scholarly journals 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

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.

CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood

Cephalalgia ◽  
2008 ◽  
Vol 28 (8) ◽  
pp. 887-891 ◽  
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.

scholarly journals Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine

2006 ◽  
Vol 14 (5) ◽  
pp. 555-560 ◽  
Author(s):  
Kaate R J Vanmolkot ◽  
Esther E Kors ◽  
Ulku Turk ◽  
Dylsad Turkdogan ◽  
Antoine Keyser ◽  
...  
Keyword(s):  
De Novo ◽  
Familial Hemiplegic Migraine ◽  
De Novo Mutations ◽  
Hemiplegic Migraine ◽  
Atpase Gene

Differential effect of FHM2 mutation on synaptic plasticity in distinct hippocampal regions

Cephalalgia ◽  
2019 ◽  
Vol 39 (10) ◽  
pp. 1333-1338 ◽  
Author(s):  
Antonio de Iure ◽  
Petra Mazzocchetti ◽  
Guendalina Bastioli ◽  
Barbara Picconi ◽  
Cinzia Costa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Familial Hemiplegic Migraine ◽  
Loss Of Function ◽  
Hemiplegic Migraine ◽  
Term Potentiation ◽  
Atp1a2 Gene ◽  
Ca1 Area ◽  
Reduced Rate

Introduction Familial hemiplegic migraine 2 is a pathology linked to mutation of the ATP1A2 gene producing loss of function of the α2 Na+/K+-ATPase (NKA). W887R/+ knock-in (KI) mice are used to model the familial hemiplegic migraine 2 condition and are characterized by 50% reduced NKA expression in the brain and reduced rate of K+ and glutamate clearance by astrocytes. These alterations might, in turn, produce synaptic changes in synaptic transmission and plasticity. Memory and learning deficits observed in familial hemiplegic migraine patients could be ascribed to a possible alteration of hippocampal neuronal plasticity and measuring possible changes of long-term potentiation in familial hemiplegic migraine 2 KI mice might provide insights to strengthen this link. Results Here we have investigated synaptic plasticity in distinct hippocampal regions in familial hemiplegic migraine 2 KI mice. We show that the dentate gyrus long-term potentiation of familial hemiplegic migraine 2 mice is abnormally increased in comparison with control animals. Conversely, in the CA1 area, KI and WT mice express long-term potentiation of similar amplitude. Conclusions The familial hemiplegic migraine 2 KI mice show region-dependent hippocampal plasticity abnormality, which might underlie some of the memory deficits observed in familial migraine.

scholarly journals Early-onset familial hemiplegic migraine due to a novel SCN1A mutation

Cephalalgia ◽  
2016 ◽  
Vol 36 (13) ◽  
pp. 1238-1247 ◽  
Author(s):  
Chunxiang Fan ◽  
Stefan Wolking ◽  
Frank Lehmann-Horn ◽  
Ulrike BS Hedrich ◽  
Tobias Freilinger ◽  
...  
Keyword(s):  
Early Onset ◽  
Novel Mutation ◽  
Familial Hemiplegic Migraine ◽  
Inhibitory Neurons ◽  
Clinical Genetic ◽  
Hemiplegic Migraine ◽  
Gene Encoding ◽  
Whole Cell Patch Clamp ◽  
Steady State Inactivation ◽  
Epilepsy Gene

Introduction Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. The FHM3 subtype is caused by mutations in SCN1A, which is also the most frequent epilepsy gene encoding the voltage-gated Na+ channel NaV1.1. The aim of this study was to explore the clinical, genetic and pathogenetic features of a pure FHM3 family. Methods A three-generation family was enrolled in this study for genetic testing and assessment of clinical features. Whole cell patch-clamp was performed to determine the functions of identified mutant NaV1.1 channels, which were transiently expressed in human tsA201 cells together with β1 and β2 subunits. Results and conclusions We identified a novel SCN1A (p.Leu1624Pro) mutation in a pure FHM family with notably early-onset attacks at mean age of 7. L1624P locates in S3 of domain IV, the same domain as two of four known pure FHM3 mutations. Compared to WT channels, L1624P displayed an increased threshold-near persistent current in addition to other gain-of-function features such as: a slowing of fast inactivation, a positive shift in steady-state inactivation, a faster recovery and higher channel availability during repetitive stimulation. Similar to the known FHM3 mutations, this novel mutation predicts hyperexcitability of GABAergic inhibitory neurons.

De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine

Neurology ◽  
2010 ◽  
Vol 75 (11) ◽  
pp. 967-972 ◽  
Author(s):  
F. Riant ◽  
A. Ducros ◽  
C. Ploton ◽  
C. Barbance ◽  
C. Depienne ◽  
...  
Keyword(s):  
Early Onset ◽  
De Novo ◽  
De Novo Mutations ◽  
Hemiplegic Migraine

scholarly journals Early-onset epileptic encephalopathy and severe developmental delay in an association with de novo double mutations in NF1 and MAGEL2

2017 ◽  
Vol 3 (1) ◽  
pp. 81-85 ◽  
Author(s):  
Satoshi Akamine ◽  
Noriaki Sagata ◽  
Yasunari Sakai ◽  
Takahiro A. Kato ◽  
Takeshi Nakahara ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Early Onset ◽  
De Novo ◽  
Epileptic Encephalopathy

scholarly journals Familial Hemiplegic Migraine with Prolonged Coma and Cerebellar Atrophy: CACNA1A T666M Mutation in a Korean Family

2012 ◽  
Vol 27 (9) ◽  
pp. 1124 ◽  
Author(s):  
Kyung-Ho Choi ◽  
Jang Su Kim ◽  
Seo-Young Lee ◽  
Suk-won Ryu ◽  
Sam Su Kim ◽  
...  
Keyword(s):  
Cerebellar Atrophy ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Korean Family ◽  
Prolonged Coma

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy

Neurology ◽  
2000 ◽  
Vol 55 (7) ◽  
pp. 1040-1042 ◽  
Author(s):  
K. Vahedi ◽  
C. Denier ◽  
A. Ducros ◽  
V. Bousson ◽  
C. Levy ◽  
...  
Keyword(s):  
De Novo ◽  
Cerebellar Atrophy ◽  
De Novo Mutation ◽  
Hemiplegic Migraine ◽  
Cacna1a Gene

scholarly journals Brain atrophy following hemiplegic migraine attacks

Cephalalgia ◽  
2017 ◽  
Vol 38 (6) ◽  
pp. 1199-1202 ◽  
Author(s):  
Nadine Pelzer ◽  
Evelien S Hoogeveen ◽  
Michel D Ferrari ◽  
Bwee Tien Poll-The ◽  
Mark C Kruit ◽  
...  
Keyword(s):  
Sodium Valproate ◽  
Brain Atrophy ◽  
Prophylactic Treatment ◽  
De Novo ◽  
Early Stage ◽  
Cerebellar Atrophy ◽  
Hemiplegic Migraine ◽  
Permanent Brain Damage ◽  
Cytotoxic Oedema

Background Patients with hemiplegic migraine (HM) may sometimes develop progressive neurological deterioration of which the pathophysiology is unknown. Patient We report a 16-year clinical and neuroradiological follow-up of a patient carrying a de novo p.Ser218Leu CACNA1A HM mutation who had nine severe HM attacks associated with seizures and decreased consciousness between the ages of 3 and 12 years. Results Repeated ictal and postictal neuroimaging revealed cytotoxic oedema during severe HM attacks in the symptomatic hemisphere, which later showed atrophic changes. In addition, progressive cerebellar atrophy was observed. Brain atrophy halted after cessation of severe attacks, possibly due to prophylactic treatment with flunarizine and sodium valproate. Conclusion Severe HM attacks may result in brain atrophy and prophylactic treatment of these attacks might be needed in an early stage of disease to prevent permanent brain damage.

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