RARE DISEASE
Familial paroxysmal ataxia
Familial paroxysmal ataxia
Familial paroxysmal ataxia
Synonyms: Episodic ataxia type 2
Synonyms: Episodic ataxia type 2
Synonyms: Episodic ataxia type 2
Drug discovery
125
papers
On emerging therapies
Overview
Familial paroxysmal ataxia is a rare autosomal dominant disorder characterized by recurrent episodes of gait instability, dysarthria, and limb incoordination lasting minutes to hours, often triggered by stress, exertion, or caffeine [1][9][12]. Interictal nystagmus and mild progressive cerebellar dysfunction may occur [9][12]. Attacks typically begin in childhood and respond to acetazolamide or 4-aminopyridine [8][12].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
125 drug discovery papers about Familial paroxysmal ataxia. Recent publications:
125 drug discovery papers about Familial paroxysmal ataxia. Recent publications:
categories:
Small molecules
small molecules
2026-06-30 | Clinical and Radiological Variability in Episodic Ataxia Type 2: A Case Report and Review of the Literature.
Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy caused by CACNA1A mutations, typically presenting with recurrent episodes of ataxia, vertigo, and hemiplegic migraine, often with a normal brain MRI or cerebellar atrophy. This report describes a 47-year-old man with a 22-year history of recurrent severe headaches, limb weakness, truncal ataxia, sensory disturbances, and profound fatigue, triggered by stress or minor trauma. Interictal recovery was complete, but serial MRI revealed extensive T2/FLAIR white matter hyperintensities, initially raising concern for multiple sclerosis or cerebral vasculitis. Lumbar puncture was unremarkable. Genetic testing identified a pathogenic heterozygous CACNA1A variant (c.7411 C > T, p.R2471*), confirming EA2. Symptomatic management with acetazolamide and trigger avoidance improved episode frequency and severity. This case highlights the diagnostic challenges of EA2 when MRI shows atypical white matter lesions and emphasizes the value of genetic testing in atypical presentations. Recognizing these findings can prevent misdiagnosis, guide targeted therapy, and inform family counseling. Pearls: · The variability of CACNA1A- related disorders is broad and continues to expand. The gene-phenotype spectrum includes episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FMH1), sporadic hemiplegic migraine (SHM), spinocerebellar ataxia type 6, epilepsy and developmental epileptic encephalopathy. · Patients with episodic ataxia type 2 have either a normal MRI or cerebellar atrophy, mainly at the vermis. · Episodic ataxia type 2, may be treated with acetazolamide and 4-aminopyridine. Oysters: · EA2 may present in the absence of family history. · It is very common for patients with EA2, to be erroneously diagnosed with another disorder, and the disease is very infrequent. · CACNA1A associated diseases may present with clinical overlap.
2026-05-04 | Episodic Ataxia Type 2 Presenting with Fluctuating Weakness in a Child with a De Novo CACNA1A Variant.
Episodic ataxia type 2 (EA2) is the most common subtype of episodic ataxia and is primarily caused by pathogenic variants in the CACNA1A gene. Although classically characterized by paroxysmal ataxia, CACNA1A-related disorders are increasingly recognized as an age-dependent phenotypic continuum that extends beyond episodic cerebellar dysfunction to include fluctuating weakness, persistent neurological signs, and neurodevelopmental impairments. A 12-year-old boy presented with episodic vertigo. His medical history was notable for infantile paroxysmal tonic upward gaze beginning at 6 months of age. From the age of 7 years, he developed frequent episodes of vertigo and ataxia lasting 2 to 3 h. At 10 years of age, he experienced an episode of acute lower limb weakness with diminished deep tendon reflexes, without prominent ataxia. Guillain-Barré syndrome was initially suspected, and he received two courses of intravenous immunoglobulin, with only transient improvement. Neurophysiological studies were largely unremarkable, except for an isolated decremental response on repetitive nerve stimulation. In addition to paroxysmal events, he exhibited persistent interictal cerebellar signs, including dysmetria, dysdiadochokinesia, and downbeat nystagmus. Neuropsychological testing revealed mild intellectual disability with prominent visuospatial deficits. Trio-based whole-exome sequencing identified a de novo CACNA1A splice donor variant (c.978 + 1G > A), confirming the diagnosis of EA2. Treatment with acetazolamide resulted in marked improvement in episodic ataxic events. This case highlights EA2 as part of a broader CACNA1A-related phenotypic continuum rather than a purely paroxysmal disorder. Awareness of atypical and age-dependent manifestations is crucial to avoid diagnostic pitfalls and to facilitate the timely initiation of targeted therapy and appropriate developmental support.
2026-03-18 | Adrenergic receptor activation triggers stress-induced dystonia in a CACNA1A mutant mouse model.
Episodic ataxia type 2 (EA2) is caused by loss-of-function mutations in CACNA1A, resulting in P/Q-type Ca2+ channel dysfunction in cerebellar Purkinje cells (PCs) causing ataxia and stress-induced dystonia. Using Cacna1apurk(-/-) (purky) mice, which display selective P/Q-type channels deletion in PCs, the effects of adrenergic receptor (AR) blockade on stress-induced dystonia were examined. Systemic administration of the α1-AR antagonist prazosin increased dystonia frequency, but shortened attack duration, while the α1D-AR selective antagonist BMY-7378 significantly reduced dystonia occurrence without altering onset or duration. Strikingly, universal blockade of α2-ARs using yohimbine, as well as agonist of α2A-AR autoreceptors completely abolished stress-induced dystonia. Electrophysiological recordings of cerebellar PCs demonstrated that norepinephrine (NE) strongly inhibited the PC simple spike firing, which was partially rescued by yohimbine, implicating α2-AR-dependent modulation of PC activity. Histological analysis of purky mice revealed increased dopamine-β-hydroxylase (DβH) immunoreactivity on PC somata, which was accompanied by increased numbers of noradrenergic neurons in locus coeruleus (LC), indicating enhanced cerebellar noradrenergic innervation. These findings strengthen the idea that stress-induced dystonia formation is facilitated by increased noradrenergic innervation to cerebellar PCs and suggest that α2-AR signalling contributes to dystonia in EA2. Our findings emphasise cerebellar ARs as promising therapeutic targets in EA2.
2025-10-31 | Dissociable effects of medication on visual-vestibular brain excitability by visual motion stimuli in episodic ataxia type 2.
The clinical hallmark of episodic ataxia type 2 (EA2) consists of episodes of recurrent severe vestibulo-cerebellar dysfunction, characterized by marked postural unsteadiness and oscillopsia. Triggering factors of EA2 attacks, such as physical exertion and sensory stimulation, the high comorbidity with migraine, and the increased risk of epilepsy in EA2 suggest abnormal brain excitability. To investigate this, we assessed brain excitability in response to visual (checkerboard) and visual motion (optic flow) stimuli using interictal functional magnetic resonance imaging. Visual stimulation elicited strong bilateral neural activity in the primary visual cortex (V1-V3) and in motion-sensitive visual areas (V5) in 21 EA2 patients and 21 age-matched healthy participants (HP). Compared to HP, EA2 patients revealed decreased activity in the primary visual cortex (V1), cerebellar Crus I and II and caudal vermis but increased activation of multisensory vestibular processing areas (posterior insula, superior temporal and supramarginal gyrus, inferior parietal lobe). Interestingly, the abnormal excitability in the vestibular processing cortex areas was primarily found in patients without medication (4-aminopyridine, acetazolamide) but hardly seen in patients on medication. Our findings in treatment-naïve patients reflect disease-inherent changes in visual cortical excitability in EA2, which may be reversible through anti-episodic medication. As excitability by visual motion stimuli in multi-sensory vestibular processing cortical areas was largely found in patients on medication it may also indicate an inhibitory effect on the physiological reciprocal inhibitory visual-vestibular interaction as a multisensory mechanism for self-motion perception: the annoying oscillopsia of EA2 patients is counterbalanced by decreased visual cortex activity and hence smaller inhibition of the vestibular cortex.
2025-10-06 | Cerebellar α1D- adrenergic receptors mediate stress-induced dystonia in totteringtg/tg mice.
Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs in cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE), differentially expressed and required for initiation of dystonia, while α2-ARs are not. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of Ca2+ from intracellular stores, thus preventing stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tg mice.
small molecules
2026-06-30 | Clinical and Radiological Variability in Episodic Ataxia Type 2: A Case Report and Review of the Literature.
Episodic ataxia type 2 (EA2) is an autosomal dominant channelopathy caused by CACNA1A mutations, typically presenting with recurrent episodes of ataxia, vertigo, and hemiplegic migraine, often with a normal brain MRI or cerebellar atrophy. This report describes a 47-year-old man with a 22-year history of recurrent severe headaches, limb weakness, truncal ataxia, sensory disturbances, and profound fatigue, triggered by stress or minor trauma. Interictal recovery was complete, but serial MRI revealed extensive T2/FLAIR white matter hyperintensities, initially raising concern for multiple sclerosis or cerebral vasculitis. Lumbar puncture was unremarkable. Genetic testing identified a pathogenic heterozygous CACNA1A variant (c.7411 C > T, p.R2471*), confirming EA2. Symptomatic management with acetazolamide and trigger avoidance improved episode frequency and severity. This case highlights the diagnostic challenges of EA2 when MRI shows atypical white matter lesions and emphasizes the value of genetic testing in atypical presentations. Recognizing these findings can prevent misdiagnosis, guide targeted therapy, and inform family counseling. Pearls: · The variability of CACNA1A- related disorders is broad and continues to expand. The gene-phenotype spectrum includes episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FMH1), sporadic hemiplegic migraine (SHM), spinocerebellar ataxia type 6, epilepsy and developmental epileptic encephalopathy. · Patients with episodic ataxia type 2 have either a normal MRI or cerebellar atrophy, mainly at the vermis. · Episodic ataxia type 2, may be treated with acetazolamide and 4-aminopyridine. Oysters: · EA2 may present in the absence of family history. · It is very common for patients with EA2, to be erroneously diagnosed with another disorder, and the disease is very infrequent. · CACNA1A associated diseases may present with clinical overlap.
2026-05-04 | Episodic Ataxia Type 2 Presenting with Fluctuating Weakness in a Child with a De Novo CACNA1A Variant.
Episodic ataxia type 2 (EA2) is the most common subtype of episodic ataxia and is primarily caused by pathogenic variants in the CACNA1A gene. Although classically characterized by paroxysmal ataxia, CACNA1A-related disorders are increasingly recognized as an age-dependent phenotypic continuum that extends beyond episodic cerebellar dysfunction to include fluctuating weakness, persistent neurological signs, and neurodevelopmental impairments. A 12-year-old boy presented with episodic vertigo. His medical history was notable for infantile paroxysmal tonic upward gaze beginning at 6 months of age. From the age of 7 years, he developed frequent episodes of vertigo and ataxia lasting 2 to 3 h. At 10 years of age, he experienced an episode of acute lower limb weakness with diminished deep tendon reflexes, without prominent ataxia. Guillain-Barré syndrome was initially suspected, and he received two courses of intravenous immunoglobulin, with only transient improvement. Neurophysiological studies were largely unremarkable, except for an isolated decremental response on repetitive nerve stimulation. In addition to paroxysmal events, he exhibited persistent interictal cerebellar signs, including dysmetria, dysdiadochokinesia, and downbeat nystagmus. Neuropsychological testing revealed mild intellectual disability with prominent visuospatial deficits. Trio-based whole-exome sequencing identified a de novo CACNA1A splice donor variant (c.978 + 1G > A), confirming the diagnosis of EA2. Treatment with acetazolamide resulted in marked improvement in episodic ataxic events. This case highlights EA2 as part of a broader CACNA1A-related phenotypic continuum rather than a purely paroxysmal disorder. Awareness of atypical and age-dependent manifestations is crucial to avoid diagnostic pitfalls and to facilitate the timely initiation of targeted therapy and appropriate developmental support.
2026-03-18 | Adrenergic receptor activation triggers stress-induced dystonia in a CACNA1A mutant mouse model.
Episodic ataxia type 2 (EA2) is caused by loss-of-function mutations in CACNA1A, resulting in P/Q-type Ca2+ channel dysfunction in cerebellar Purkinje cells (PCs) causing ataxia and stress-induced dystonia. Using Cacna1apurk(-/-) (purky) mice, which display selective P/Q-type channels deletion in PCs, the effects of adrenergic receptor (AR) blockade on stress-induced dystonia were examined. Systemic administration of the α1-AR antagonist prazosin increased dystonia frequency, but shortened attack duration, while the α1D-AR selective antagonist BMY-7378 significantly reduced dystonia occurrence without altering onset or duration. Strikingly, universal blockade of α2-ARs using yohimbine, as well as agonist of α2A-AR autoreceptors completely abolished stress-induced dystonia. Electrophysiological recordings of cerebellar PCs demonstrated that norepinephrine (NE) strongly inhibited the PC simple spike firing, which was partially rescued by yohimbine, implicating α2-AR-dependent modulation of PC activity. Histological analysis of purky mice revealed increased dopamine-β-hydroxylase (DβH) immunoreactivity on PC somata, which was accompanied by increased numbers of noradrenergic neurons in locus coeruleus (LC), indicating enhanced cerebellar noradrenergic innervation. These findings strengthen the idea that stress-induced dystonia formation is facilitated by increased noradrenergic innervation to cerebellar PCs and suggest that α2-AR signalling contributes to dystonia in EA2. Our findings emphasise cerebellar ARs as promising therapeutic targets in EA2.
2025-10-31 | Dissociable effects of medication on visual-vestibular brain excitability by visual motion stimuli in episodic ataxia type 2.
The clinical hallmark of episodic ataxia type 2 (EA2) consists of episodes of recurrent severe vestibulo-cerebellar dysfunction, characterized by marked postural unsteadiness and oscillopsia. Triggering factors of EA2 attacks, such as physical exertion and sensory stimulation, the high comorbidity with migraine, and the increased risk of epilepsy in EA2 suggest abnormal brain excitability. To investigate this, we assessed brain excitability in response to visual (checkerboard) and visual motion (optic flow) stimuli using interictal functional magnetic resonance imaging. Visual stimulation elicited strong bilateral neural activity in the primary visual cortex (V1-V3) and in motion-sensitive visual areas (V5) in 21 EA2 patients and 21 age-matched healthy participants (HP). Compared to HP, EA2 patients revealed decreased activity in the primary visual cortex (V1), cerebellar Crus I and II and caudal vermis but increased activation of multisensory vestibular processing areas (posterior insula, superior temporal and supramarginal gyrus, inferior parietal lobe). Interestingly, the abnormal excitability in the vestibular processing cortex areas was primarily found in patients without medication (4-aminopyridine, acetazolamide) but hardly seen in patients on medication. Our findings in treatment-naïve patients reflect disease-inherent changes in visual cortical excitability in EA2, which may be reversible through anti-episodic medication. As excitability by visual motion stimuli in multi-sensory vestibular processing cortical areas was largely found in patients on medication it may also indicate an inhibitory effect on the physiological reciprocal inhibitory visual-vestibular interaction as a multisensory mechanism for self-motion perception: the annoying oscillopsia of EA2 patients is counterbalanced by decreased visual cortex activity and hence smaller inhibition of the vestibular cortex.
2025-10-06 | Cerebellar α1D- adrenergic receptors mediate stress-induced dystonia in totteringtg/tg mice.
Episodic ataxia type 2 (EA2) is an inherited neurological disorder, where patients suffer from chronic ataxia and severe episodes of motor dysfunction exhibited as dystonia. Despite other factors, physical and emotional stress triggers those episodes reliably in both human and mice. We used the well-established EA2 mouse model tottering to explore the cerebellar adrenergic receptor (AR) involvement in stress-induced dystonic attacks. We found that α1-ARs in cerebellar Purkinje cells (PCs) are activated by norepinephrine (NE), differentially expressed and required for initiation of dystonia, while α2-ARs are not. Moreover, pharmacological blockade and shRNA-induced knock down of cerebellar α1D-ARs was sufficient to effectively prevent stress-induced dystonia in homozygous totteringtg/tg mice but had no impact on ataxia amelioration. In vivo recordings and live calcium (Ca2+) imaging of PCs demonstrated that α1D-AR blockade successfully protects PCs from NE-mediated erratic firing patterns through decreased release of Ca2+ from intracellular stores, thus preventing stress-induced dystonia. Together, our data show the modulatory effects of NE on dystonia severity and suggest a predominant role of cerebellar α1D-ARs in the formation of stress-induced dystonia in totteringtg/tg mice.
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