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The electrophysiological footprint of CACNA1A disorders
Elisabetta Indelicato1, Iris Unterberger2, Wolfgang Nachbauer1
1Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
Insights
Interictal EEG abnormalities are common in CACNA1A episodic disorders, particularly in younger patients with earlier disease onset. These findings highlight an age-dependent effect of CACNA1A variants on neurological function.
Area of Science:
- Neuroscience
- Genetics
- Clinical Electrophysiology
Background:
- CACNA1A gene variants are linked to familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6).
- Electroencephalography (EEG) is used to study episodic neurological symptoms, but interictal findings remain under-explored.
Purpose of the Study:
- To investigate the prevalence and characteristics of interictal EEG abnormalities in patients with genetically confirmed CACNA1A disorders.
- To compare EEG findings between CACNA1A patients and phenocopies.
Main Methods:
- Analysis of 85 repeated EEG recordings from 38 genetically confirmed CACNA1A patients (EA2, FHM1, SCA6) between 1994 and 2019.
- Comparison of EEG findings with 15 CACNA1A-negative phenocopies.
- Literature review of related studies.
Main Results:
- 55% of CACNA1A patients exhibited abnormal baseline EEGs, most commonly lateralized intermittent slowing in the temporal region.
- Interictal epileptic discharges (IEDs) were detected in 8 patients.
- EEG abnormalities and IEDs were significantly associated with younger age at examination and earlier disease onset.
- EEG findings in CACNA1A-negative phenocopies were largely unremarkable.
Conclusions:
- Interictal EEG abnormalities are highly prevalent in episodic CACNA1A disorders.
- These abnormalities are strongly associated with younger age and earlier disease onset, suggesting an age-dependent effect of CACNA1A variants.
- Early manifestation of P/Q channel dysfunction due to CACNA1A variants may lead to more severe neurological impairment.
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.
