From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

Indelicato, Elisabetta; Boesch, Sylvia

doi:10.3389/fneur.2021.639994

Cited by 61 publications

(61 citation statements)

References 118 publications

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“…Previous studies suggested that gain-of-function FHM1 mutations were associated with increased susceptibility to CSD. However, a recent study reported a de novo CACNA1A mutation causing hemiplegic migraine and developmental delay but without epilepsy, revealing a loss-of-function of Ca v 2.1 channel [ 38 ]. This confirmed that different functional consequences may occur in patients with intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Tang

et al. 2021

J Headache Pain

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Background Mutations in ATP1A2, the gene encoding the α2 subunit of Na+/K+-ATPase, are the main cause of familial hemiplegic migraine type 2 (FHM2). The clinical presentation of FHM2 with mutations in the same gene varies from pure FHM to severe forms with epilepsy and intellectual disability, but the correlation of these symptoms with different ATP1A2 mutations is still unclear. Methods Ten ATP1A2 missense mutations were selected according to different phenotypes of FHM patients. They caused pure FHM (FHM: R65W, R202Q, R593W, G762S), FHM with epilepsy (FHME: R548C, E825K, R938P), or FHM with epilepsy and intellectual disability (FHMEI: T378N, G615R, D718N). After ouabain resistance and fluorescence modification, plasmids carrying those mutations were transiently transfected into HEK293T and HeLa cells. The biochemical functions were studied including cell survival assays, membrane protein extraction, western blotting, and Na+/K+-ATPase activity tests. The electrophysiological functions of G762S, R938P, and G615R mutations were investigated in HEK293T cells using whole-cell patch-clamp. Homology modeling was performed to determine the locational distribution of ATP1A2 mutations. Results Compared with wild-type pumps, all mutations showed a similar level of protein expression and decreased cell viability in the presence of 1 µM ouabain, and there was no significant difference among the mutant groups. The changes in Na+/K+-ATPase activity were correlated with the severity of FHM phenotypes. In the presence of 100 µM ouabain, the Na+/K+-ATPase activity was FHM > FHME > FHMEI. The ouabain-sensitive Na+/K+-ATPase activity of each mutant was significantly lower than that of the wild-type protein, and there was no significant difference among all mutant groups. Whole-cell voltage-clamp recordings in HEK293T cells showed that the ouabain-sensitive pump currents of G615R were significantly reduced, while those of G762S and R938P were comparable to those of the wild-type strain. Conclusions ATP1A2 mutations cause phenotypes ranging from pure FHM to FHM with epilepsy and intellectual disability due to varying degrees of deficits in biochemical and electrophysiological properties of Na+/K+-ATPase. Mutations associated with intellectual disability presented with severe impairment of Na+/K+-ATPase. Whether epilepsy is accompanied, or the type of epilepsy did not seem to affect the degree of impairment of pump function.

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Section: Discussionmentioning

confidence: 99%

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Tang

et al. 2021

J Headache Pain

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“…This patient's clinical picture is most consistent with paroxysmal kinesigenic dyskinesia, as she has attacks of dystonia that are triggered by voluntary movement, last from a few seconds to a minute, and are relieved with rest [ 8 ]. Her paroxysmal dystonia is likely due to her mutation in CACNA1A , as it is sometimes seen during episodes of ataxia in EA2 [ 9 ], there are other case reports of CACNA1A mutations being associated with dystonia, and CACNA1A knockout mice (Ca V 2.1 −/− ) exhibit dystonia and cerebellar atrophy [ 3 ]. Dystonia, usually cervical, can occur in EA2 during paroxysmal episodes of ataxia and can become chronic if secondarily progressive ataxia develops.…”

Section: Discussionmentioning

confidence: 99%

“…Dystonia, usually cervical, can occur in EA2 during paroxysmal episodes of ataxia and can become chronic if secondarily progressive ataxia develops. There have also been case reports of patients with EA2 who went on to develop interictal dystonia later in their disease course [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

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Novel Mutation in CACNA1A Associated with Activity-Induced Dystonia, Cervical Dystonia, and Mild Ataxia

Stampfl

Fee

2021

Case Reports in Neurological Medicine

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CACNA1A encodes the pore-forming α1 subunit of the neuronal voltage-gated Cav2.1 (P/Q-type) channels, which are predominantly localized at the presynaptic terminals of the brain and cerebellar neurons and play an important role in controlling neurotransmitter release. Mutations in CACNA1A have been associated with several autosomal dominant neurologic disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6. A 37-year-old woman presented with a history of slowly progressive, activity-induced stiffness, and pain in her right leg since age 15 and cervical dystonia since age 20. She denied any right leg stiffness or pain at rest, but when she began to walk, her right foot turned in and her right leg stiffened up. She also had neck pain, stiffness, and spams. There was no family history of similar symptoms. On physical exam, her strength, tone, and reflexes were normal in all extremities at rest. There was mild head titubation and very mild past pointing on finger-to-nose testing. MRI of the brain and spinal cord was unremarkable. This patient’s clinical picture was felt to be most consistent with paroxysmal kinesigenic dyskinesia, as she has attacks of dystonia that are triggered by voluntary movement, last from a few seconds to a minute, and are relieved with rest. She was trialed on carbidopa/levodopa without improvement. A dystonia panel showed two potentially pathologic mutations, one in CACNA1A and the other in PNKP, along with a variant of unknown significance in ATP7B. The mutation in CACNA1A is C2324 G < A. It is heterozygous, autosomal dominant, and computer modeling suggests pathogenicity. This mutation has not been reported previously and is likely the cause of her paroxysmal dystonia; dystonia is sometimes seen during episodes of ataxia in EA2, and CACNA1A knockout mice exhibit dystonia and cerebellar atrophy. After receiving her genetic diagnosis, the patient was trialed on acetazolamide without improvement in her dystonia symptoms. This is the second case report of a patient with cervical dystonia and cerebellar ataxia associated with a mutation in CACNA1A.

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“…CACNA1A disease spectrum encompasses a number of autosomal-dominant allelic disorders, which feature a various combination of episodic and chronic neurological signs [1]. Episodic manifestations include migraine with hemiplegic aura, attacks of paroxysmal ataxia, paroxysmal dystonia and epilepsy [1]. Chronic neurological symptoms consist of various degree of cerebellar ataxia, developmental delay, cognitive and psychiatric symptoms [1].…”

Section: Introductionmentioning

confidence: 99%

Instrumented gait analysis defines the walking signature of CACNA1A disorders

et al. 2021

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Background Gait disturbances are a frequent symptom in CACNA1A disorders. Even though, data about their severity and progression are lacking and no CACNA1A-specific scale or assessment for gait is available. Methods We applied a gait assessment protocol in 20 ambulatory patients with genetically confirmed CACNA1A disorders and 39 matched healthy controls. An instrumented gait analysis (IGA) was performed by means of wearable sensors in basal condition and after a treadmill/cycloergometer challenge in selected cases. Results CACNA1A patients displayed lower gait speed, shorter steps with increased step length variability, a reduced landing acceleration as well as a reduced range of ankle motion compared to controls. Furthermore, gait-width in patients with episodic CACNA1A disorders was narrower as compared to controls. In one patient experiencing mild episodic symptoms after the treadmill challenge, the IGA was able to detect a deterioration over all gait parameters. Conclusions In CACNA1A patients, the IGA with wearable sensors unravels specific gait signatures which are not detectable at naked eye. These features (narrow-based gait, lower landing acceleration) distinguish these patients from other ataxic disorders and may be target of focused rehabilitative interventions. IGA can potentially be applied to monitor the neurological fluctuations associated with CACNA1A disorders.

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From Genotype to Phenotype: Expanding the Clinical Spectrum of CACNA1A Variants in the Era of Next Generation Sequencing

Cited by 61 publications

References 118 publications

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Functional correlation of ATP1A2 mutations with phenotypic spectrum: from pure hemiplegic migraine to its variant forms

Novel Mutation in CACNA1A Associated with Activity-Induced Dystonia, Cervical Dystonia, and Mild Ataxia

Instrumented gait analysis defines the walking signature of CACNA1A disorders

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