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Journal of Medical Genetics Feb 2020Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in , encoding the voltage-gated K channel subunit...
BACKGROUND
Since 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in , encoding the voltage-gated K channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as 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 , 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 . 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.
Topics: Ataxia; Channelopathies; Child; Child, Preschool; Dyskinesias; Epilepsy; Female; Gene Expression Regulation; Homozygote; Humans; Infant; Infant, Newborn; Kv1.1 Potassium Channel; Male; Mutation; Myokymia; Oxcarbazepine; Pedigree; Exome Sequencing
PubMed: 31586945
DOI: 10.1136/jmedgenet-2019-106373 -
Journal of Neuro-ophthalmology : the... Sep 2019We describe successful surgical treatment of superior oblique myokymia, which had recurred after superior oblique tenectomy.
BACKGROUND
We describe successful surgical treatment of superior oblique myokymia, which had recurred after superior oblique tenectomy.
METHODS
Single case report.
RESULTS
The distal stump of the superior oblique tendon was extirpated by stripping it from the globe. The ipsilateral superior rectus muscle also was recessed, to correct a hypertropia that had resulted from the original superior oblique tenectomy.
CONCLUSIONS
Complete removal of the distal superior oblique muscle tendon provided definitive relief of superior oblique myokymia. Superior rectus muscle recession, combined with previous inferior oblique myectomy, compensated effectively for loss of superior oblique function.
Topics: Eye Movements; Female; Humans; Middle Aged; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Tendons; Treatment Outcome; Trochlear Nerve Diseases
PubMed: 30289792
DOI: 10.1097/WNO.0000000000000718 -
Clinical Neurophysiology Practice 2021We report a case of sustained atypical myokymia associated with short bursts of neuromyotonic discharges involving the abductor pollicis brevis (APB) muscle and describe...
OBJECTIVE
We report a case of sustained atypical myokymia associated with short bursts of neuromyotonic discharges involving the abductor pollicis brevis (APB) muscle and describe a useful way of detecting a focal slowing involving a small number of median nerve motor fibers with a concentric needle using the filter setting for single fiber electromyography (EMG).
METHODS AND RESULTS
A 62-year-old woman developed right thumb twitches at regular interval of 1.7-3.3 s (0.6-0.3 Hz), which continued for more than four months. Muscle twitches remained the same during altered hand position, psychological stress, or sleep. A concentric needle inserted in the active zone of the APB muscle revealed myokymic bursts with a characteristic of neuromyotonic discharges. Inching study, stimulating at 5 mm increment along the median nerve and recording with a concentric needle using a filter setting for single fiber EMG, revealed a focal slowing of the motor fibers at a point 5-10 mm distal from the distal crease of the wrist, an entrapment site occasionally seen in the carpal tunnel syndrome. One injection of botulinum toxin type A eliminated the myokymia, which then recurred two and a half years later, showing less prominent muscle twitches.
CONCLUSIONS
Sustained atypical myokymia seen in our case represented bursts of neuromyotonic discharges originated from a focal demyelinating lesion involving a few median nerve motor fibers.
PubMed: 33490741
DOI: 10.1016/j.cnp.2020.11.003 -
International Journal of Molecular... Oct 2020(1) Background: Episodic ataxia type 1 is caused by mutations in the gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in...
(1) Background: Episodic ataxia type 1 is caused by mutations in the gene encoding for the voltage-gated potassium channel Kv1.1. There have been many mutations in Kv1.1 linked to episodic ataxia reported and typically investigated by themselves or in small groups. The aim of this article is to determine whether we can define a functional parameter common to all Kv1.1 mutants that have been linked to episodic ataxia. (2) Methods: We introduced the disease mutations linked to episodic ataxia in the drosophila analog of Kv1.1, the Shaker Kv channel, and expressed the channels in Xenopus oocytes. Using the cut-open oocyte technique, we characterized the gating and ionic currents. (3) Results: We found that the episodic ataxia mutations variably altered the different gating mechanisms described for Kv channels. The common characteristic was a conductance voltage relationship and inactivation shifted to less polarized potentials. (4) Conclusions: We suggest that a combination of a prolonged action potential and slowed and incomplete inactivation leads to development of ataxia when Kv channels cannot follow or adapt to high firing rates.
Topics: Animals; Ataxia; Humans; Ion Channel Gating; Kv1.1 Potassium Channel; Mutation; Myokymia; Xenopus
PubMed: 33066705
DOI: 10.3390/ijms21207602 -
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 -
Annals of Indian Academy of Neurology 2020
PubMed: 32606527
DOI: 10.4103/aian.AIAN_590_19