Migraine Genetics: Part II

Migraine clusters in families and is considered to be a strongly heritable disorder. Hemiplegic migraine is a rare subtype of migraine with aura that may occur as a familial or a sporadic condition. Three genes have been identified studying families with familial hemiplegic migraine (FHM). The first FHM gene that was identified is CACNA1A. A second gene, FHM2, has been mapped to chromosome 1 q 21‐23. The defect is a new mutation in the α2 subunit of the Na/K pump (ATP1A2). A third gene (FHM3) has been linked to chromosome 2q24. It is due to a missense mutation in gene SCN1A (Gln1489Lys), which encodes an α1 subunit of a neuronal voltage‐gated Na+ channel. Genome‐wide association studies have identified many non‐coding variants associated with common diseases and traits, like migraine. These variants are concentrated in regulatory DNA marked by deoxyribonuclease I hypersensitive sites. A role has been suggested for the two‐pore domain potassium channel, TWIK‐related spinal cord potassium channel. TWIK‐related spinal cord potassium channel is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine.     

Genetics of Migraine: An Update

Observations including the long-recognized tendency of migraine to run in families, the high concordance rates for migraine in twins reared together or apart, and the association of specific mutations with a rare migraine form are consistent with a genetic contribution to the disorder. This paper summarizes major findings to date on the genetics of migraine. Study of the heritability of migraine, particularly the common forms of migraine, is beset by several challenges including the absence of easily measurable biological markers, uncertainty about the etiologic and clinical overlap among migraine types, and the apparently complex interplay of environmental and genetic factors in determining migraine phenotype. Nevertheless, significant progress has been realized in recent years. Familial hemiplegic migraine, a rare migraine variant, appears to be transmitted by a Mendelian, autosomal dominant mode of inheritance involving mutations in at least 2 genes. These genes do not seem to be critically involved in the other forms of migraine; however, several other susceptibility loci for more common forms of migraine have been identified in recent genome-wide screens and candidate-locus studies. These and other data suggest that the genetic contribution to migraine is complex, multifactorial, and subject to significant modification by environmental factors.     

Human Studies in the Pathophysiology of Migraine: Genetics and Functional Neuroimaging

The expansion of technologies available for the study of migraine pathophysiology has evolved greatly over the last 15 years. Two areas of rapid progress are investigations focusing on the genetics of migraine and others utilizing novel functional neuroimaging techniques. Genetic studies are increasingly focusing on sporadic migraine and the utilization of unbiased searches of the human genome to identify novel variants associated with disease susceptibility. At the same time, neuroimaging studies have provided novel insights into the altered neuronal and network dynamics of the migrainous brain. These 2 parallel approaches provide complementary insights into the complexity and heterogeneity of migraine.     

Molecular genetics of migraine headaches: a review

Following the recent discovery of neural calcium channel mutations in familial hemiplegic migraine, genetic linkage and association studies have been performed world‐wide in an effort to unveil the genetic basis of the more common types of migraine too. Mutations in neural calcium channels, rnitochondrial DNA, serotonin receptors and transporter, dopamine receptors and genetic prothrombotic risk factors have been especially investigated and are discussed here. No unambiguous conclusions have, however, been reached. FHM remains an isolated success story in the quest for the genetic basis of migraine.     

Migraine and Epilepsy: Review of the Literature

Migraine and epilepsy are disorders that are common, paroxysmal, and chronic. In many ways they are clearly different diseases, yet there are some pathophysiological overlaps, and overlaps in clinical symptomatology, particularly with regard to visual and other sensory disturbances, pain, and alterations of consciousness. Epidemiological studies have revealed that the two diseases are comorbid in a number of individuals. Both are now recognized as originating from electrical disturbances in the brain, although their wider manifestations involve the recruitment of multiple pathogenic mechanisms. An initial excess of neuronal activity in migraine leads to cortical spreading depression and aura, with the subsequent recruitment of the trigeminal nucleus leading to central sensitization and pain. In epilepsy, neuronal overactivity leads to the recruitment of larger populations of neurons firing in a rhythmic manner that constitutes an epileptic seizure. Migraine aura and headaches may act as a trigger for epileptic seizures. Epilepsy is not infrequently accompanied by preictal, ictal, and postictal headaches that often have migrainous features. Genetic links are also apparent between the two disorders, and are particularly evident in the familial hemiplegic migraine syndromes where different mutations can produce either migraine, epilepsy, or both. Also, various medications are found to be effective for both migraine and epilepsy, again pointing to a commonality and overlap between the two disorders.     

The Shared Genetics of Migraine and Anxious Depression

(Headache 2010;50:1549‐1560) Objectives.— To investigate (1) whether shared genetic factors influence migraine and anxious depression; (2) whether the genetic architecture of migraine depends on anxious depression; (3) whether the association between migraine and anxious depression is causal. Background.— Migraine and anxious depression frequently occur together, but little is known about the mechanisms causing this association. Methods.— A twin study was conducted to model the genetic architecture of migraine and anxious depression and the covariance between them. Anxious depression was also added to the model as a moderator variable to examine whether anxious depression affects the genetic architecture of migraine. Causal models were explored with the co‐twin control method. Results.— Modest but significant phenotypic (rP = 0.28), genetic (rG = 0.30), and nonshared environmental (rE = 0.26) correlations were found between the 2 traits. Interestingly, the heritability of migraine depended on the level of anxious depression: the higher the anxious depression score, the lower the relative contribution of genetic factors to the individual differences in migraine susceptibility. The observed risk patterns in discordant twins are most consistent with a bidirectional causal relationship. Conclusions.— These findings confirm the genetic association between migraine and anxious depression and are consistent with a syndromic association between the 2 traits. This highlights the importance of taking comorbidity into account in genetic studies of migraine, especially in the context of selection for large‐scale genotyping efforts. Genetic studies may be most effective when migraine with and without comorbid anxious depression are treated as separate phenotypes.     

Familial Hemiplegic Migraine and Recurrent Episodes of Psychosis: A Case Report

Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with motor aura. We present a case report of a father and son with very similar attacks of hemiplegic migraine and recurrent episodes of accompanying psychoses. Previously, such episodes led to hospitalization and extended clinical examinations, which further worsened the psychoses. Since the episodes were recognized as related to the hemiplegic migraine, a treatment strategy combining sleep and sedation was initiated and progression onto psychosis was almost completely avoided in both father and son. Genetic analyses found no causal gene mutation in the three known FHM genes, suggesting that the phenotype is caused by a yet unidentified mutation.     

The Neurogenic Basis of Migraine

There is accumulating evidence of a neurogenic basis of migraine. This evidence arises from both the clinical and experimental domains. Many of the well known clinical features of migraine attacks including the prodrome are not explained by changes in vascular caliber. Despite the fact that ergotamines and triptans are vasoactive does not provide substantive proof that vasoconstriction is their most important mechanism of action. Several effective treatments for migraine, both old and new, do not affect vascular caliber. Experimental evidence from investigation of both the aura and headache phases of migraine clearly supports a neural basis of migraine. All genes thus far conclusively associated with hemiplegic migraine code for neural proteins.     

A review of the genetic relation between migraine and epilepsy

A possible relation between migraine and epilepsy has been a matter of debate for many decades. Clinical, epidemiological and therapeutic similarities may be coincidental and are no proof of a common aetiological background. However, a genetically determined dysfunction of ion channels seems to point to a common underlying mechanism for both paroxysmal disorders. For example, mutations in the three known genes for familial hemiplegic migraine can cause epilepsy. It is likely that the development of specific drugs aimed at restoring ion-channel function and/or related cellular signalling pathways might benefit patients with epilepsy as well as those with migraine. This review will briefly summarize the clinical, epidemiological, pathophysiological and therapeutic similarities between migraine and epilepsy. Most attention will be paid to the genetic relationship between these two paroxysmal disorders.     

New Insights into the Genetics of Alzheimer's Disease

In early 1993, the genetic data implicating the amyloid precursor protein as one of the loci leading to early onset Alzheimer's disease were reviewed (Hardy and Duff, Annals of Medicine, 25: 437–440), together with the evidence implicating abnormal deposition of beta-amyloid as the initiating point of the process leading to the disease. Since that time, three other genetic loci have been directly implicated in the aetiology of the disease: the apolipoprotein E locus on chromosome 19, the presenilin 1 gene on chromosome 14 and the presenilin 2 gene on chromosome 1. In this article, I review the progress over the last three years and attempt to assess whether the evidence for the amyloid cascade hypothesis still stands scrutiny.     

Family-based association study of chromosome 6p12.2-p21.1 migraine locus

Background.— One of the genome‐wide linkage studies performed in migraine has yielded a significant linkage of migraine (with and without aura) with markers located at 6p12.2‐21.1. This locus (named MIGR3) has not been replicated in the only genome‐wide association scan study performed to date or in previous genome‐wide linkage studies. Objective.— Our objective had been to replicate the MIGR3 locus performing a family‐based association study. Methods.— A sample of 594 subjects belonging to 134 migraine families of diverse complexity underwent genotyping for the markers previously published as linked at 6p12.2‐21.1 migraine locus. Family‐based association test, under different models of inheritance, and also the model‐free TDT analysis were performed. Results.— The best result was obtained with the D6S1650 marker under the additive model (rank [S observed] = 265.0; permuted P = .0006), using family‐based association test program (HBAT subprogram). Similar results were obtained with the model‐free TDTPHASE algorithm (P < .0001, corrected). Nominal significant P values were obtained for D6S1630, D6S452, and D6S257. After correction for multiple testing with the stratified false‐discovery rate, all markers showed significant association (P < .0001). Conclusion.— We corroborated that the MIGR3 locus at 6p12 is a genetic risk for migraine with and without aura. (Headache 2012;52:393‐399)     

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.     

Migraine headache: a review of the molecular genetics of a common disorder

This tutorial summarises the state-of-the-art on migraine genetics and looks at the possible future direction of this field of research. The view of migraine as a genetic disorder, initially based on epidemiological observations of transmission of the condition within families, was subsequently confirmed by the identification of monogenic forms of “syndromic” migraine, such as familial hemiplegic migraine. We are currently witnessing a change in the way genetic analysis is used in migraine research: rather than studying modalities of inheritance in non-monogenic forms of migraine and in the persistent modalities of migraine headache, researchers are now tending to focus on the search for genetic markers of dysfunction in biological systems. One example of the evolution of migraine genetic research is provided by the recent efforts to shed light on the pharmacogenomic mechanisms of drug response in migraineurs. In addition, novel molecular approaches about to be introduced are expected to further increase knowledge on this topic and improve patient management.