior digastric complex of suprahyoid muscles and orbicularis oculi muscle. In our patient's case, onabotulinum toxin A treatment provided good therapeutic response. Swallow-induced eyelid myokymia is a unique and previously unreported variety of facial nerve synkinesis.
PubMed: 32395158
DOI: 10.1080/01658107.2019.1587637 -
International Journal of Molecular... Apr 2020Kv1.1 belongs to the subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous... (Review)
Review
Kv1.1 belongs to the subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential.
Topics: Alleles; Animals; Channelopathies; Disease Management; Gene Expression Regulation; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Ion Channel Gating; Kv1.1 Potassium Channel; Molecular Targeted Therapy; Mutation; Phenotype; Structure-Activity Relationship
PubMed: 32331416
DOI: 10.3390/ijms21082935 -
The Journal of Pharmacology and... Jun 2020Loss of function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to...
Loss of function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to isoform-selectively activate specific Kv channels. One example is KCNA1 Potassium Voltage-Gated Channel Subfamily A Member 1 (KCNA1) (Kv1.1), an archetypal -type Kv channel, in which loss-of-function mutations cause episodic ataxia type 1 (EA1). EA1 causes constant myokomia and episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter -aminobutyric acid and modified versions of glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of fluorine atoms within the fluorophenyl ring of glycine derivatives produces isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1. The findings refine our understanding of the molecular basis for KCNQ versus KCNA1 activation and isoform selectivity and constitute, to our knowledge, the first reported isoform-selective KCNA1 opener. SIGNIFICANCE STATEMENT: Inherited loss-of-function gene sequence variants in , which encodes the KCNA1 (Kv1.1) voltage-gated potassium channel, cause episodic ataxia type 1 (EA1), a movement disorder also linked to epilepsy and developmental delay. We have discovered several isoform-specific KCNA1-activating small molecules, addressing a notable gap in the field and providing possible lead compounds and a novel chemical space for the development of potential future therapeutic drugs for EA1.
Topics: Animals; Ataxia; Epilepsy; Glycine; Humans; Kv1.1 Potassium Channel; Mutation; Myokymia; Protein Isoforms; Xenopus laevis
PubMed: 32217768
DOI: 10.1124/jpet.119.264507 -
Intractable & Rare Diseases Research Feb 2020Multiple sclerosis is considered the most frequent demyelinating disorder of the Central Nervous System (CNS) among young adults, yet is very rare before 10 years old....
Multiple sclerosis is considered the most frequent demyelinating disorder of the Central Nervous System (CNS) among young adults, yet is very rare before 10 years old. Acute disseminated encephalomyelitis is a monophasic, polysymptomatic disorder that involves the CNS white matter with demyelinating lesions, which usually occurs after systemic viral infections. These two demyelinating diseases can present initially as an acute focal neurological syndrome and they can be difficult to distinguish. We describe a case of a nine-year-old girl that presented initially with dysphonia, gait ataxia, eyelid myokymia and brainstem disturbances. This was her second episode; the first episode was at the age of four years old. She recovered without neurological sequelae. The brain magnetic resonance imaging (MRI) demonstrated multiple demyelinating lesions in the white matter, cortical regions of the frontal lobe, periventricular distribution, internal capsule, corpus callosum and cerebellum. The purpose of the presentation of this case was to highlight the similarities between these two entities, since the clinical picture and neuroimaging are difficult to distinguish, mainly in relation to the first episode.
PubMed: 32201679
DOI: 10.5582/irdr.2020.01009 -
Clinical Ophthalmology (Auckland, N.Z.) 2020Eyelid myokymia, commonly referred to as "eyelid twitching", is a common, benign condition that resolves in most individuals within hours to days; however, chronic cases...
Eyelid myokymia, commonly referred to as "eyelid twitching", is a common, benign condition that resolves in most individuals within hours to days; however, chronic cases can persist for several weeks to months, prompting the search for home remedies that may reduce the frequency or duration of symptoms. In this article, we discuss the proposed pathophysiologic mechanism and safety concerns surrounding tonic water as a treatment for eyelid myokymia.
PubMed: 32184555
DOI: 10.2147/OPTH.S235895 -
Neurology India 2020
Topics: Deglutition Disorders; Electromyography; Facial Nerve Diseases; Guillain-Barre Syndrome; Humans; Lower Extremity; Male; Middle Aged; Myokymia; Neural Conduction; Neurologic Examination
PubMed: 32129287
DOI: 10.4103/0028-3886.279682 -
JA Clinical Reports Feb 2020Isaacs' syndrome is a peripheral nerve hyperexcitability syndrome and rare acquired channel disease. The symptoms (myokymia, neuromyotonia, and muscle spasm) emerge even...
BACKGROUND
Isaacs' syndrome is a peripheral nerve hyperexcitability syndrome and rare acquired channel disease. The symptoms (myokymia, neuromyotonia, and muscle spasm) emerge even during sleep. This report describes the anesthetic management, especially neuromuscular blocking drugs and postoperative pain, in a case of Isaacs' syndrome.
CASE PRESENTATION
A 63-year-old woman with Isaacs' syndrome underwent elective laparoscopic distal gastrectomy under general anesthesia without epidural anesthesia. She received double filtration plasmapheresis four times to alleviate symptoms before surgery. To avoid a prolonged neuromuscular blockade, we performed total intravenous anesthesia and titrated muscle relaxant with neuromuscular monitoring. Anesthetic management was performed without any problems. However, pain management after surgery proved difficult as she experienced severe pain due to myokymia.
CONCLUSIONS
Despite attempts to minimize symptoms, severe postoperative pain associated with myokymia occurred. Continuous regional anesthesia should be considered to treat pain from abnormal discharge in the central nervous system in Isaacs' syndrome.
PubMed: 32062811
DOI: 10.1186/s40981-020-00321-y