Hemiplegic Migraine: Leveraging Genetic Susceptibilities to Identify Treatment Targets
“There have been a number of susceptibility gene variants identified through large case-control consortium studies, and these studies are still ongoing.”
While migraine is often triggered by environmental factors such as stress, impaired sleep, and menstruation, recent findings have shed light on the significant genetic influence associated with the disorder. Monogenic subtypes of migraine are caused by mutations in specific genes, and common migraine, which is mostly polygenic, has been found to cluster in families. There is up to a 4-fold increase in risk in people with a first-degree relative affected by migraines, and twin studies have demonstrated approximately 42% heritability.1,2
“There have been a number of susceptibility gene variants identified through large case-control consortium studies, and these studies are still ongoing,” said Lyn Griffiths, PhD, executive director of the Institute of Health and Biomedical Innovation at Queensland University of Technology in Brisbane, Australia, who co-authored a recent review on the topic of genetic factors in migraine.3 “For rarer subtype forms of migraine, there are some genes already identified that play definite causative roles – particularly with familial hemiplegic migraine,” she told Neurology Advisor.
Familial hemiplegic migraine (FHM) comprises an estimated two-thirds of HM cases and is diagnosed when a patient with HM has at least 1 first- or second-degree relative with the disorder. While it is considered to be monogenic, FHM shows genetic heterogeneity with 70% to 90% penetrance. “The phenotypes of the three FHM subtypes are nearly identical clinically, although overlapping features may vary,” the review noted.3 Family linkage studies have identified 3 main causative genes, which differentiate the following 3 subtypes of FHM: 4
- FHM1 due to mutations in the CACNA1A gene at chromosome (chr) 19p13
This gene “encodes the pore-forming α1 subunit of the neuronal voltage-gated Cav2.1 (P/Q-type) channels,” which are “predominantly localized at the presynaptic terminals of cortical glutamatergic and GABAergic neurons in the cerebral cortex, trigeminal ganglia, brainstem nuclei, and cerebellum, where they play an important role in controlling neurotransmitter release,” the investigators stated.5
Severity of FHM1 varies depending on the causal mutation involved; more than 25 have been reported.6 These typically lead to elevated glutamatergic transmission via increased Ca2+ influx. Models using FHM1 knock-in (KI) mice revealed altered synaptic plasticity, excitatory-inhibitory balance, and calcitonin gene-related peptide (CGRP)-mediated trigeminal pain signaling.
The findings further showed increased susceptibility to cortical spreading depression (CSD), which most likely results from “enhanced synaptic release of glutamate as a result of the Cav2.1 channel gain-of-function mutation selectively affecting glutamatergic neurons, but not GABA-ergic inhibitory interneurons,” as explained in the review.7 Gene expression analysis of both wild-type and mutant brains found CSD-modulated inflammatory processes that “may lead to an increased activation of meningeal nociceptors and trigeminal ganglia and drive the activation of pain-related brain structures to cause migraine headache.”
- FHM2 due to mutations in the ATP1A2 gene at chr 1q23
ATP1A2 encodes the α2 subunit of the Na+/K+ pump in the cell membranes of the central nervous system (CNS), heart, and skeletal and smooth muscle tissue. “In the CNS, it is mainly expressed on astrocytes at tripartite synapses, where it is codistributed with the excitatory amino acid transporter (EAAT) glutamate transporters, and is required for clearance of extracellular K+ and production of the Na+ gradient used in the reuptake of glutamate,” as the paper describes.
More than 80 causal mutations have been associated with FHM2, including roughly 25 of which have also been identified in sporadic hemiplegic migraine (SHM), in which there is no family history of the disorder.8 An overlap has been observed with certain pathologies, including epilepsy or seizures in approximately 15% of cases. Atp1A2 knockout (KO) mice models exhibit alterations in CSD, which was found to result from defective glutamate clearance in W887R heterozygous mice.9
“Collectively these ﬁndings suggest that ATP1A2 mutations in migraine primarily cause a disorder of glutamatergic neurotransmission with defective regulation of the excitatory/inhibitory balance in the brain, which facilitates CSD and downstream effects.”
- FHM3 due to mutations in the SCN1A gene on chr 2q24.66
Less than 5% of diagnosed cases of FHM are due to mutations in SCN1A, the gene that encodes the α1 subunit of the voltage-gated sodium channel Nav1.1, which has a significant role in the production of action potentials. Hundreds of SCN1A mutations have been linked with epilepsy syndromes, including Dravet syndrome and generalized epilepsy with febrile seizures. In addition, epileptic seizures and ataxia have been observed in SCN1A KO mice.10
In FHM3, 10 causal SCN1A mutations have been identified that typically exhibit gain-of-function effect, thought they sometimes exhibit loss-of-function effects or both. Gain-of-function in GABAergic neurons may be most relevant to FHM.11 “As NaV1.1 is the predominant channel in GABAergic interneurons, SCN1A mutations predict increased ﬁring of inhibitory GABAergic neurons, which could lead to higher extracellular potassium concentrations, enhanced glutamate release, and triggering of CSD,” according to the review.
Clinical Implications and Future Directions
“There are currently available diagnostic tests via DNA sequencing that can be used to define these FHM gene mutations, and this information helps in defining the treatment choice for these subtypes,” said Dr Griffiths. However, FHM genes have not been identified in all cases, indicating that there are other associated genes. Dr Griffiths and her colleagues, as well as other researchers, are currently attempting to identify these genes in sequencing studies, while other research is focusing on genes involved in more common migraine types. “The aim of this work is to develop better diagnostics for more targeted treatment choices but also to provide basic information to develop new treatments for migraine,” she emphasized.
- Russell MB, Iselius L, Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia. 1996; 16(5):305-309. doi:10.1046/j.1468-2982.1996.1605305.x
- Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache. 1995; 35(2):70-78.
- Sutherland HG, Griffiths LR. Genetics of migraine: insights into the molecular basis of migraine disorders. Headache. 2017; 57(4):537-569. doi:10.1111/head.13053
- Silberstein SD, Dodick DW. Migraine genetics: part II. Headache. 2013; 53:1218-1229. doi:10.1111/head.12169
- Catterall WA. Structure and function of neuronal Ca21 channels and their role in neurotransmitter release. Cell Calcium. 1998; 24(5-6):307-323.
- de Vries B, Frants RR, Ferrari MD, van den Maagdenberg AM. Molecular genetics of migraine. Hum Genet. 2009; 126(1):115-132. doi:10.1007/s00439-009-0684-z
- Tottene A, Conti R, Fabbro A, et al. Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. Neuron. 2009; 61(5): 762-773. doi:10.1016/j.neuron.2009.01.027
- Friedrich T, Tavraz NN, Junghans C. ATP1A2 mutations in migraine: Seeing through the facets of an ion pump onto the neurobiology of disease. Front Physiol. 2016; 7:239. doi:10.3389/fphys.2016.00239
- Capuani C, Melone M, Tottene A, et al. Defective glutamate and K1 clearance by cortical astrocytes in familial hemiplegic migraine type 2. EMBO Mol Med. 2016; 8(8):967-986. doi:10.15252/emmm.201505944
- Fan C, Wolking S, Lehmann-Horn F, et al. Early-onset familial hemiplegic migraine due to a novel SCN1A mutation. Cephalalgia. 2016; pii:10333102415608360
- Cestele S, Labate A, Rusconi R, et al. Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine. Epilepsia. 2013; 54(5):927-935. doi:10.1111/epi.12123