CACNA1A-P.THR501MET mutation associated with familial hemiplegic migraine: A family report

Abstract Background Hemiplegic migraines represent a heterogeneous disorder with various presentations. Hemiplegic migraines are classified as sporadic or familial based on the presence of family history, but both subtypes have an underlying genetic etiology. Mutations in the ATP1A2 gene are responsible for Familial Hemiplegic type 2 (FHM2) or the sporadic hemiplegic migraine (SHM) counterpart if there is no family history of the disorder. Manifestations include migraine with aura and hemiparesis along with a variety of other symptoms likely dependent upon the specific mutation(s) present. Case presentation We report the case of an adult man who presented with headache, aphasia, and right-sided weakness. Workup for stroke and various infectious agents was unremarkable during the patient’s extended hospital stay. We emphasize the changes in the Magnetic Resonance Imaging (MRI) over time and the delay from onset of symptoms to MRI changes in Isotropic Diffusion Map (commonly referred to as Diffusion Weighted Imaging (DWI)) as well as Apparent Diffusion Coefficient (ADC). Conclusions We provide a brief review of imaging findings correlated with signs/symptoms and specific mutations in the ATP1A2 gene reported in the literature. Description of the various mutations and consequential presentations may assist neurologists in identifying cases of Hemiplegic Migraine, which may include transient changes in ADC and DWI imaging throughout the course of an attack.

Download Full-text

The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function

Molecular Brain ◽

10.1186/s13041-021-00745-2 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Maria A. Gandini ◽

Ivana A. Souza ◽

Laurent Ferron ◽

A. Micheil Innes ◽

Gerald W. Zamponi

Keyword(s):

Developmental Delay ◽

Early Onset ◽

Structural Damage ◽

De Novo ◽

Splice Variants ◽

Cerebellar Atrophy ◽

Familial Hemiplegic Migraine ◽

Significant Loss ◽

Loss Of Function ◽

Hemiplegic Migraine

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.

Download Full-text

Familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2

The Journal of Headache and Pain ◽

10.1186/s10194-021-01221-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Fabio Antonaci ◽

Sabrina Ravaglia ◽

Gaetano S. Grieco ◽

Stella Gagliardi ◽

Cristina Cereda ◽

...

Keyword(s):

Case Reports ◽

3D Structure ◽

Familial Hemiplegic Migraine ◽

Transmembrane Helices ◽

Hemiplegic Migraine ◽

Case Presentation ◽

Italian Family ◽

Protein Prediction ◽

Functional Consequences

Abstract Background The mechanisms of genotype-phenotype interaction in Familiar Hemiplegic migraine type 2 (FHM2) are still far from clear. Different ATP1A2 mutations have been described, with a spectrum of phenotypes ranging from mild to severe. No genotype-phenotype correlations have been attempted. Case presentation We describe an Italian family with FHM and a missense ATP1A2 variant (L425H) not previously described. The clinical picture was mild in all the affected members. Conclusions Co-segregation of the variant with the aura phenotype was complete in this family, suggesting a 100% penetrance. In silico protein prediction softwares indicate that this variant may change the 3D structure of ATPA1A2 at the cytoplasmic loop between the two central transmembrane helices. Milder FHM phenotypes are rarely reported in literature, likely because case reports are biased towards the most severe phenotypes, with milder forms possibly misdiagnosed as sporadic migraine with aura forms (MAs), even with complex auras. Further studies taking into account intra-familiar variability and functional consequences on the channel protein may help clarify genotype-phenotype correlations.

Download Full-text

Widespread brain parenchymal HMGB1 and NF-κB neuroinflammatory responses upon cortical spreading depolarization in familial hemiplegic migraine type 1 mice

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105424 ◽

2021 ◽

pp. 105424

Author(s):

Anisa Dehghani ◽

Thas Phisonkunkasem ◽

Sinem Yilmaz Ozcan ◽

Turgay Dalkara ◽

Arn M.J.M. van den Maagdenberg ◽

...

Keyword(s):

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Spreading Depolarization ◽

Brain Parenchymal

Download Full-text

Epilepsy in Patients with Familial Hemiplegic Migraine

Seizure ◽

10.1016/j.seizure.2021.03.028 ◽

2021 ◽

Author(s):

Buse Rahime Hasırcı Bayır ◽

Kemal Tutkavul ◽

Metin Eser ◽

Betül Baykan

Keyword(s):

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine

Download Full-text

Early Treatment in Acute Severe Encephalopathy Caused by ATP1A2 Mutation of Familial Hemiplegic Migraine Type 2: Case Report and Literature Review

Neuropediatrics ◽

10.1055/s-0039-3400986 ◽

2019 ◽

Vol 51 (03) ◽

pp. 215-220

Author(s):

Ying Du ◽

Chuan Li ◽

Feng-ju Duan ◽

Chao Zhao ◽

Wei Zhang

Keyword(s):

Magnetic Resonance ◽

Literature Review ◽

Neuronal Damage ◽

Brain Magnetic Resonance Imaging ◽

Familial Hemiplegic Migraine ◽

Resonance Spectroscopy ◽

Rapid Progression ◽

Complete Disappearance ◽

Hemiplegic Migraine

AbstractFamilial hemiplegic migraine type 2 (FHM2) is an autosomal dominant inheritance disorder caused by ATP1A2 mutation, and the clinical spectrum is heterogeneous even with acute severe encephalopathy. However, up to now, early treatments against acute and severe attacks in FHM2 are still insufficient. Here, we report a 15-year-old female with intellectual disability due to FHM2 caused by a pathogenic ATP1A2 gene mutation, presenting mild-to-moderate headache at the onset, followed by confusion, complete right hemiparalysis, epileptic partial seizures, and conscious disturbance with rapid progression in acute attack. Brain magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have revealed left extensive cerebral cortex edema, slightly decreased N-acetylaspartate for neuronal damage, and mildly increased lactate acid for mitochondrial dysfunction throughout the hemispheric swollen cortex. The patient is diagnosed as severe encephalopathy caused by FHM2. Based on literature review about pathophysiologic mechanism described in FHM2 recently, we use early treatments including prevention of glutamatergic excitotoxicity and protection of mitochondria function, as well as traditional antimigraine drug. The symptoms are all greatly improved and recovered within a short time, and follow-up MRI also shows complete disappearance of edema throughout the left hemispheric cortex. Altogether, the approach in our case may reduce the severity and duration of encephalopathy effectively, expend therapeutic options, and provide helpful references for acute severe encephalopathy in FHM2.

Download Full-text

Widespread c-Fos expression after cortical spreading depression; possible differences between two types of animal models of familial hemiplegic migraine 2

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2666 ◽

2017 ◽

Vol 381 ◽

pp. 947

Author(s):

M. Unekawa ◽

K. Ikeda ◽

Y. Tomita ◽

K. Kawakami ◽

N. Suzuki

Keyword(s):

Animal Models ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Fos Expression

Download Full-text

CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood

Cephalalgia ◽

10.1111/j.1468-2982.2008.01596.x ◽

2008 ◽

Vol 28 (8) ◽

pp. 887-891 ◽

Cited By ~ 34

Author(s):

B de Vries ◽

AH Stam ◽

F Beker ◽

AMJM van den Maagdenberg ◽

KRJ Vanmolkot ◽

...

Keyword(s):

Clinical Features ◽

Molecular Mechanisms ◽

De Novo ◽

Monozygotic Twin ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Mutation Scanning ◽

Alternating Hemiplegia Of Childhood ◽

Neurological Phenotype ◽

Cacna1a Mutation

Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.

Download Full-text

Evidence for a separate type of migraine with aura

Neurology ◽

10.1212/01.wnl.0000046524.25369.7d ◽

2003 ◽

Vol 60 (4) ◽

pp. 595-601 ◽

Cited By ~ 87

Author(s):

Lise L. Thomsen ◽

Elsebet Ostergaard ◽

Jes Olesen ◽

Michael B. Russell

Keyword(s):

Migraine With Aura ◽

Telephone Interview ◽

Clinical Symptoms ◽

Familial Hemiplegic Migraine ◽

Computer Search ◽

Hemiplegic Migraine ◽

Motor Weakness ◽

National Patient Register ◽

National Patient ◽

Sequential Appearance

Objective: To compare clinical characteristics of patients with sporadic hemiplegic migraine (SHM) with those of patients with migraine with typical aura (MA) and patients with familial hemiplegic migraine (FHM).Methods: The authors used a computer search of Denmark’s National Patient Register to screen the population for patients with migraine with aura with motor weakness, and also examined case records from headache clinics and private practicing neurologists and placed advertisements. The authors screened patients and their relatives with a semi-structured validated telephone interview. All recruited patients were then interviewed by a physician and given a neurologic examination.Results: A total of 105 patients with SHM were identified. Seventy-two percent had four typical aura symptoms: visual, sensory, aphasic, and motor. All had at least two symptoms present during SHM attacks. A gradual progression and sequential appearance of aura symptoms was typical; compared with MA, the duration of each aura symptom was usually prolonged and bilateral motor symptoms were more frequent. Of the patients with SHM, 72% fulfilled the criteria for basilar migraine during SHM attacks. The aura was usually followed by headache, as is common in FHM but not MA.Conclusions: Patients with sporadic hemiplegic migraine had clinical symptoms identical to familial hemiplegic migraine and significantly different from migraine with typical aura. Sporadic hemiplegic migraine is a separate entity, and should be classified with familial hemiplegic migraine.

Download Full-text

Familial Hemiplegic Migraine: Follow-up Findings of Diffusion-Weighted Magnetic Resonance Imaging (MRI), Perfusion-MRI and [99mTc] HMPAO-SPECT in a Patient with Prolonged Hemiplegic Aura

Cephalalgia ◽

10.1111/j.1468-2982.2003.00706.x ◽

2004 ◽

Vol 24 (7) ◽

pp. 533-539 ◽

Cited By ~ 55

Author(s):

S Oberndorfer ◽

C Wöber ◽

C Nasel ◽

S Asenbaum ◽

H Lahrmann ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Photon Emission ◽

Familial Hemiplegic Migraine ◽

Migraine Aura ◽

Resonance Imaging ◽

Hemiplegic Migraine ◽

Diffusion Weighted ◽

Hmpao Spect ◽

Weighted Magnetic Resonance Imaging

Familial hemiplegic migraine (FHM) is a rare inherited autosomal dominant disorder. Migraine aura may last up to several weeks and then resolve without sequel. We report a 21-year-old male with FHM since the age of 3 years. Diffusion-weighted magnetic resonance imaging (DWI), perfusion-MR imaging (P-MRI) and [99mTc] hexamethyl-propyleneamine-oxime-single photon emission tomography (HMPAO-SPECT) were performed on day 2, when he was somnolent with right-sided hemiplegia, on day 9 when a mild hemiparesis was still present and on day 24 after recovery. The right central region showed normal findings in DWI, whereas P-MRI and SPECT revealed hyperperfusion on day 2, less marked on day 9, and normal findings on day 24. In conclusion, this case report indicates for the first time, by means of SPECT, P-MRI and DWI studies, that even extremely long-lasting migraine aura is not associated with cerebral ischaemia. Therefore, it supports the revised International Headache Society criteria where the term ‘persistent’ aura is proposed.

Download Full-text