CACNA1A Mutations Research Articles

7. EEG findings in three patients with Alternating Hemiplegia of childhood (AHC)

Aim First reported by Verret and Steele in 1971, Alternating hemiplegia of childhood (AHC) is a rare disorder. The incidence is reported at 1 in 1,000,000 but this is most likely higher as AHC is often misdiagnosed. Infants often present with recurrent attacks of hemiplegia affecting either side of the body, abnormalities of ocular movement, movement disorders, and progressive developmental delay. It has been reported to be associated with mutations in CACNA1A, a calcium channel gene, and ATP1A2, a sodium potassium ATPase gene. It has been reported in large cohort studies that close to 50% of children with AHC will develop epilepsy. The purpose of this study is to examine the EEG finding with patient with AHC to further help clarify diagnosis. Methods This paper will explore 3 patients, chart review, with confirmed genetic testing of the APT1A2 gene mutation, EEG findings. Results Patient 1(R.G) low background activity in left temporal region, irregular sharp slow ave complex at 2 Hz, mild epileptiform focus in right posterior T6, T4 (temporal region. Patient 2 (A.K). slow wave at 4 Hz over both hemispheres that progressed to vertex waves and hypnagogic hypersynchrony after gamma hydroxbutyrate administration. Patient 3 (A.B), normal EEG. Summary Although the findings seen in patient with AHC are not pathognomonic, EEG is still a powerful tool in diagnosing patients especially in situations where genetic testing is not available.

EHMTI-0187. A novel ATP1A2 mutation in a case of familial hemiplegic migraine with especially severe attacks

Familial hemiplegic migraine (FHM) is a rare disorder characterized by migraine attacks with motor weakness during aura phase. Mutations in CACNA1A, ATP1A2, SCN1A and PRRT2 genes have been described.

Clinical and genetic analysis in alternating hemiplegia of childhood: Ten new patients from Southern Europe

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder featuring attacks of hemiplegia and other paroxysmal and non-paroxysmal manifestations leading to progressive neurological impairment. De novo mutations in ATP1A3 have been identified in up to 80% of patients. AHC is also associated with rare mutations in other genes involved in episodic neurological disorders.We sought to find mutations in ATP1A3, CACNA1A, ATP1A2, SCN1A and SLC2A1 in a cohort of ten unrelated patients from Spain and Greece.All patients fulfilled AHC diagnostic criteria. All five genes were amplified by PCR and Sanger sequenced. Copy number variation (CNV) analysis of SLC2A1 and CACNA1A was performed using two different approaches.We identified three previously described heterozygous missense ATP1A3 mutations (p.Asp801Asn, p.Glu815Lys and p.Gly947Arg) in five patients. No disease-causing mutations were found in the remaining genes. All mutations occurred de novo; carriers presented on average earlier than non-carriers. Intellectual disability was more severe with the p.Glu815Lys variant. A p.Gly947Arg carrier harbored a maternally-inherited CACNA1A p.Ala454Thr variant. Of note, three of our patients exhibited remarkable clinical responses to the ketogenic diet.We confirmed ATP1A3 mutations in half of our patients. Further AHC genetic studies will need to investigate large rearrangements in ATP1A3 or consider greater genetic heterogeneity than previously suspected.

Congenital ataxia and hemiplegic migraine with cerebral edema associated with a novel gain of function mutation in the calcium channel CACNA1A

Mutations in the CACNA1A gene, encoding the α1 subunit of the voltage-gated calcium channel CaV2.1 (P/Q-type), have been associated with three neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6). We report a child with congenital ataxia, abnormal eye movements and developmental delay who presented severe attacks of hemiplegic migraine triggered by minor head traumas and associated with hemispheric swelling and seizures. Progressive cerebellar atrophy was also observed. Remission of the attacks was obtained with acetazolamide. A de novo 3bp deletion was found in heterozygosity causing loss of a phenylalanine residue at position 1502, in one of the critical transmembrane domains of the protein contributing to the inner part of the pore. We characterized the electrophysiology of this mutant in a Xenopus oocyte in vitro system and showed that it causes gain of function of the channel. The mutant CaV2.1 activates at lower voltage threshold than the wild type. These findings provide further evidence of this molecular mechanism as causative of FHM1 and expand the phenotypic spectrum of CACNA1A mutations with a child exhibiting severe SHM1 and non-episodic ataxia of congenital onset.

Familial hemiplegic migraine: A model for the genetic studies of migraine

FHM3 is a rare subtype of familial hemiplegic migraine (FHM) caused by mutations in the neuronal sodium channel gene SCN1A (1). Only five FHM3 mutations have been described in a few families since the identification of SCN1A as the third FHM gene in 2005 (1–4). In the present issue of Cephalalgia, Weller et al. (5) report the identification of two novel SCN1A FHM3 mutations in two families with pure FHM. This study is important for clinicians managing patients with FHM, and should also encourage geneticists to consider or reconsider FHM as one of the major targets in the continuing quest for migraine genes. Despite extensive studies, migraine genes remain difficult to identify (6). The common migraines (migraine without aura and migraine with aura) are characterized by high prevalence in the general population, high phenotypic variability, absence of any objective diagnosis marker and polygenic inheritance. Therefore, a successful approach in the search for migraine genes has been the study of FHM, a rare autosomal dominant subform of migraine with aura characterized by the presence of a motor weakness during the aura phase. However, studies of FHM have shown that being monogenic does not imply being a ‘‘simple’’ model. Indeed, FHM is genetically heterogeneous, i.e. mutations in different genes can cause the same phenotype of recurrent migraine attacks with complex aura. From 1996 to 2005, three FHM genes have been identified that all encode ion transporters: a neuronal calcium channel (CACNA1A, FHM1) (7), a glial sodium/potassium pump (ATP1A2, FHM2) (8) and a neuronal sodium channel (SCN1A, FHM3) (1). In 2012, the proline-rich transmembrane protein 2 gene (PRRT2), encoding a protein associated with the exocytosis complex, was proposed as the fourth FHM gene (9,10). Mutations in CACNA1A, ATP1A2 and PRRT2 have also been found in patients with sporadic hemiplegic migraine (SHM) and are often de novo mutations (9,11–13). Study of cellular and murine models have shown that FHM mutations in CACNA1A and ATP1A2 facilitated the initiation of cortical spreading depression waves, the mechanism underlying the migraine aura, and increased neuronal excitability with an excess of glutamatergic neurotransmission (11,13). A proportion of cases with FHM or SHM do not harbor a mutation in the four known genes, indicating that other FHM genes are still to be discovered. Furthermore, genotype-phenotype correlations studies have described the wide clinical spectrum of FHM and the high clinical variability among patients with the same mutation (13). While most cases have so-called ‘‘pure’’ hemiplegic migraine, a small subset of familial and sporadic cases have associated manifestations including permanent cerebellar signs (nystagmus and/ or ataxia), epilepsy, cognitive impairment, elicited repetitive daily blindness and paroxysmal dyskinesia. Some patients can present with early-onset severe attacks with coma, prolonged hemiplegia, fever and brain edema (13). Moreover, different mutations in FHM genes induce other monogenic neurological disorders. CACNA1A mutations can cause episodic ataxia type 2 and spinocerebellar ataxia type 6 (7,13). PRRT2 mutations are associated with benign familial infantile convulsions, infantile convulsions with choreoathetosis, and paroxysmal dyskinesias (10). SCN1A was already known as an epilepsy gene previous to its identification as the FHM3 gene (1). Diagnosing HM might be a challenge. The first step relies on a detailed description of the aura (13). Apart from the presence of a motor weakness during the aura and the frequency of prolonged auras, most HM attacks are similar to attacks of migraine with typical or with brain stem aura. Single cases are diagnosed as sporadic HM, while at least two affected firstand/or

Episodic ataxia type 2: phenotype characteristics of a novel CACNA1A mutation and review of the literature

Episodic ataxia type 2 (EA2) is an autosomal dominant inherited neurological disorder that is characterized by paroxysmal episodes of ataxia. The causative gene for EA2 is CACNA1A which codes for the alpha 1A subunit of the voltage-gated P/Q-type calcium channel (Cav2.1). We detected a novel point mutation in the CACNA1A gene in a large Austrian family. All ten affected family members harbored a heterozygous c.3089+2T>C nucleotide exchange in intron 19. In silico modeling demonstrated a loss of the splice site of exon 19 by the mutation, which most likely results in exon skipping without frameshifting or use of an alternative splice site.Clinically, the family exhibited frequent ataxic episodes accompanied by headache in some individuals, which showed a good treatment response to acetazolamide or aminopyridine. Interictal phenotype variability was high ranging from an unremarkable clinical examination to a progressive cerebellar syndrome. Detailed cognitive testing with standardized neuropsychological tests revealed specific deficits in various domains including memory,executive functions and visual abilities. Moreover, a striking coincidence of socio-phobic behavior and anxiety disorders was detected within this family, which interfered with activities of daily living and has to be taken in consideration in EA2 patient management. We here characterize the phenotype of this novel CACNA1A mutation,review the respective literature and discuss implications on diagnosis and patient management.

Biochemical changes in the brain of hemiplegic migraine patients measured with 7 tesla 1H-MRS

The aim of this study was to assess biochemical changes in the brain of patients with hemiplegic migraine in between attacks. Eighteen patients with hemiplegic migraine (M:F, 7:11; age 38 ± 14 years) of whom eight had a known familial hemiplegic migraine (FHM) mutation (five in the CACNA1A gene (FHM1), three in the ATP1A2 gene (FHM2)) and 19 age- and sex-matched healthy controls (M:F, 7:12; mean age 38 ± 12 years) were studied. We used single-voxel 7 tesla (1)H-MRS (STEAM, TR/TM/TE = 2000/19/21 ms) to investigate four brain regions in between attacks: cerebellum, hypothalamus, occipital lobe, and pons. Patients with hemiplegic migraine showed a significantly lower total N-acetylaspartate/total creatine ratio (tNAA/tCre) in the cerebellum (median 0.73, range 0.59-1.03) than healthy controls (median 0.79, range (0.67-0.95); p = 0.02). In FHM1 patients with a CACNA1A mutation, the tNAA/tCre was lowest. We found a decreased cerebellar tNAA/tCre ratio that might serve as an early biomarker for neuronal dysfunction and/or loss. This is the first high-spectral resolution 7 tesla (1)H-MRS study of interictal biochemical brain changes in hemiplegic migraine patients.

A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties.In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.

A loss-of-function CACNA1A mutation causing benign paroxysmal torticollis of infancy

Benign paroxysmal torticollis of infancy (BPTI) is a rare paroxysmal disorder characterized by recurrent episodes of head tilt and accompanying general symptoms which remit spontaneously. The rare association with gain-of-function CACNA1A mutations, similar to hemiplegic migraine, has been reported. We report here two new BPTI patients from the same family carrying a heterozygous mutation in the CACNA1A gene leading to the change p.Glu533Lys. Functional analysis revealed that this mutation induces a loss of channel function due to impaired gating by voltage and much lower current density. Our data suggest that BPTI, a periodic syndrome commonly considered a migraine precursor, constitutes an age-specific manifestation of defective neuronal calcium channel activity.

Diagnostic utility of whole exome sequencing in patients showing cerebellar and/or vermis atrophy in childhood

Cerebellar and/or vermis atrophy is recognized in various types of childhood disorders with clinical and genetic heterogeneity. Although careful evaluation of clinical features and neuroimaging can lead to correct diagnosis of disorders, their diagnosis is sometimes difficult because clinical features can overlap with each other. In this study, we performed family-based whole exome sequencing of 23 families including 25 patients with cerebellar and/or vermis atrophy in childhood, who were unable to be diagnosed solely by clinical examination. Pathological mutations of seven genes were found in ten patients from nine families (9/23, 39.1%): compound heterozygous mutations in FOLR1, C5orf42, POLG, TPP1, PEX16, and de novo mutations in CACNA1A, and ITPR1. Patient 1A with FOLR1 mutations showed extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid and serum, and Patient 6 with TPP1 mutations demonstrated markedly lowered tripeptidyl peptidase 1 activity in leukocytes. Furthermore, Patient 8 with PEX16 mutations presented a mild increase of very long chain fatty acids in the serum as supportive data for genetic diagnosis. The main clinical features of these ten patients were nonspecific and mixed, and included developmental delay, intellectual disability, ataxia, hypotonia, and epilepsy. Brain MRI revealed both cerebellar and vermis atrophy in eight patients (8/10, 80%), vermis atrophy/hypoplasia in two patients (2/10, 20%), and brainstem atrophy in one patient (1/10, 10%). Our data clearly demonstrate the utility of whole exome sequencing for genetic diagnosis of childhood cerebellar and/or vermis atrophy.

Novel CACNA1A mutation(s) associated with slow saccade velocities

Mutations in the voltage-gated Cav2.1 P/Q-type calcium channel (CACNA1A) can cause a wide spectrum of phenotypes, including the episodic ataxia type 2. Beside the growing number of descriptions of novel CACNA1A mutations with episodic ataxia type 2 phenotype; there are only rare reports on interictal oculomotor signs other than nystagmus. We describe a novel CACNA1A mutation and an unclassified CACNA1A in-frame variant in a Swiss family presenting as the episodic ataxia type 2 phenotype associated with reduced saccade velocity. In this case series interictal clinical examination showed only minimal neurological findings as mild limb ataxia and nystagmus, but most interestingly saccade analysis of all three affected individuals demonstrated reduced mean saccade velocity. Genetic testing of CACNA1A revealed a de novo frame-shift mutation (c.2691dupC/p.Thyr898Leufs 170) in the index patient in addition to an unclassified in-frame variant (c.6657_6659dupCCA/p.His2220dup) segregating in all three affected individuals. The de novo frame-shift CACNA1A mutation and the unclassified in-frame CACNA1A variant were associated with the episodic ataxia type 2 phenotype and reduced mean saccade velocity, which suggests involvement of brainstem or neural pathways connecting brainstem and the cerebellum in this disease.

Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies

Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.

CaV2.1 ablation in cortical interneurons selectively impairs fast‐spiking basket cells and causes generalized seizures

Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function (LOF) mutations in Cacna1a, which encodes the α1 pore-forming subunit of CaV 2.1 (P/Q-type) voltage-gated Ca(2+) channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype. We investigated how different cortical interneuron subtypes are affected by the loss of CaV 2.1 channel function and how this contributes to the onset of generalized epilepsy. We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical γ-aminobutyric acidergic (GABAergic) and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics, and in vivo video electroencephalographic recordings. We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)(+) and somatostatin (SST)(+) interneurons, results in severe generalized epilepsy. Loss of CaV 2.1 channel function compromises GABA release from PV(+) but not SST(+) interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV 2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability. Our findings demonstrate that conditional ablation of CaV 2.1 channel function from cortical PV(+) interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability, and is sufficient to cause generalized seizures.

Génétique de la migraine

The aim of genetic studies in migraine is to identify key proteins in order to better understand the molecular mechanisms of this frequent but still incompletely understood condition. This review describes the current knowledge in the field of migraine genetics. Migraine genes have been, and still are, difficult to identify. The more common varieties of migraine are characterized by a high prevalence in the general population, and a high phenotypic variability. In the absence of any objective diagnosis marker, the status for genetic studies is established only clinically. The first breakthrough was permitted by the study of familial hemiplegic migraine, a variety of migraine with motor aura. This rare condition has a monogenic, autosomal dominant mode of inheritance, thus enabling genetic studies. The three first genes, identified from 1996 to 2005, all encode ion-channel transporters: a neuronal calcium channel (CACNA1A, FHM1), a glial sodium/potassium pump (ATP1A2, FHM2) and a neuronal sodium channel (SCN1A, FHM3). Study of cellular and animal models have shown that mutations in CACNA1A and ATP1A2 facilitated the initiation of cortical spreading depression waves, the mechanism underlying the migraine aura, and most likely increased neuronal excitability with an excess of glutamatergic neurotransmission. In 2012, PRRT2 has been identified as the fourth FHM gene, and encodes an axonal protein associated to the exocytosis complex. In the 1990s, family and twin studies showed that the more common varieties of migraine (migraine without aura and migraine with typical aura) were polygenic, with an overall heritability nearing 50 %. These genetic factors interact with environmental factors. The initial attempts to identify migraine genes by candidate gene approaches or by linkage studies were deceiving. Since 2010, three large genome-wide association studies (GWAS) have identified six genetic variants associated with migraine. Each variant has only a modest contribution to the overall genetic risk of migraine, suggesting a marked genetic heterogeneity. Three of the migraine-associated variants affect genes involved in glutamate homeostasis. Another variant concerns a gene encoding a protein implicated in nociception. Three of the four polymorphisms are associated both with migraine without aura and migraine with aura, supporting the existence of molecular mechanisms shared by all varieties of migraine. The vast majority of the migraine genes are still to be identified. Future researches will rely on new GWAS on larger cohorts of patients and controls, with a better phenotypic assessment, and on extensive sequencing.

Cerebellar Ataxia, Hemiplegic Migraine, and Related Phenotypes Due to a CACNA1A Missense Mutation

To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene. Observational 12-year follow-up study. Community and hospital care. Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%. Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded. A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A -related disorders is much broader than strictly familial hemiplegic migraine.

A loss-of-function CACNA1A mutation causing benign paroxysmal torticollis of infancy

Benign paroxysmal torticollis of infancy (BPTI) is a rare paroxysmal disorder characterized by recurrent episodes of head tilt and accompanying general symptoms which remit spontaneously. The rare association with gain-of-function CACNA1A mutations, similar to hemiplegic migraine, has been reported. We report here two new BPTI patients from the same family carrying a heterozygous mutation in the CACNA1A gene leading to the change p.Glu533Lys. Functional analysis revealed that this mutation induces a loss of channel function due to impaired gating by voltage and much lower current density. Our data suggest that BPTI, a periodic syndrome commonly considered a migraine precursor, con- stitutes an age-specific manifestation of defective neuronal calcium channel activity.

Possible anticipation associated with a novel splice site mutation in episodic ataxia type 2

Anticipation is a phenomenon characterized by decreasing age at onset and increasing severity of symptoms of a disease in successive generations within a pedigree. Anticipation mostly occurs in neurodegenerative diseases with expansion of unstable trinucleotide repeats. However, it has not been previously pointed out in episodic ataxia type 2 (EA2). Clinical and genetic analyses were performed in nine members from three consecutive generations of a Korean family with EA2. We performed a polymerase chain reaction (PCR)-based direct sequence analysis of all coding regions of CACNA1A using genomic DNA. The clinically affected family members showed recurrent vertigo, interictal nystagmus, and childhood epilepsy. There is a decrease in the age onset (possible genetic anticipation) in three succeeding generations of the family. Genetic analysis identified a splice site mutation (p.Val1465Glyfs13X) and normal trinucleotide repeats in CACNA1A in all clinically affected and one unaffected members. Recognizing anticipation would aid in genetic counseling in EA2.

A novel de novo pathogenic mutation in the CACNA1A gene

Episodic ataxia type 2 (EA2) is clinically characterized by recurrent attacks of ataxia associated with acetazolamide responsiveness.1 EA2 is caused by mutations in calcium channel, voltage-dependent, P/Q type, alpha 1A subunit (CACNA1A) gene.2 We report an EA2 case with a novel de novo pathogenic CACNA1A mutation, presenting with two different types of episodic attacks. A 23-year-old female requested an evaluation for recurrent episodes of imbalance. According to her mother, who accompanied her, her illness started at age 15 months with repeating attacks of head nodding that always disappeared after naps (see video). Her physician at that time diagnosed her with a benign paroxysmal tonic upgaze, and he described the presence of nystagmus without any more specific description.. The frequency of the episodes gradually increased from occasional to once a week. When a preschooler, she complained of a sudden sensation of dizziness and ataxia followed by vomiting, which would last up to two hours. The second type of attack became noticeable during her high school years. She experienced recurrent episodes of dysphagia and general weakness, which would last up to two hours. The first type of attack was more common, occurring about 70% of the time. Only rarely did both presentations occur together. A dull headache was sometimes present in both types of attacks. Despite her health problems, she was able to attend school but she always avoided involvement in any sports. She had no neurological abnormalities, except for horizontal gaze-evoked nystagmus. Electroencephalography, electromyography, and autonomic testing revealed no significant abnormalities. Head magnetic resonance imaging (MRI) obtained at age 13 years displayed no abnormalities (Figure 1a and 1b). MRI performed at age 23 years revealed a slight prominence of the cerebellar sulci (Figure 1c and 1d). Acetazolamide (125mg/day) reduced the severity and number of attacks, especially of ataxia type. Her elder brother and both parents did not show similar symptoms. Figure 1 Head magnetic resonance imaging (MRI) with T1-weighted image, and DNA sequencing and restriction fragment length polymorphism Genetic sequencing of the 48 exons of CACNA1A and their flanking donor/acceptor sequences detected a nonsense mutation, p.R1346Stop, in the patient, but it was not found in her family members or in 1423 healthy controls. Haplotype analyses confirmed maternal and paternal relationships (Figure 1e). Most EA2 cases present only with episodic ataxia but some present with attacks of both ataxia and weakness occurring together. Acetazolamide is beneficial for both types of attacks, even in a previously published single case, where attacks of ataxia and weakness occurred independently.3 The response to acetazolamide in our case was better for attacks of ataxia. Therefore, it is possible that there are different mechanisms causing these two phenotypes, perhaps related to the specific mutation. It is difficult to identify attacks before the child develops full walking and speech skills.4–7 In our case, vertical nystagmus occurring in infancy most likely represented disease onset. A similar phenotype has been observed in another case, but without video documentation.7 Therefore, head nodding and nystagmus may be a useful diagnostic feature in infancy. Genetic sequencing is an important tool for diagnosis of this disorder. Further studies are warranted to elucidate the underlying pathogenic mechanisms of disease associated with CACNA1A mutations.

A novel CACNA1A mutation results in episodic ataxia with migrainous features without headache

The mechanisms subtending migrainous features, like sensoriphobia, remain poorly understood even though recent works have shed new light on their mechanisms. A 24-year-old woman consulted the headache clinic because of frequent paroxysmal attacks of strong sensoriphobia, digestive signs, moderate ataxia and a need to lie in the dark, without any headache. The symptoms had begun in infancy and the patient had been treated for hysteria, then for epilepsy. As she had some typical features of episodic ataxia type 2, an analysis of CACNA1A gene was performed and demonstrated a novel c3995 + 1G>A mutation. The same mutation was also discovered in her young son, who had an ataxia of unknown origin. Both remarkably improved under acetazolamide. This observation suggests that paroxysmal sensoriphobia and digestive signs can occur together in bouts in neurological conditions other than migraine, and in the absence of head pain. It raises interesting hypotheses about the central pathways driving these symptoms.

Variable Manifestations of Familial Hemiplegic Migraine Associated With Reversible Cerebral Edema in Children

Three children with familial hemiplegic migraine presented with right-sided weakness, speech difficulty, altered mental status, and gait abnormalities. These persistent aura signs were accompanied by left-sided slowing and cerebral dysfunction, documented by electroencephalograms. Cranial magnetic resonance imaging revealed cortical edema restricted to the left cerebral hemisphere. Follow-up electroencephalogram and imaging studies produced normal results 1-4 months afterward. However, cognitive changes persisted. Genetic testing demonstrated variable results: one child manifested a CACNA1A mutation compatible with familial hemiplegic migraine type 1, whereas another demonstrated an ATP1A2 sequence alteration. No known mutations were evident in the third child, with minor head trauma thought to precipitate the familial hemiplegic migraine. These findings demonstrate the variable clinical and genetic heterogeneity of childhood familial hemiplegic migraine.