Two novel KCNA1 variants identified in two unrelated Chinese families affected by episodic ataxia type 1 and neurodevelopmental disorders

Abstract

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Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants

“…However, GoF variants causing neuronal hyperexcitability have been described in several K + channel-encoding genes, 20 and it has been suggested that faster action potential repolarization may lead to sodium channels repriming, 21 thereby increasing firing frequency and synchronization, hallmarks of neuronal hyperexcitability in the epileptic tissue. The marked anticonvulsant efficacy of the sodium-channel blocker carbamazepine observed in our patient and in Patient 1 of Yuan et al, 10 who also carried the same p. A261T KCNA1 variant, but not in those with loss-of-function mutations, appears to support such a hypothesis.…”

Episodic Ataxias: Faux or Real?

“…Epilepsy with or without developmental delay or permanent ataxia has also been frequently reported in the context of both EA1 [30][31][32][33][34][35]) and EA2 [36][37][38]. A severe form of Early Infantile Epileptic Encephalopathy (EIEE) is reported in some members of EA2 families with CACNA1A loss-of-function mutations [39][40][41].…”

Interictal Headache, Pseudodystonia, and Persistent Ataxia in Episodic Ataxia Type 1 Due to a Novel KCNA1 Gene Mutation

“…Episodic ataxia type 1 (EA1) is rare genetic ataxia due to a mutation of the KCNA1 gene. [2][3][4][5] The KCNA1 gene encodes the 495 amino acid (aa) Kv1.1 voltage-gated potassium (Kv) channel subunit. The Kv1.1 plays a pivotal role in regulating neuronal excitability by controlling the action potential, repolarization, and firing properties.…”

“…2 A variety of clinical manifestations like ataxia, seizure, neuromyotonia, myokymia, seizures, encephalopathy, chorea, cognitive deficit, asterixis, muscle weakness, hyperthermia, and hypomagnesemia were reported in KCNA1 gene mutation. [2][3][4][5] Identical twins with KCNA1 mutation can demonstrate a different degree of ataxic symptoms. Such a wide range of symptoms with the KCNA1 gene mutation reflects the ubiquitous presence the voltage-gated potassium channel in the human body and its important role in various physiological functions.…”

“…Previously, EA1 with homozygous pathogenic with KCNA1 variant (pVal368Leu) almost similar to our patient (pVal174Ala) was found to be associated with seizures and neurodevelopmental disorders. 3,4 Two other almost similar KCNA1 variants (p.Val408Met and p.Val408Leu) were reported to be associated with cognitive impairment and epilepsy. 3,5 Contrary to the variants mentioned above, our patient had only one seizure, and had daily migraine headaches.…”