KCNA2 Epilepsy: Difference between revisions
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<div class="editorbox"> '''Original Editor '''- [[User:Lauren Heydenrych|Lauren Heydenrych]] <br> | |||
<div class="editorbox"> '''Original Editor '''- [[User: | |||
'''Top Contributors''' - {{Special:Contributors/{{FULLPAGENAME}}}}</div> | '''Top Contributors''' - {{Special:Contributors/{{FULLPAGENAME}}}}</div> | ||
== Introduction == | == Introduction == | ||
'''KCNA2 [[epilepsy]]''' is an epileptic condition caused by a malfunction in the potassium channels located within the Central nervous System (CNS).<ref name=":0">KCNA2 Epilepsy Organisation. What is KCNA2 Epilepsy. Available from: https://www.kcna2epilepsy.org/kcna2-epilepsy/what-is-kcna2-epilepsy/ (accessed 26 June 2023).</ref> | '''KCNA2 [[epilepsy]]''' is an epileptic condition caused by a malfunction in the potassium channels located within the Central nervous System (CNS).<ref name=":0">KCNA2 Epilepsy Organisation. What is KCNA2 Epilepsy. Available from: https://www.kcna2epilepsy.org/kcna2-epilepsy/what-is-kcna2-epilepsy/ (accessed 26 June 2023).</ref> KCNQ2-related disorders are rare. However in studies on individuals with presumed genetic epilepsies, KCNQ2 ranks among the most frequently implicated genes.<ref>Miceli F, Soldovieri MV, Weckhuysen S, Cooper E, Taglialatela M. [https://www.ncbi.nlm.nih.gov/books/NBK32534/ KCNQ2-related disorders].Available:https://www.ncbi.nlm.nih.gov/books/NBK32534/ (accessed 7.10.2023)</ref> | ||
== Clinically Relevant Anatomy == | == Clinically Relevant Anatomy == | ||
'''KCNA2''' is a gene located on chromosome 1p13.3. It encodes the voltage-gated potassium (K+) channels, many of which are located in the CNS. Mutations occurring in K+ channel-coding genes cause different neurological diseases. <ref name=":1">Wang H, Zhu Y, Cao D, Chen H, Ding X, Zeng Q, Zou H, Liao J. [https://aepi.biomedcentral.com/articles/10.1186/s42494-021-00069-7 Successful medical treatment of west syndrome with a KCNA2 variant: a case report]. Acta Epileptologica. 2022 Mar 2;4(1):6.</ref> | '''KCNA2''' is a gene located on chromosome 1p13.3. It encodes the voltage-gated potassium (K+) channels, many of which are located in the CNS. Mutations occurring in K+ channel-coding genes cause different [[Neurological Disorders|neurological diseases]]. <ref name=":1">Wang H, Zhu Y, Cao D, Chen H, Ding X, Zeng Q, Zou H, Liao J. [https://aepi.biomedcentral.com/articles/10.1186/s42494-021-00069-7 Successful medical treatment of west syndrome with a KCNA2 variant: a case report]. Acta Epileptologica. 2022 Mar 2;4(1):6.</ref> | ||
== Mechanism of Injury / Pathological Process == | == Mechanism of Injury / Pathological Process == | ||
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Malfunction of the KCNA2 channels can be seen as 3 different [https://www.genome.gov/genetics-glossary/Phenotype phenotypes]:<ref name=":0" /> | Malfunction of the KCNA2 channels can be seen as 3 different [https://www.genome.gov/genetics-glossary/Phenotype phenotypes]:<ref name=":0" /> | ||
# '''A gain of function (GOF)''' - where the channel does not close properly. This leads to an increased amount of K+ in the brain. | # '''A gain of function (GOF)''' - where the channel does not close properly. This leads to an increased amount of K+ in the [[Brain Anatomy|brain.]] | ||
# '''A loss of function''' '''(LOF)''' - where the channel does not open properly. This leads to a low amount of K+ in the brain. | # '''A loss of function''' '''(LOF)''' - where the channel does not open properly. This leads to a low amount of K+ in the brain. | ||
# '''A mix of functions''' - Where the K+ channel does both. | # '''A mix of functions''' - Where the K+ channel does both. | ||
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KCNA2 epilepsy is often linked with encephalopathy in the research literature.<ref>Masnada S, Hedrich UB, Gardella E, Schubert J, Kaiwar C, Klee EW, Lanpher BC, Gavrilova RH, Synofzik M, Bast T, Gorman K. [https://www.researchgate.net/publication/320372444_Clinical_spectrum_and_genotype-phenotype_associations_of_KCNA2-related_encephalopathies Clinical spectrum and genotype–phenotype associations of KCNA2-related encephalopathies.] Brain. 2017 Sep 1;140(9):2337-54.</ref> Encephalopathy itself can be defined as a "... dysfunction of the level or contents of consciousness due to brain dysfunction and can result from global brain insults or focal lesions." <ref>Erkkinen MG, Berkowitz AL. [https://www.amjmed.com/article/S0002-9343(19)30571-6/fulltext A clinical approach to diagnosing encephalopathy]. The American Journal of Medicine. 2019 Oct 1;132(10):1142-7.</ref> | KCNA2 epilepsy is often linked with encephalopathy in the research literature.<ref>Masnada S, Hedrich UB, Gardella E, Schubert J, Kaiwar C, Klee EW, Lanpher BC, Gavrilova RH, Synofzik M, Bast T, Gorman K. [https://www.researchgate.net/publication/320372444_Clinical_spectrum_and_genotype-phenotype_associations_of_KCNA2-related_encephalopathies Clinical spectrum and genotype–phenotype associations of KCNA2-related encephalopathies.] Brain. 2017 Sep 1;140(9):2337-54.</ref> Encephalopathy itself can be defined as a "... dysfunction of the level or contents of consciousness due to brain dysfunction and can result from global brain insults or focal lesions." <ref>Erkkinen MG, Berkowitz AL. [https://www.amjmed.com/article/S0002-9343(19)30571-6/fulltext A clinical approach to diagnosing encephalopathy]. The American Journal of Medicine. 2019 Oct 1;132(10):1142-7.</ref> | ||
LOF is the most common phenotype presented in the literature. It has been reported that epilepsy in this group tends to have an early onset - within infancy or early childhood. Intellectual disability (mild-to-moderate) and motor regression often appear after the onset of seizures. Ataxia has been associated with LOF.<ref name=":1" /> | LOF is the most common phenotype presented in the literature. It has been reported that epilepsy in this group tends to have an early onset - within infancy or early childhood. Intellectual disability (mild-to-moderate) and motor regression often appear after the onset of seizures. [[Ataxia]] has been associated with LOF.<ref name=":1" /> | ||
GOF has also been linked to ataxia and intellectual disability, with the severity of these presentations as well as seizures being greater. In addition, hypotonia and myoclonus have also been reported for this phenotype.<ref name=":1" /> | GOF has also been linked to ataxia and intellectual disability, with the severity of these presentations as well as seizures being greater. In addition, hypotonia and [[myoclonus]] have also been reported for this phenotype.<ref name=":1" /> | ||
The mixed phenotype can present with particularly severe seizures and conditions described in the LOF and GOF phenotypes. | The mixed phenotype can present with particularly severe seizures and conditions described in the LOF and GOF phenotypes. | ||
| Line 37: | Line 33: | ||
== Diagnostic Procedures == | == Diagnostic Procedures == | ||
An electroencephalogram (EEG) is performed to define the epileptogenic zone.<ref>Noachtar S, Rémi J. [https://www.sciencedirect.com/science/article/abs/pii/S1525505009000924 The role of EEG in epilepsy: a critical review]. Epilepsy & Behavior. 2009 May 1;15(1):22-33.</ref>The Epileptogenic zone is the region of the brain that generates the seizure. | An [[Electrodiagnosis|electroencephalogram]] (EEG) is performed to define the epileptogenic zone.<ref>Noachtar S, Rémi J. [https://www.sciencedirect.com/science/article/abs/pii/S1525505009000924 The role of EEG in epilepsy: a critical review]. Epilepsy & Behavior. 2009 May 1;15(1):22-33.</ref>The Epileptogenic zone is the region of the brain that generates the seizure. | ||
An MRI can also be performed to analyze the structures of the brain, looking for any malformations or types of lesions commonly caused by epilepsy.<ref name=":0" /> | An [[MRI Scans|MRI]] can also be performed to analyze the structures of the brain, looking for any malformations or types of lesions commonly caused by epilepsy.<ref name=":0" /> | ||
Genetic testing is ultimately needed to detect mutations in the KCNA2 gene. | Genetic testing is ultimately needed to detect mutations in the KCNA2 gene. | ||
| Line 52: | Line 48: | ||
=== Medical treatment === | === Medical treatment === | ||
Medical treatment often involves a team approach and can include:<ref name=":0" /> | |||
* Pediatrician | |||
* Pharmacist | |||
* Neurologist | |||
* Geneticist | |||
* Endocrinologist | |||
* Developmental pediatrician | |||
Intervention includes medication to control seizures (anticonvulsants), although there is no real clarity on which anticonvulsants work best with those diagnosed with KCNA2 epilepsy.<ref name=":0" />An article published in 2021 showed promising results of a medication administered to 11 individuals diagnosed with KCNA2 epilepsy. This medication, known as 4-Aminopyridine (4-AP), acts as a K+ channel blocker. 4-AP was able to antagonize the GOF defects observed in this phenotype.<ref>Hedrich UB, Lauxmann S, Wolff M, Synofzik M, Bast T, Binelli A, Serratosa JM, Martínez-Ulloa P, Allen NM, King MD, Gorman KM. [https://www.science.org/doi/10.1126/scitranslmed.aaz4957 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy]. Science translational medicine. 2021 Sep 1;13(609):eaaz4957.</ref> | |||
=== Allied treatment === | === Allied treatment === | ||
As each individual presents differently, different intervention approaches are needed. | As each individual presents differently, different intervention approaches are needed. Currently, there are no clinical practice guidelines in the literature specifically for KCNA2 epilepsy. | ||
A common theme, however, in all research and information websites is the need for a team approach to the management and care of those with KCNA2 epilepsy. One such approach can be the [[Multidisciplinary Team|multidisciplinary approach.]] | |||
Aspects of development and function to consider when assessing and treating a patient with KCNA2 include: | |||
* [[Motor Development Principles|Motor development]] (both fine and gross). | |||
* Cognitive development. | |||
* Feeding and speech development - typically addressed by a [[Role of Speech and Language Therapist in a Rehabilitation Team|speech and language therapist.]]<br> | |||
== Resources <br> == | == Resources <br> == | ||
| Line 66: | Line 78: | ||
<references /> | <references /> | ||
[[Category:Paediatrics]] | |||
[[Category:Paediatrics - Conditions]] | |||
[[Category:Neurological - Conditions]] | |||
Latest revision as of 07:39, 7 October 2023
Introduction[edit | edit source]
KCNA2 epilepsy is an epileptic condition caused by a malfunction in the potassium channels located within the Central nervous System (CNS).[1] KCNQ2-related disorders are rare. However in studies on individuals with presumed genetic epilepsies, KCNQ2 ranks among the most frequently implicated genes.[2]
Clinically Relevant Anatomy[edit | edit source]
KCNA2 is a gene located on chromosome 1p13.3. It encodes the voltage-gated potassium (K+) channels, many of which are located in the CNS. Mutations occurring in K+ channel-coding genes cause different neurological diseases. [3]
Mechanism of Injury / Pathological Process[edit | edit source]
KCNA2 epilepsy is caused by a variation in the KCNA2 gene leading to a malfunction in the K+ channel.[4][5][3]
Malfunction of the KCNA2 channels can be seen as 3 different phenotypes:[1]
- A gain of function (GOF) - where the channel does not close properly. This leads to an increased amount of K+ in the brain.
- A loss of function (LOF) - where the channel does not open properly. This leads to a low amount of K+ in the brain.
- A mix of functions - Where the K+ channel does both.
In all three malfunctions, epilepsy may be observed.
Clinical Presentation[edit | edit source]
KCNA2 epilepsy is often linked with encephalopathy in the research literature.[6] Encephalopathy itself can be defined as a "... dysfunction of the level or contents of consciousness due to brain dysfunction and can result from global brain insults or focal lesions." [7]
LOF is the most common phenotype presented in the literature. It has been reported that epilepsy in this group tends to have an early onset - within infancy or early childhood. Intellectual disability (mild-to-moderate) and motor regression often appear after the onset of seizures. Ataxia has been associated with LOF.[3]
GOF has also been linked to ataxia and intellectual disability, with the severity of these presentations as well as seizures being greater. In addition, hypotonia and myoclonus have also been reported for this phenotype.[3]
The mixed phenotype can present with particularly severe seizures and conditions described in the LOF and GOF phenotypes.
Diagnostic Procedures[edit | edit source]
An electroencephalogram (EEG) is performed to define the epileptogenic zone.[9]The Epileptogenic zone is the region of the brain that generates the seizure.
An MRI can also be performed to analyze the structures of the brain, looking for any malformations or types of lesions commonly caused by epilepsy.[1]
Genetic testing is ultimately needed to detect mutations in the KCNA2 gene.
Whole Exome Sequencing (WES) is commonly performed in the literature in order to identify KCNA2 mutations. This is a sequencing done of the exome - the coding portion of the genome.
The Promise of Whole-Exome Sequencing in Medical Genetics is an article that discusses this procedure and its development in more detail.
Management / Interventions[edit | edit source]
Medical treatment[edit | edit source]
Medical treatment often involves a team approach and can include:[1]
- Pediatrician
- Pharmacist
- Neurologist
- Geneticist
- Endocrinologist
- Developmental pediatrician
Intervention includes medication to control seizures (anticonvulsants), although there is no real clarity on which anticonvulsants work best with those diagnosed with KCNA2 epilepsy.[1]An article published in 2021 showed promising results of a medication administered to 11 individuals diagnosed with KCNA2 epilepsy. This medication, known as 4-Aminopyridine (4-AP), acts as a K+ channel blocker. 4-AP was able to antagonize the GOF defects observed in this phenotype.[11]
Allied treatment[edit | edit source]
As each individual presents differently, different intervention approaches are needed. Currently, there are no clinical practice guidelines in the literature specifically for KCNA2 epilepsy.
A common theme, however, in all research and information websites is the need for a team approach to the management and care of those with KCNA2 epilepsy. One such approach can be the multidisciplinary approach.
Aspects of development and function to consider when assessing and treating a patient with KCNA2 include:
- Motor development (both fine and gross).
- Cognitive development.
- Feeding and speech development - typically addressed by a speech and language therapist.
Resources
[edit | edit source]
- KCNA2 Global Support Community
- Get to Know KCNA2 page on the Rare Epilepsy Network website
References[edit | edit source]
- ↑ 1.0 1.1 1.2 1.3 1.4 KCNA2 Epilepsy Organisation. What is KCNA2 Epilepsy. Available from: https://www.kcna2epilepsy.org/kcna2-epilepsy/what-is-kcna2-epilepsy/ (accessed 26 June 2023).
- ↑ Miceli F, Soldovieri MV, Weckhuysen S, Cooper E, Taglialatela M. KCNQ2-related disorders.Available:https://www.ncbi.nlm.nih.gov/books/NBK32534/ (accessed 7.10.2023)
- ↑ 3.0 3.1 3.2 3.3 Wang H, Zhu Y, Cao D, Chen H, Ding X, Zeng Q, Zou H, Liao J. Successful medical treatment of west syndrome with a KCNA2 variant: a case report. Acta Epileptologica. 2022 Mar 2;4(1):6.
- ↑ McGinn RJ, Von Stein EL, Stromberg JE, Li Y. Precision medicine in epilepsy. Progress in Molecular Biology and Translational Science. 2022 Jan 1;190(1):147-88.
- ↑ Syrbe S, Hedrich U, Riesch E, Djémié T, Müller S, Møller RS, Maher B, Hernandez-Hernandez L, Synofzik M, Caglayan HS, Arslan M. De novo loss-or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature genetics. 2015 Apr;47(4):393-9.
- ↑ Masnada S, Hedrich UB, Gardella E, Schubert J, Kaiwar C, Klee EW, Lanpher BC, Gavrilova RH, Synofzik M, Bast T, Gorman K. Clinical spectrum and genotype–phenotype associations of KCNA2-related encephalopathies. Brain. 2017 Sep 1;140(9):2337-54.
- ↑ Erkkinen MG, Berkowitz AL. A clinical approach to diagnosing encephalopathy. The American Journal of Medicine. 2019 Oct 1;132(10):1142-7.
- ↑ Life with Episodic Ataxia. Dominant KCNA2 gene mutaion causing episodic ataxia with tremor and erratic myoclonic jerks evident. Available from: https://www.youtube.com/watch?v=i572sSLEcN8 [last accessed 5/5/2013]
- ↑ Noachtar S, Rémi J. The role of EEG in epilepsy: a critical review. Epilepsy & Behavior. 2009 May 1;15(1):22-33.
- ↑ Epilepsy Foundation. Specific Gene Mutation Screening in Infants: Children’s Hosp. PA, Epilepsy Neurogenetics Initiative. Available from: https://www.youtube.com/watch?v=_yV9ovVISes [last accessed 5/5/2013]
- ↑ Hedrich UB, Lauxmann S, Wolff M, Synofzik M, Bast T, Binelli A, Serratosa JM, Martínez-Ulloa P, Allen NM, King MD, Gorman KM. 4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy. Science translational medicine. 2021 Sep 1;13(609):eaaz4957.
