A Novel <i>KCNA1</i> Mutation in an Episodic Ataxia Type 1 Patient with Asterixis and Falls

Lee, Geum Bong; Kim, Ga Yeon; Jeong, In Du; Kim, Namhee; Kim, Jae Woo

doi:10.3988/jcn.2021.17.2.333

Cited by 6 publications

(6 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The T268K mutation was identified in a patient with multiple musculoskeletal abnormalities including tip-toe ambulation, kyphoscoliosis, lumbar hyperlordosis, and flat feet [34]. Finally, as discussed above, the P264LfsTer10 mutation was associated with asterixis in which the wrist or arm would suddenly drop [33].…”

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 88%

“…A de novo heterozygous frameshift mutation P264LfsTer10 was identified in a female patient with EA1, episodes of generalized myoclonic seizure, mild cognitive impairment related to epileptic encephalopathy, asterixis (i.e., a sudden drop of the wrist or arm), falls, and cerebellar atrophy [33]. This is the first frameshift mutation discovered for KCNA1.…”

Section: A Frameshift Variant Affecting Both Voltage-sensing and Pore...mentioning

confidence: 89%

“…Although both mutations cause epilepsy, the two alleles behave differently. In the patient, the mutation caused epilepsy by an autosomal-dominant mechanism, whereas in mceph mice, the mutation shows recessive inheritance requiring homozygosity for epilepsy manifestation [33,92].…”

Section: A Frameshift Variant Affecting Both Voltage-sensing and Pore...mentioning

confidence: 99%

See 2 more Smart Citations

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Paulhus

Glasscock

2023

IJMS

View full text Add to dashboard Cite

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype–phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype–phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

show abstract

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 88%

Section: A Frameshift Variant Affecting Both Voltage-sensing and Pore...mentioning

confidence: 89%

See 1 more Smart Citation

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Paulhus

Glasscock

2023

IJMS

View full text Add to dashboard Cite

show abstract

“…Although both mutations cause epilepsy, the two alleles behave differently. In the patient, the mutation caused epilepsy by an autosomaldominant mechanism, whereas in mceph mice, the mutation shows recessive inheritance requiring homozygosity for epilepsy manifestation [33,91].…”

Section: A Frameshift Variant Affecting Both Voltage-sensing and Pore...mentioning

confidence: 99%

Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Paulhus¹,

Glasscock²

2023

Preprint

View full text Add to dashboard Cite

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

show abstract

“…[ 1 ] Lee et al . [ 4 ] (2021) reported another phenotype with KCNA1 gene mutation wherein a patient aged 51 years had progressive cerebellar syndrome with generalized myoclonus. Brain MRI showed cerebellar atrophy.…”

mentioning

confidence: 99%

Cervical Dystonia with Cerebellar Ataxia in KCNA1 Mutation

Mahale¹,

Jayanth²,

Dutta³

et al. 2022

Annals of Indian Academy of Neurology

View full text Add to dashboard Cite

A Novel KCNA1 Mutation in an Episodic Ataxia Type 1 Patient with Asterixis and Falls

Cited by 6 publications

References 6 publications

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Cervical Dystonia with Cerebellar Ataxia in KCNA1 Mutation

Contact Info

Product

Resources

About