Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

Nardello, Rosaria; Plicato, Giorgia; Mangano, Giuseppe Donato; Gennaro, Elena Di; Mangano, Salvatore; Brighina, Filippo; Raieli, Vincenzo; Fontana, Antonina

doi:10.1186/s12883-020-01704-5

Cited by 15 publications

(15 citation statements)

References 26 publications

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“…7 ). Together these data in EA2 mice are in agreement with EA2 patient studies that show memory deficits and anxiety disorders ( 11 , 13 , 14 , 26 ).…”

Section: Discussionsupporting

confidence: 90%

“…The majority of adult EA2 patients displayed cognitive dysfunctions in attention, memory both working, visual and figural, visuoconstructive abilities and executive functions. Additionally, some EA2 individuals showed psychiatric symptoms including attention deficit hyperactivity disorder (ADHD), anxiety and personality disorders, psychosis, autism, schizophrenia and depression ( 11 , 13–15 ). Case studies from cerebellar lesion and EA2 patients strengthen the hypothesis that the cerebellum may be involved in the processing of our emotions and cognitive functions.…”

Section: Introductionmentioning

confidence: 99%

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Cognitive deficits in episodic ataxia type 2 mouse models

Bohne

Mourabit

Josten

et al. 2021

Human Molecular Genetics

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Episodic ataxia type 2 (EA2) is a rare autosomal dominant disorder characterized by motor incoordination, paroxysmal dystonia, vertigo, nystagmus and more recently cognitive deficits. To date over 100 mutations in the CACNA1A gene have been identified in EA2 patients leading to a loss of P/Q-type channel activity, dysfunction of cerebellar Purkinje cells (PC) and motor incoordination. To determine if the cerebellum is contributing to these cognitive deficits, we examined 2 different EA2 mouse models for cognition impairments where CACNA1A was removed specifically from cerebellar Purkinje or granule cells postnatally. Both mutant mouse models showed anxiolytic behavior to lighted, open areas in the open field and light/dark place preference tests but enhanced anxiousness in the novel suppressed feeding test. However, EA2 mice continued to show augmented latencies in the light/dark preference test and when the arena was divided into 2 dark zones in the dark/dark preference test. Moreover, increased latencies were also displayed in the novel object recognition test, indicating that EA2 mice are indecisive and anxious to explore new territories and objects and may have memory recognition deficits. Exposure to a foreign mouse led to deficiencies in attention and sniffing as well as social and genital sniffing were observed. These data suggest that postnatal removal of the P/Q type calcium channel from the cerebellum regulates neuronal activity involved in anxiety, memory, decision making and social interactions. Our EA2 mice will provide a model to identify the mechanisms and therapeutic agents underlying cognitive and psychiatric disorders seen in EA2 patients.

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“…7 ). Together these data in EA2 mice are in agreement with EA2 patient studies that show memory deficits and anxiety disorders ( 11 , 13 , 14 , 26 ).…”

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Cognitive deficits in episodic ataxia type 2 mouse models

Bohne

Mourabit

Josten

et al. 2021

Human Molecular Genetics

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“…The CACNA1A variant has the same characteristic, and is prone to SE, while attacks in clusters are rare. SE probably shares a similar pathogenesis with HM-related encephalopathy (27). Both patients with focal SE (patients 4 and 6) and patients with HM-related encephalopathy (patients 1 and 2) displayed an asymmetric background EEG rhythm with slow waves in one hemisphere, which were associated with cerebral edema in the hemisphere due to repeated CSD activity.…”

Section: Discussionmentioning

confidence: 88%

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

et al. 2020

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Background: The CACNA1A gene encodes the voltage-dependent P/Q-type calcium channel subunit alpha-1A, which is widely expressed throughout the CNS. The biological roles of the P/Q channel are diverse and the phenotypic spectrum caused by CACNA1A mutations is wide. The aim of this study is to demonstrate its phenotypic diversity and analyze the genotype-phenotype correlations in a cohort of Chinese patients.Methods: Patients with hemiplegic migraine, cerebellar ataxia, developmental delay, or epilepsy without known causes were tested by trios whole-exome sequencing. Patients with pathogenic CACNA1A gene variants were recruited. The clinical information of the patients was collected, and the association between the genotype and the phenotype was investigated.Results: In total, eight patients (six females and two males) were found to have CACNA1A gene variants. All the variants were de novo including six missense variants and one frameshift variant. Four de novo missense variants were found in five patients located in the S4, S5, or S6 transmembrane segments of Domain II and III (p.R1352Q, p.G701V, p.A713T, p.V1393M). All of them were correlated with severe phenotypes, including three with sporadic hemiplegic migraine type 1 and epilepsy, and two with developmental and epileptic encephalopathy. The other two missense variants, p.Y62C and p.F1814L, located in the cytoplasmic side of the N-terminus and C-terminus, respectively. The variant p.Y62C was associated with severe hemiconvulsion-hemiplegia-epilepsy syndrome, and p.F1814L was associated with relatively mild phenotypes. All the missense variants were speculated as gain-of-function (GOF) mutations. The only frameshift variant, p.Q681Rfs*100, a lose-of-function (LOF) mutation, was found in a patient with episodic ataxia type 2. Meanwhile, all the patients had developmental delay ranging from mild to severe, as well as cerebellar ataxia including one with congenital ataxia, one with episodic ataxia, and six with non-progressive ataxia.Conclusions:CACNA1A variants could lead to a wide spectrum of neurological disorders including epileptic or non-epileptic paroxysmal events, cerebellar ataxia, and developmental delay. The variants could be both GOF and LOF mutations. There appeared to be some correlations between genotypes and phenotypes.

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“…Notably, IEDs were also detected in several other EA2 families with no history of seizures [41,42,52,53]. Generalized 3 Hz spike-wave discharges were a recurrent EEG pattern [37,39,41,54,55].…”

Section: Review Of the Literaturementioning

confidence: 86%

The electrophysiological footprint of CACNA1A disorders

et al. 2021

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Objectives CACNA1A variants underlie three neurological disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). EEG is applied to study their episodic manifestations, but findings in the intervals did not gain attention up to date. Methods We analyzed repeated EEG recordings performed between 1994 and 2019 in a large cohort of genetically confirmed CACNA1A patients. EEG findings were compared with those of CACNA1A-negative phenocopies. A review of the related literature was performed. Results 85 EEG recordings from 38 patients (19 EA2, 14 FHM1, 5 SCA6) were analyzed. Baseline EEG was abnormal in 55% of cases (12 EA2, 9 FHM1). The most common finding was a lateralized intermittent slowing, mainly affecting the temporal region. Slowing was more pronounced after a recent attack but was consistently detected in the majority of patients also during the follow-up. Interictal epileptic discharges (IEDs) were detected in eight patients (7 EA2,1 FHM1). EEG abnormalities and especially IEDs were significantly associated with younger age at examination (16 ± 9 vs 43 ± 21 years in those without epileptic changes, p = 0.003) and with earlier onset of disease (1 (1–2) vs 12 (5–45) years, p = 0.0009). EEG findings in CACNA1A-negative phenocopies (n = 15) were largely unremarkable (p = 0.03 in the comparison with CACNA1A patients). Conclusions EEG abnormalities between attacks are highly prevalent in episodic CACNA1A disorders and especially associated with younger age at examination and earlier disease onset. Our findings underpin an age-dependent effect of CACNA1A variants, with a more severe impairment when P/Q channel dysfunction manifests early in life.

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Two distinct phenotypes, hemiplegic migraine and episodic Ataxia type 2, caused by a novel common CACNA1A variant

Cited by 15 publications

References 26 publications

Cognitive deficits in episodic ataxia type 2 mouse models

Cognitive deficits in episodic ataxia type 2 mouse models

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

The electrophysiological footprint of CACNA1A disorders

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