Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Sutherland, Heidi G.; Maksemous, Neven; Albury, Cassie L.; Ibrahim, Omar; Smith, Robert A.; Lea, Rod A.; Haupt, Larisa M.; Jenkins, Bronwyn; Tsang, Benjamin; Griffiths, Lyn R.

doi:10.3390/cells9112368

Cited by 21 publications

(38 citation statements)

References 51 publications

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“…Moreover, in a large population of HM patients with no mutation on the main genes (CACNA1A, ATP1A2, or SCN1A), 1.3% of cases presented with a mutation on SLC2A1 and having HM episodes as the main clinical feature (8). Conversely, other studies postulated that SLC2A1 mutations alone might not be sufficient for the development of isolated migraine symptoms and they were not described in patients with HM as a unique clinical manifestation (9).…”

Section: Discussionmentioning

confidence: 99%

“…In the International Classification of Headache Disorders-3, two different HM subtypes are included: familial and sporadic hemiplegic migraine (6). Mutations in the ion transportation genes CACNA1A, ATP1A2, and SCN1A are well-known to cause HM; despite this, mutations in these genes are found in <20% of HM cases (4,8). Other genes with roles in synaptic function and neurotransmission have also been implicated in the pathogenesis of HM and HM-like disorders such as PRRT2 mutations (4,8,9).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the ion transportation genes CACNA1A, ATP1A2, and SCN1A are well-known to cause HM; despite this, mutations in these genes are found in <20% of HM cases (4,8). Other genes with roles in synaptic function and neurotransmission have also been implicated in the pathogenesis of HM and HM-like disorders such as PRRT2 mutations (4,8,9). The management of HM is not specific; among the most commonly used prophylactic and effective treatments, Verapamil, Lamotrigine, Flunarizine, Naloxone, and Acetazolamide are described (4,5).…”

Section: Discussionmentioning

confidence: 99%

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CACNA1A-Linked Hemiplegic Migraine in GLUT 1 Deficiency Syndrome: A Case Report

et al. 2021

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Background: Glucose-transporter-1 deficiency syndrome (GLUT1-DS), due to SLC2A1 gene mutation, is characterized by early-onset seizures, which are often drug-resistant, developmental delay, and hypotonia. Hemiplegic migraine (HM) is a rare form of migraine, defined by headache associated with transient hemiplegia, and can be caused by mutations in either CACNA1A, ATP1A2, or SCN1A. Paroxysmal movements, other transient neurological disorders, or hemiplegic events can occur in GLUT1-DS patients with a mild phenotype.Case: We report on a girl with GLUT1-DS, due to SLC2A1 mutation, with a mild phenotype. In early childhood, she developed epilepsy and mild cognitive impairment, balance disorders, and clumsiness. At the age of 9, the patient reported a first hemiplegic episode, which regressed spontaneously. Over the next 3 years, two similar episodes occurred, accompanied by headache. Therefore, in the hypothesis of HM, genetic testing was performed and CACNA1A mutation was identified. The treatment with Lamotrigine avoided the recurrence of HM episodes.Discussion: To our knowledge, among the several cases of GLUT1-DS with HM symptoms described in the literature, genetic testing was only performed in two of them, which eventually proved to be negative. In all other cases, no other genes except for SLC2A1 were examined. Consequently, our patient would be the first description of GLUT1-DS with HM due to CACNA1A mutation. We would emphasize the importance of performing specific genetic testing in patients with GLUT1-DS with symptoms evocative of HM, which may allow clinicians to use specific pharmacotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CACNA1A-Linked Hemiplegic Migraine in GLUT 1 Deficiency Syndrome: A Case Report

et al. 2021

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“…An alternative approach used to study the complex genetic pathways of this neurological disorder is to examine monogenic subtypes of migraine, 12,27 and there have been a number of multigenerational studies performed on MA pedigrees 29 and unrelated hemiplegic migraine probands. 30,31 Familial Migraine with Aura A study of particular families which show strong inheritance of MA showed that a frameshift mutation of the KCNK18/TRESK gene segregated with migraine diagnosis, suggesting that it was causal. 29 This was further corroborated in a study by Pettingill et al, which demonstrated through the use of CRISPR-Cas9 that frameshift mutations of TRESK are associated with migraine phenotypes.…”

Section: Monogenic Forms Of Migrainementioning

confidence: 99%

“…15,62,63 Several research groups have reported increased diagnostic rates for several neurological diseases, through the use of whole exome sequencing (WES) [64][65][66] and targeted gene panels. [67][68][69] WES analysis has shown that not all suspected HM cases have exonic mutations in the known FHM genes, 30,31 or genes that cause overlapping disorders, which suggests that additional genes or other factors as yet unknown are causative of HM, 12 some of which may be revealed through WES or whole genome sequencing and structural analysis.…”

Section: Hemiplegic Migrainementioning

confidence: 99%

Exploring the Hereditary Nature of Migraine

Bron¹,

Sutherland²,

Griffiths³

2021

NDT

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Migraine is a common neurological disorder which affects 15-20% of the population; it has a high socioeconomic impact through treatment and loss of productivity. Current forms of diagnosis are primarily clinical and can be difficult owing to comorbidity and symptom overlap with other neurological disorders. As such, there is a need for better diagnostic tools in the form of genetic testing. Migraine is a complex disorder, encompassing various subtypes, and has a large genetic component. Genetic studies conducted on rare monogenic subtypes, including familial hemiplegic migraine, have led to insights into its pathogenesis via identification of causal mutations in three genes (CACNA1A, ATP1A2 and SCN1A) that are involved in transport of ions at synapses and glutamatergic transmission. Study of familial migraine with aura pedigrees has also revealed other causal genes for monogenic forms of migraine. With respect to the more common polygenic form of migraine, large genome-wide association studies have increased our understanding of the genes, pathways and mechanisms involved in susceptibility, which are largely involved in neuronal and vascular functions. Given the preponderance of female migraineurs (3:1), there is evidence to suggest that hormonal or X-linked components can also contribute to migraine, and the role of genetic variants in mitochondrial DNA in migraine has been another avenue of exploration. Epigenetic studies of migraine have shown links between hormonal variation and alterations in DNA methylation and gene expression. While there is an abundance of preliminary studies identifying many potentially causative migraine genes and pathways, more comprehensive genomic and functional analysis to better understand mechanisms may aid in better diagnostic and treatment outcomes.

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Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes

et al. 2023

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Hemiplegic migraine (HM) is a rare subtype of migraine with aura. Given that causal missense mutations in the voltage-gated calcium channel α1A subunit gene CACNA1A have been identified in a subset of HM patients, we investigated whether HM patients without a mutation have an increased burden of such variants in the “CACNA1x gene family”. Whole exome sequencing data of an Australian cohort of unrelated HM patients (n = 184), along with public data from gnomAD, as controls, was used to assess the burden of missense variants in CACNA1x genes. We performed both a variant and a subject burden test. We found a significant burden for the number of variants in CACNA1E (p = 1.3 × 10−4), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). There was also a significant burden of subjects with missense variants in CACNA1E (p = 6.2 × 10−3), CACNA1H (p < 2.2 × 10−16) and CACNA1I (p < 2.2 × 10−16). Both the number of variants and number of subjects were replicated for CACNA1H (p = 3.5 × 10−8; p = 0.012) and CACNA1I (p = 0.019, p = 0.044), respectively, in a Dutch clinical HM cohort (n = 32), albeit that CACNA1I did not remain significant after multiple testing correction. Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease.

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Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants

Cited by 21 publications

References 51 publications

CACNA1A-Linked Hemiplegic Migraine in GLUT 1 Deficiency Syndrome: A Case Report

CACNA1A-Linked Hemiplegic Migraine in GLUT 1 Deficiency Syndrome: A Case Report

Exploring the Hereditary Nature of Migraine

Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes

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