Brainstem depolarization-induced lethal apnea associated with gain-of-function SCN1AL263V is prevented by sodium channel blockade.

Apneic events are frightening but largely benign events that often occur in infants. Here, we report apparent life-threatening apneic events in an infant with the homozygous SCN1AL263V missense mutation, which causes familial hemiplegic migraine type 3 in heterozygous family members, in the absence of epilepsy. Observations consistent with the events in the infant were made in an Scn1aL263V knock-in mouse model, in which apnea was preceded by a large brainstem DC-shift, indicative of profound brainstem depolarization. The L263V mutation caused gain of NaV1.1 function effects in transfected HEK293 cells. Sodium channel blockade mitigated the gain-of-function characteristics, rescued lethal apnea in Scn1aL263V mice, and decreased the frequency of severe apneic events in the patient. Hence, this study shows that SCN1AL263V can cause life-threatening apneic events, which in a mouse model were caused by profound brainstem depolarization. In addition to being potentially relevant to sudden infant death syndrome pathophysiology, these data indicate that sodium channel blockers may be considered therapeutic for apneic events in patients with these and other gain-of-function SCN1A mutations.

Increased presynaptic excitability in a migraine with aura mutation.

Migraine is a common and disabling neurological disorder. The headache and sensory amplifications of migraine are attributed to hyperexcitable sensory circuits, but a detailed understanding remains elusive. A mutation in casein kinase 1 delta (CK1δ) was identified in non-hemiplegic familial migraine with aura and advanced sleep phase syndrome. Mice carrying the CK1δT44A mutation were more susceptible to spreading depolarization (the phenomenon that underlies migraine aura), but mechanisms underlying this migraine-relevant phenotype were not known. We used a combination of whole-cell electrophysiology and multiphoton imaging, in vivo and in brain slices, to compare CK1δT44A mice (adult males) to their wild-type littermates. We found that despite comparable synaptic activity at rest, CK1δT44A neurons were more excitable upon repetitive stimulation than wild-type, with a reduction in presynaptic adaptation at excitatory but not inhibitory synapses. The mechanism of this adaptation deficit was a calcium-dependent enhancement of the size of the readily releasable pool of synaptic vesicles, and a resultant increase in glutamate release, in CK1δT44A compared to wild-type synapses. Consistent with this mechanism, CK1δT44A neurons showed an increase in the cumulative amplitude of excitatory post-synaptic currents, and a higher excitation-to-inhibition ratio during sustained activity compared to wild-type. At a local circuit level, action potential bursts elicited in CK1δT44A neurons triggered an increase in recurrent excitation compared to wild-type, and at a network level, CK1δT44A mice showed a longer duration of 'up state' activity, which is dependent on recurrent excitation. Finally, we demonstrated that the spreading depolarization susceptibility of CK1δT44A mice could be returned to wild-type levels with the same intervention (reduced extracellular calcium) that normalized presynaptic adaptation. Taken together, these findings show a stimulus-dependent presynaptic gain of function at glutamatergic synapses in a genetic model of migraine, that accounts for the increased spreading depolarization susceptibility and may also explain the sensory amplifications that are associated with the disease.

Spontaneous and optogenetically induced cortical spreading depolarization in familial hemiplegic migraine type 1 mutant mice.

Mechanisms underlying the migraine aura are incompletely understood, which to large extent is related to a lack of models in which cortical spreading depolarization (CSD), the correlate of the aura, occurs spontaneously. Here, we investigated electrophysiological and behavioural CSD features in freely behaving mice expressing mutant CaV2.1 Ca2+ channels, either with the milder R192Q or the severer S218L missense mutation in the α1 subunit, known to cause familial hemiplegic migraine type 1 (FHM1) in patients. Very rarely, spontaneous CSDs were observed in mutant but never in wildtype mice. In homozygous Cacna1aR192Q mice exclusively single-wave CSDs were observed whereas heterozygous Cacna1aS218L mice displayed multiple-wave events, seemingly in line with the more severe clinical phenotype associated with the S218L mutation. Spontaneous CSDs were associated with body stretching, one-directional slow head turning, and rotating movement of the body. Spontaneous CSD events were compared with those induced in a controlled manner using minimally invasive optogenetics. Also in the optogenetic experiments single-wave CSDs were observed in Cacna1aR192Q and Cacna1aS218L mice (whereas the latter also showed multiple-wave events) with movements similar to those observed with spontaneous events. Compared to wildtype mice, FHM1 mutant mice exhibited a reduced threshold and an increased propagation speed for optogenetically induced CSD with a more profound CSD-associated dysfunction, as indicated by a prolonged suppression of transcallosal evoked potentials and a reduction of unilateral forepaw grip performance. When induced during sleep, the optogenetic CSD threshold was particularly lowered, which may explain why spontaneous CSD events predominantly occurred during sleep. In conclusion, our data show that key neurophysiological and behavioural features of optogenetically induced CSDs mimic those of rare spontaneous events in FHM1 R192Q and S218L mutant mice with differences in severity in line with FHM1 clinical phenotypes seen with these mutations.

Investigating the causal association between systemic lupus erythematosus and migraine using Mendelian randomization analysis.

OBJECTIVE: To assess whether systemic lupus erythematosus (SLE) may be genetically causally associated with migraine, including the two primary subtypes: migraine with aura (MWA) and migraine without aura (MWoA). BACKGROUND: The association between SLE and migraine has been investigated extensively. Previous studies have shown a higher prevalence of migraine in patients with SLE, although the exact relationship remains unclear. This study investigated the potential causal association between SLE and migraine using the powerful analytical tool of Mendelian randomization (MR). METHODS: We performed two-sample MR analysis of publicly available summary statistic datasets using inverse variance-weighted (IVW), weighted median, and MR-Egger methods based on an SLE genome-wide association study (GWAS; 5201 cases; 9066 controls; the exposure frequency is 36.5%) as an exposure and migraine GWAS (15,905 cases; 264,662 controls) in individuals with European ancestry as outcomes, focusing on the two migraine subtypes MWA (6780 cases; 264,662 controls) and MWoA (5787 cases; 264,662 controls). Thepleiotropy and heterogeneity were performed. RESULTS: We selected 42 single-nucleotide polymorphisms from SLE GWAS as instrumental variables (IVs) for SLE on migraine, and 41 SNP IVs for SLE on MWA or MWoA. The IVW (odds ratio [OR] = 1.01, 95% confidence interval [CI] = [0.99, 1.03], p = 0.271), weighted median (OR = 1.00, 95% CI = [0.97, 1.03], p = 0.914), and MR-Egger (OR = 1.04, 95% CI = [0.99, 1.09], p = 0.153) methods showed no causal effect of SLE on migraine. A causal effect of SLE was observed on MWA (IVW: OR = 1.05, 95% CI = [1.02, 1.08], p = 0.001; weighted median: OR = 1.05, 95% CI = [1.01, 1.10], p = 0.018; MR-Egger: OR = 1.07, 95% CI = [1.01, 1.14], p = 0.035 and pIVW < 0.017 [Bonferroni correction]) but not MWoA (IVW: OR = 0.99, 95% CI = [0.96, 1.02], p = 0.331; weighted median: OR = 0.98, 95% CI = [0.94, 1.03], p = 0.496; MR-Egger: OR = 1.02, 95% CI = [0.95, 1.09], p = 0.652). The results showed no significant pleiotropy or heterogeneity. CONCLUSION: Our MR analysis demonstrated the complex relationship between SLE and migraine, suggesting a potential effect of SLE on the risk of MWA but not MWoA. These findings can aid in the development of improved subtype-specific management of migraine in patients with SLE.

Familial hemiplegic migraine in Indian children-a tertiary center experience.

Familial hemiplegic migraine (FHM), an autosomal dominant subtype of hemiplegic migraine, is a channelopathy presenting with severe headache, visual field defect, paresthesia, unilateral motor deficit, encephalopathy, seizures and aphasia. This cross-sectional study was conducted over 10 months in children aged 1-18 years suspected of hemiplegic migraine at a tertiary care pediatric hospital. Fourteen children were screened and five children with genetically confirmed FHM were included. The symptoms in the study population were paroxysmal hemiparesis (5/5), headache (5/5) and focal seizures (1/5). The hemiplegia episodes lasted from 4 h to 7 days. The mean age at the onset of neurological symptoms was 6.8 ± 0.7 years and the mean age at diagnosis was 12.8 ± 1.7 years, with a mean delay of 6.1 ± 1.9 years for the diagnosis. Neuroimaging during acute episodes revealed accentuated gray, white differentiation in the contralateral cerebral hemisphere with mild effacement of sulcal spaces in T2/fluid-attenuated inversion recovery (FLAIR) images. Genetic testing revealed ATP1A2 mutations (FHM2) in 4/5 and SCN1A (FHM3) in 1/5 patients. All of them (5/5) were initiated on oral topiramate and had favorable treatment responses with a mean follow-up duration of 7 ± 1.4 months. Diagnosis of FHM is mainly clinical and can be confirmed by genetic analysis. Perfusion and diffusion-weighted MRI should be considered during acute headache episodes, as it is mostly normal in symptom-free periods. Routine MRI sequences like T1 weighted, T2 weighted, FLAIR and contrast remain normal even during acute attacks.

Migraine - a borderland disease to epilepsy: near it but not of it.

BACKGROUND: Migraine and epilepsy are two paroxysmal chronic neurological disorders affecting a high number of individuals and being responsible for a high individual and socioeconomic burden. The link between these disorders has been of interest for decades and innovations concerning diagnosing and treatment enable new insights into their relationship. FINDINGS: Although appearing to be distinct at first glance, both diseases exhibit a noteworthy comorbidity, shared pathophysiological pathways, and significant overlaps in characteristics like clinical manifestation or prophylactic treatment. This review aims to explore the intricate relationship between these two conditions, shedding light on shared pathophysiological foundations, genetic interdependencies, common and distinct clinical features, clinically overlapping syndromes, and therapeutic similarities. There are several shared pathophysiological mechanisms, like CSD, the likely underlying cause of migraine aura, or neurotransmitters, mainly Glutamate and GABA, which represent important roles in triggering migraine attacks and seizures. The genetic interrelations between the two disorders can be observed by taking a closer look at the group of familial hemiplegic migraines, which are caused by mutations in genes like CACNA1A, ATP1A2, or SCN1A. The intricate relationship is further underlined by the high number of shared clinical features, which can be observed over the entire course of migraine attacks and epileptic seizures. While the variety of the clinical manifestation of an epileptic seizure is naturally higher than that of a migraine attack, a distinction can indeed be difficult in some cases, e.g. in occipital lobe epilepsy. Moreover, triggering factors like sleep deprivation or alcohol consumption play an important role in both diseases. In the period after the seizure or migraine attack, symptoms like speech difficulties, tiredness, and yawning occur. While the actual attack of the disease usually lasts for a limited time, research indicates that individuals suffering from migraine and/or epilepsy are highly affected in their daily life, especially regarding cognitive and social aspects, a burden that is even worsened using antiseizure medication. This medication allows us to reveal further connections, as certain antiepileptics are proven to have beneficial effects on the frequency and severity of migraine and have been used as a preventive drug for both diseases over many years. CONCLUSION: Migraine and epilepsy show a high number of similarities in their mechanisms and clinical presentation. A deeper understanding of the intricate relationship will positively advance patient-oriented research and clinical work.

Proteome-wide Mendelian randomization identified potential drug targets for migraine.

BACKGROUND: Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR). METHODS: We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein-protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets. RESULTS: We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10-6), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets-FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3-that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%). CONCLUSIONS: A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments.

Functional characterization of a novel PRRT2 variant found in a Portuguese patient with hemiplegic migraine.

Familial hemiplegic migraine (FHM) is a rare autosomal-dominant form of migraine with aura. Three disease-causing genes have been identified for FHM: CACNA1A, ATP1A2 and SCN1A. However, not all families are linked to one of these three genes.PRRT2 variants were also commonly associated with HM symptoms; therefore, PRRT2 is hypothesized as the fourth gene causing FHM. PRRT2 plays an important role in neuronal migration, spinogenesis, and synapse mechanisms during development and calcium-dependent neurotransmitter release. We performed exome sequencing to unravel the genetic cause of migraine in one family, and a novel PRRT2 variant (c.938C > T;p.Ala313Val) was identified with further functional studies to confirm its pathogenicity. PRRT2-A313V reduced protein stability, led to protein premature degradation by the proteasome and altered the subcellular localization of PRRT2 from the plasma membrane (PM) to the cytoplasm. We identified and characterized for the first time in a Portuguese patient, a novel heterozygous missense variant in PRRT2 associated with HM symptoms. We suggest that PRRT2 should be included in the diagnosis of HM.

Astrocytic Glutamate Transporters and Migraine.

Glutamate levels and lifetime in the brain extracellular space are dinamically regulated by a family of Na+- and K+-dependent glutamate transporters, which thereby control numerous brain functions and play a role in numerous neurological and psychiatric diseases. Migraine is a neurological disorder characterized by recurrent attacks of typically throbbing and unilateral headache and by a global dysfunction in multisensory processing. Familial hemiplegic migraine type 2 (FHM2) is a rare monogenic form of migraine with aura caused by loss-of-function mutations in the α2 Na/K ATPase (α2NKA). In the adult brain, this pump is expressed almost exclusively in astrocytes where it is colocalized with glutamate transporters. Knockin mouse models of FHM2 (FHM2 mice) show a reduced density of glutamate transporters in perisynaptic astrocytic processes (mirroring the reduced expression of α2NKA) and a reduced rate of glutamate clearance at cortical synapses during neuronal activity and sensory stimulation. Here we review the migraine-relevant alterations produced by the astrocytic glutamate transport dysfunction in FHM2 mice and their underlying mechanisms, in particular regarding the enhanced brain susceptibility to cortical spreading depression (the phenomenon that underlies migraine aura and can also initiate the headache mechanisms) and the enhanced algesic response to a migraine trigger.

Familial hemiplegic migraine in pediatric patients: A genetic, clinical, and follow-up study.

OBJECTIVE: The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. BACKGROUND: Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts. METHODS: We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years. RESULTS: We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2). CONCLUSION: The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.

Migraine with prolonged aphasic aura associated with a CACNA1A mutation: A case report and narrative review.

OBJECTIVE: To demonstrate that a known CACNA1A variant is associated with a phenotype of prolonged aphasic aura without hemiparesis. BACKGROUND: The usual differential diagnosis of prolonged aphasia without hemiparesis includes vascular disease, seizure, metabolic derangements, and migraine. Genetic mutations in the CACNA1A gene can lead to a myriad of phenotypes, including familial hemiplegic migraine (FHM) type 1, an autosomal dominant disorder characterized by an aura of unilateral, sometimes prolonged weakness. Though aphasia is a common feature of migraine aura, with or without hemiparesis, aphasia without hemiparesis has not been reported with CACNA1A mutations. METHODS: We report the case of a 51-year-old male who presented with a history of recurrent episodes of aphasia without hemiparesis lasting days to weeks. His headache was left sided and was heralded by what his family described as "confusion." On examination, he had global aphasia without other focal findings. Family history revealed several relatives with a history of severe headaches with neurologic deficits including aphasia and/or weakness. Imaging revealed T2 hyperintensities in the left parietal/temporal/occipital regions on MRI scan with corresponding hyperperfusion on SPECT. Genetic testing revealed a missense mutation in the CACNA1A gene. CONCLUSIONS: This case expands the phenotypic spectrum of the CACNA1A mutation and FHM to include prolonged aphasic aura without hemiparesis. Our patient's SPECT imaging demonstrated hyperperfusion in areas correlating with aura symptoms which can occur in prolonged aura.

Hemiplegic Migraine.

PURPOSE OF REVIEW: In this article, we review recent updates to the epidemiology, diagnostic testing, genetics, pathophysiology, and management of hemiplegic migraine. RECENT FINDINGS: While three genes have been historically associated with hemiplegic migraine, recent studies suggest two additional genes may also be implicated including PPRT2 and SLC1A3. Hemiplegic migraine is a severe subset of migraine with aura with symptoms including reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech. The exact pathophysiology of hemiplegic migraine is not clear, but it is thought that this phenomenon is due to neuronal and glial depolarization causing cortical spreading depression. Due to the severity of presentation as well as the numerous mimickers, it is important to know a comprehensive differential and work-up. Given the low prevalence of the disease, most studies regarding treatment are limited to case studies. There is still an important need for further and larger studies regarding management of these cases.

A novel CACNA1A R2201W variant in a woman with hemiplegic migraine.

INTRODUCTION: Familial hemiplegic migraine type 1 (FHM1) is a monogenic rare disease that is characterized by migraine attacks accompanied by unilateral weakness and is caused by mutations in the CACNA1A gene. We report the case of a patient with a clinical history consistent with hemiplegic migraine who underwent genetic testing that revealed a variant in the CACNA1A gene. CASE PRESENTATION: A 68-year-old woman was evaluated for progressive postural instability and subjective cognitive decline. She had suffered from recurrent migraine episodes accompanied by fully reversible unilateral weakness that had started around the age of thirty and had fully disappeared at the time of evaluation. Magnetic resonance imaging (MRI) showed an extensive leukoencephalopathy, with features suggestive of small vessel disease, significantly progressing over the years. Exome sequencing revealed the heterozygous variant c.6601C>T (p.Arg2201Trp) in the CACNA1A gene. This variant, located in a highly conserved region, causes the substitution of arginine with tryptophan at codon 2202 of exon 47, with a high likelihood of a damaging effect on protein activity and/or structure. DISCUSSION: This is the first report describing the missense mutation c.6601C>T (p.Arg2201Trp) in heterozygosity in the CACNA1A gene in a patient with clinical features of hemiplegic migraine. The presence of a diffuse leukoencephalopathy on MRI is not typical of hemiplegic migraine and may suggest a phenotypic variant related to this mutation or result from the combined effect of the patient's comorbidities.

Optogenetic cortical spreading depolarization induces headache-related behaviour and neuroinflammatory responses some prolonged in familial hemiplegic migraine type 1 mice.

BACKGROUND: Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation. METHODS: CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor. RESULTS: In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx308 inhibited CSD-induced headache related behaviour and HMGB1 release. CONCLUSIONS: CSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine.

Mutation screening and association analysis of NOTCH3 p.R544C in patients with migraine with or without aura.

BACKGROUND: The role of the NOTCH3 p.R544C variant, the predominant variant of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in multiple East Asian regions, in migraine is unknown. METHODS: Migraine patients (n = 2,884) (2,279F/605M, mean age 38.8 ± 11.7 years), including 324 (11.2%) with migraine with aura, were prospectively enrolled by headache specialists according to the International Classification of Headache Disorders criteria. These patients and 3,502 population controls free of stroke, dementia, and headache were genotyped for NOTCH3 p.R544C by TaqMan genotyping assay or Axiom Genome-Wide TWB 2.0 Array. Clinical manifestations and brain magnetic resonance images were examined and compared between migraine patients with and without NOTCH3 p.R544C. RESULTS: Thirty-two migraine patients (1.1%) and 36 controls (1.0%) harbored the p.R544C variant, and the percentages were comparable among migraine patients without and with aura, and controls (1.2%, vs. 0.6% vs. 1.0%, p = 0.625). Overall, migraine patients with and without the p.R544C variant had similar percentages of migraine with aura, headache characteristics, frequencies and disabilities. However, those with p.R544C were less likely to have pulsatile headaches (50.0% vs. 68.2%, p = 0.028), and more likely to have moderate to severe white matter hyperintensities in the external capsule (18.8% vs. 1.2%, p = 0.006) and anterior temporal lobe (12.5% vs. 0%, p = 0.008). CONCLUSIONS: Our findings suggest that NOTCH3 p.R544C does not increase the risk of migraine with aura, or migraine as a whole, and generally does not alter clinical manifestations of migraine. The role of NOTCH3 variants, as well as potential influences from ethnicity or modifier genes, in migraine needs to be further clarified.

Haploinsufficiency of PRRT2 Leading to Familial Hemiplegic Migraine in Chromosome 16p11.2 Deletion Syndrome.

Microdeletion in the 16p11.2 loci lead to a distinct neurodevelopmental disorder with intellectual disability and autism spectrum disorder in addition to dysmorphia, macrocephaly, and increased body mass index. One of the deleted genes in this region is PRRT2 which codes for proline-rich transmembrane protein 2. Heterozygous variants in PRRT2 cause four distinct neurological disorders including benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions, and familial hemiplegic migraine (FHM). A 13-year-old male with a known history of 16p11.2 deletion and resultant cognitive delay presented with sudden onset of headache, left-sided weakness, facial droop, and aphasia concerning for acute ischemic stroke. Magnetic resonance imaging of the brain was performed urgently which did not reveal any acute processes and his presentation met criteria for hemiplegic migraine. There have been reports of PKD and BFIE in this microdeletion syndrome; however, our proband is the first case that presented with FHM related to haploinsufficiency of PRRT2. This report highlights the importance of counseling patient families regarding acute paroxysmal presentations in this syndrome.

Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Gradually shifting clinical phenomics in migraine spectrum: a cross-sectional, multicenter study of 5438 patients.

BACKGROUND: The aim of the study was to investigate whether MwoA and MwA are different manifestations of a single disease, distinct clinical entities, or located at two poles of a spectrum. METHODS: In this cross-sectional study, 5438 patients from 10 hospitals in China were included: 4651 were diagnosed with migraine without aura (MwoA) and 787 with migraine with aura (MwA). We used a validated standardized electronic survey to collect multidimensional data on headache characteristics and evaluated the similarities and differences between migraine subtypes. To distinguish migraine subtypes, we employed correlational analysis, factor analysis of mixed data (FAMD), and decision tree analysis. RESULTS: Compared to MwA, MwoA had more severe headaches, predominantly affected females, were more easily produced by external factors, and were more likely to have accompanying symptoms and premonitory neck stiffness. Patients with MwA are heterogeneous, according to correlation analysis; FAMD divided the subjects into three clear clusters. The majority of the differences between MwoA and MwA were likewise seen when typical aura with migraine headache (AWM) and typical aura with non-migraine headache (AWNM) were compared. Furthermore, decision trees analysis revealed that the chaotic MwA data reduced the decision tree's accuracy in distinguishing MwoA from MwA, which was significantly increased by splitting MwA into AWM and AWNM. CONCLUSIONS: The clinical phenomics of headache phenotype varies gradually from MwoA to AWM and AWNM, and AWM is a mid-state between MwoA and AWNM. We tend to regard migraine as a spectrum disorder, and speculate that different migraine subtypes have different "predominant regions" that generate attacks.

Serial magnetic resonance imaging findings during severe attacks of familial hemiplegic migraine type 2: a case report.

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.

Cognitive dysfunction in a patient with migraine and APT1A2 mutation: a case report.

BACKGROUND: Hemiplegic migraine (HM) is a rare type of migraine with aura. Some reports have described the clinical manifestations in HM patients with the ATP1A2 mutation. But the impact of the ATP1A2 mutation on cognitive profile in HM patients has not been evaluated in detail. Here we report a patient with cognitive dysfunction in specific area. CASE PRESENTATION: A 15-year-old boy with an aura that included disturbances in consciousness, associated with fever, vomiting, hemiplegia, and aphasia. He was diagnosed with HM with the ATP1A2 mutation before. He had trouble in mathematics and depicting three-dimensional things. CONCLUSIONS: The HM with ATP1A2 patient could develop permanent cognitive dysfunction. Therefore, the cognitive quotient should be carefully and comprehensively evaluated.