A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation

Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo, and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilized next‐generation sequencing (NGS) to screen the coding sequence, exon‐intron boundaries, and Untranslated Regions (UTRs) of five genes where mutation is known to produce symptoms related to EA2, including CACNA1A. We performed this screening in a group of 31 unrelated patients with EA2 symptoms. Both novel and known mutations were detected through NGS technology, and confirmed through Sanger sequencing. Genetic testing showed in total 15 mutation bearing patients (48%), of which nine were novel mutations (6 missense and 3 small frameshift deletion mutations) and six known mutations (4 missense and 2 nonsense).These results demonstrate the efficiency of our NGS‐panel for detecting known and novel mutations for EA2 in the CACNA1A gene, also identifying a novel missense mutation in ATP1A2 which is not a normal target for EA2 screening.

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“…2003; Romaniello et al. 2010), such as dysarthria, diplopia, hemiplegia, and headache (Jen et al. 2004).…”

Section: Discussionmentioning

confidence: 99%

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Maksemous

Roy

Smith

et al. 2016

Molec Gen & Gen Med

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“…Clinical syndromes include EA2 (nonsense Ͼmissense mutations), familial hemiplegic migraine 1 (FHM1) (missense type), spinocerebellar ataxia type 6 (polymorphic CAG repeat expansions), and epilepsy. [5][6][7] Sequencing of the CACNA1A gene in our patient revealed a novel nonsense mutation, R1346X, located in the fourth transmembrane segment of the homologous domain III of the channel pore-forming unit. A missense mutation at the same position, R1346Q, has been described in a family with FHM1 and features of EA2.…”

Section: Go To Section 3 Sectionmentioning

confidence: 99%

“…In one case report, 2 different types of episodes were diagnosed as BTM and EA2 in a single patient with a CACNA1A truncating mutation, with acetazolamide reducing the frequency of both episodes. 8 Epilepsy and nonepileptiform EEG abnormalities 6 in families with CACNA1A mutations have also been studied. Absence, complex partial, and generalized tonicclonic seizures have been described in the setting of severe hemiplegic migraine attacks, 5 or independent of attacks in patients with FHM1 or EA2.…”

Section: Go To Section 3 Sectionmentioning

confidence: 99%

“…1 Migraines with muscle weakness have been reported in association with cerebellar dysfunction, meeting criteria for both EA2 and FHM1. 6,7 Basilar-type migraine (BTM) has the greatest overlap in symptomatology with EA2. Its underlying genetic causes are under investigation.…”

Section: Go To Section 3 Sectionmentioning

confidence: 99%

“…Conversely, identical CACNA1A mutations may produce phenotypes that meet criteria for 2 or 3 disease categories, either in individual patients or in different family members. 3,[5][6][7] Furthermore, a single stereotyped episode can have features of multiple disorders. The figure summarizes the overlapping and unique symptoms in paroxysmal disorders that have been associated with CACNA1A mutations, including EA2, migraine with aura, and epilepsy.…”

Section: Go To Section 3 Sectionmentioning

confidence: 99%

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Clinical Reasoning: A middle-aged man with episodes of gait imbalance and a newly found genetic mutation

Yugrakh

Levy

2012

Neurology

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A 47-year-old right-handed man, with no history of alcohol use, presented with episodic unsteadiness that began in his early 20s. During the episodes, which last several hours, he is unable to walk steadily and has poor control of his limbs. These attacks are often brought on by emotional stress and occurred 1 to 2 times per month into his 30s. There is no association with headache or head movement, no diplopia, tinnitus, or hearing loss. His earlier evaluation included a brain MRI and routine EEG, which were normal. Though his diagnosis was unknown, he was given a trial of acetazolamide at age 38, and became attack-free on the medication. Questions for consideration:

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Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

Eikermann-Haerter

Arbel‐Ornath

Yalcin

et al. 2015

Annals of Neurology

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Objective Migraine is one of the most common and debilitating neurological conditions. Familial hemiplegic migraine type 1 (FHM1), a monogenic migraine subtype, is caused by gain-of-function of voltage-gated CaV2.1 calcium channels. FHM1 mice carry human pathogenic mutations in the α1A subunit of CaV2.1 channels and are highly susceptible to cortical spreading depression (CSD), the electrophysiologic event underlying migraine aura. To date, however, the mechanism underlying increased CSD/migraine susceptibility remains unclear. Methods We employed in vivo multiphoton microscopy of the genetically encoded Ca2+-indicator yellow cameleon to investigate synaptic morphology and [Ca2+]i in FHM1 mice. In order to study CSD-induced cerebral oligemia, we used in vivo laser speckle flowmetry and multimodal imaging. With electrophysiologic recordings we investigated the effect of the CaV2.1 gating modifier tert-butyl dihydroquinone on CSD in vivo. Results FHM1 mutations elevate neuronal [Ca2+]i and alter synaptic morphology as a mechanism for enhanced CSD susceptibility that we were able to normalize with a CaV2.1 gating modifier, in hyperexcitable FHM1 mice. At the synaptic level, axonal boutons were larger, and dendritic spines were predominantly mushroom type, which both provide a structural correlate for enhanced neuronal excitability. Resting neuronal [Ca2+]i was elevated in FHM1, with loss of compartmentalization between synapses and neuronal shafts. The percentage of calcium-overloaded neurons was increased. Neuronal [Ca2+]i surge during CSD was faster and larger, and post-CSD oligemia and hemoglobin desaturation were more severe in FHM1 brains. Interpretation Our findings provide a mechanism for enhanced CSD susceptibility in hemiplegic migraine. Abnormal synaptic Ca2+ homeostasis and morphology may contribute to chronic neurodegenerative changes as well as enhanced vulnerability to ischemia in migraineurs.

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A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation

Cited by 52 publications

References 22 publications

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Clinical Reasoning: A middle-aged man with episodes of gait imbalance and a newly found genetic mutation

Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

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A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation

Cited by 52 publications

References 22 publications

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2

Clinical Reasoning: A middle-aged man with episodes of gait imbalance and a newly found genetic mutation

Abnormal synaptic Ca2+ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice

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Abnormal synaptic Ca²⁺ homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice