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Episodic Ataxias: Clinical and Genetic Features

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ABSTRACT

Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recurrent spells of truncal ataxia and incoordination lasting minutes to hours. Most have an autosomal dominant inheritance pattern. To date, 8 subtypes have been defined according to clinical and genetic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical features. Furthermore, genetically confirmed EAs have mostly been identified in Caucasian families. In this article, we review the current knowledge on the clinical and genetic characteristics of EAs. Additionally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea.

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Mutations of the α1 subunit of the P/Q-type voltage-gated calcium channel in Korean patients with episodic ataxia type 2. The protein contains four homologous domains (I–IV), each with six transmembrane segments (S1–S6). The numbers in the symbol correspond to the mutations listed in Table 3.
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f1-jmd-16028: Mutations of the α1 subunit of the P/Q-type voltage-gated calcium channel in Korean patients with episodic ataxia type 2. The protein contains four homologous domains (I–IV), each with six transmembrane segments (S1–S6). The numbers in the symbol correspond to the mutations listed in Table 3.

Mentions: To date, four Korean EA2 families have been reported in the literature (Table 3, Figure 1) [7-10]. Two splice site mutations, one nonsense mutation and one missense mutation involving CACNA1A were identified, and one of them was previously reported as a pathogenic mutation in a Caucasian EA2 patient [33]. The clinical features of the Korean patients were similar to those of Caucasian EA2 patients, including recurrent episodes of ataxia or vertigo lasting hours, interictal nystagmus and a good response to acetazolamide. However, each family had an intriguing feature. In the first family with a deletion mutation (c.2042_2043delAG), the symptoms were provoked by a change in body temperature, such as heat or high fever [7]. This suggests that calcium channel function may have a strong dependence on body temperature. The second family with a nonsense mutation (c.3832C>T) presented with recurrent ataxia and vertigo that were frequently triggered by exercise, and one member developed pure downbeat nystagmus and severe postural imbalance after exercise [8]. Ictal downbeat nystagmus may be ascribed to changes in the cerebellar pH homeostasis precipitated by hyperventilation during the exercise. The third family with a splice site mutation (c.4392-1G>C) showed a decrease in the age of onset, possibly due to genetic anticipation, in three succeeding generation [9]. Anticipation mostly occurs in neurodegenerative diseases that are characterized by an expansion of unstable trinucleotide repeats, but it has not been reported in EA2. In the last family with another splice site mutation (c.4953+1G>A), one patient showed transient upbeat nystagmus on resuming primary eye position after lateral gazes that had induced GEN and downbeat nystagmus [10]. This phenomenon can be explained by a shifting in the vertical planes as a result of an adaptation to the downbeat nystagmus that developed during lateral gaze.


Episodic Ataxias: Clinical and Genetic Features
Mutations of the α1 subunit of the P/Q-type voltage-gated calcium channel in Korean patients with episodic ataxia type 2. The protein contains four homologous domains (I–IV), each with six transmembrane segments (S1–S6). The numbers in the symbol correspond to the mutations listed in Table 3.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035943&req=5

f1-jmd-16028: Mutations of the α1 subunit of the P/Q-type voltage-gated calcium channel in Korean patients with episodic ataxia type 2. The protein contains four homologous domains (I–IV), each with six transmembrane segments (S1–S6). The numbers in the symbol correspond to the mutations listed in Table 3.
Mentions: To date, four Korean EA2 families have been reported in the literature (Table 3, Figure 1) [7-10]. Two splice site mutations, one nonsense mutation and one missense mutation involving CACNA1A were identified, and one of them was previously reported as a pathogenic mutation in a Caucasian EA2 patient [33]. The clinical features of the Korean patients were similar to those of Caucasian EA2 patients, including recurrent episodes of ataxia or vertigo lasting hours, interictal nystagmus and a good response to acetazolamide. However, each family had an intriguing feature. In the first family with a deletion mutation (c.2042_2043delAG), the symptoms were provoked by a change in body temperature, such as heat or high fever [7]. This suggests that calcium channel function may have a strong dependence on body temperature. The second family with a nonsense mutation (c.3832C>T) presented with recurrent ataxia and vertigo that were frequently triggered by exercise, and one member developed pure downbeat nystagmus and severe postural imbalance after exercise [8]. Ictal downbeat nystagmus may be ascribed to changes in the cerebellar pH homeostasis precipitated by hyperventilation during the exercise. The third family with a splice site mutation (c.4392-1G>C) showed a decrease in the age of onset, possibly due to genetic anticipation, in three succeeding generation [9]. Anticipation mostly occurs in neurodegenerative diseases that are characterized by an expansion of unstable trinucleotide repeats, but it has not been reported in EA2. In the last family with another splice site mutation (c.4953+1G>A), one patient showed transient upbeat nystagmus on resuming primary eye position after lateral gazes that had induced GEN and downbeat nystagmus [10]. This phenomenon can be explained by a shifting in the vertical planes as a result of an adaptation to the downbeat nystagmus that developed during lateral gaze.

View Article: PubMed Central - PubMed

ABSTRACT

Episodic ataxia (EA) is a clinically heterogeneous group of disorders that are characterized by recurrent spells of truncal ataxia and incoordination lasting minutes to hours. Most have an autosomal dominant inheritance pattern. To date, 8 subtypes have been defined according to clinical and genetic characteristics, and five genes are known to be linked to EAs. Both EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA, but many patients with no identified mutations still exhibit EA-like clinical features. Furthermore, genetically confirmed EAs have mostly been identified in Caucasian families. In this article, we review the current knowledge on the clinical and genetic characteristics of EAs. Additionally, we summarize the phenotypic features of the genetically confirmed EA2 families in Korea.

No MeSH data available.


Related in: MedlinePlus