Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene

Roth, Christian; Freilinger, Tobias; Kirovski, Georgi; Dunkel, Juliane; Shah, Yogesh P.; Wilken, Bernd; Rautenstrauß, Bernd; Ferbert, A.

doi:10.1177/0333102413506128

Cited by 20 publications

(11 citation statements)

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“…The pump is mainly expressed on astrocytes at tripartite synapses in the CNS, and its function in the clearance of extracellular K + and production of a Na + gradient used in the reuptake of glutamate, is important to its role in HM [63]. ATP1A2 mutations (FHM2) are usually inherited in an autosomal dominant pattern, and patients have a wide clinical spectrum [62, 64], which includes neurological disorders such as alternating hemiplegia of childhood [65], epilepsy [66], seizures [67], and permanent mental retardation [68, 69], as well as neuromuscular periodic paralysis disorders [70] and recurrent coma and fever [71], secondary to recurrent FHM-like attacks. > 80 causal variants have been linked to FHM2, with ~ 25 diagnosed in sporadic cases, suggesting that de novo mutations are common at the ATP1A2 locus [62].…”

Section: Main Textmentioning

confidence: 99%

Advances in genetics of migraine

2019

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BackgroundMigraine is a complex neurovascular disorder with a strong genetic component. There are rare monogenic forms of migraine, as well as more common polygenic forms; research into the genes involved in both types has provided insights into the many contributing genetic factors. This review summarises advances that have been made in the knowledge and understanding of the genes and genetic variations implicated in migraine etiology.FindingsMigraine is characterised into two main types, migraine without aura (MO) and migraine with aura (MA). Hemiplegic migraine is a rare monogenic MA subtype caused by mutations in three main genes - CACNA1A, ATP1A2 and SCN1A - which encode ion channel and transport proteins. Functional studies in cellular and animal models show that, in general, mutations result in impaired glutamatergic neurotransmission and cortical hyperexcitability, which make the brain more susceptible to cortical spreading depression, a phenomenon thought to coincide with aura symptoms. Variants in other genes encoding ion channels and solute carriers, or with roles in regulating neurotransmitters at neuronal synapses, or in vascular function, can also cause monogenic migraine, hemiplegic migraine and related disorders with overlapping symptoms. Next-generation sequencing will accelerate the finding of new potentially causal variants and genes, with high-throughput bioinformatics analysis methods and functional analysis pipelines important in prioritising, confirming and understanding the mechanisms of disease-causing variants.With respect to common migraine forms, large genome-wide association studies (GWAS) have greatly expanded our knowledge of the genes involved, emphasizing the role of both neuronal and vascular pathways. Dissecting the genetic architecture of migraine leads to greater understanding of what underpins relationships between subtypes and comorbid disorders, and may have utility in diagnosis or tailoring treatments. Further work is required to identify causal polymorphisms and the mechanism of their effect, and studies of gene expression and epigenetic factors will help bridge the genetics with migraine pathophysiology.ConclusionsThe complexity of migraine disorders is mirrored by their genetic complexity. A comprehensive knowledge of the genetic factors underpinning migraine will lead to improved understanding of molecular mechanisms and pathogenesis, to enable better diagnosis and treatments for migraine sufferers.

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Section: Main Textmentioning

confidence: 99%

Advances in genetics of migraine

2019

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“…50–53 ATP1A2 mutations have also been demonstrated in familial epilepsy and hemiplegic migraine syndromes. 54 Patients with mutations in CACNA1A have an increasingly broad spectrum of phenotypes, including reports of acute onset of hemiplegic episodes after minor head trauma. 55 …”

Section: Differential Diagnosismentioning

confidence: 99%

The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Sweney

Newcomb

Swoboda

2015

Pediatric Neurology

131

114

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“…With respect to the known FHM genes, CACNA1A (HFM1) is mostly associated with cerebellar signs, ataxia, dysarthria, and nystagmus and possible neurological damage, such ascerebral atrophy, whereas ATP1A2 mutations (HFM2) have been found in some patients with severe symptoms including prolonged (up to several weeks), motor deficit and sometimes coma and epilepsy or cognitive deficits [4].…”

Section: Discussionmentioning

confidence: 99%

Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy

et al. 2020

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An Italian family with familial hemiplegic migraine (FHM) with the absence of mutations in the known genes associated with this disorder, namely ATP1A2, ATP1A3, CACNA1A, and SCN1A, has recently been reported. Soon afterward, whole exome sequencing allowed the identification of the carrier status of a heterozygous ATP1A4 mutation c.1798 C >T, in four affected members of this family. Here we compare the clinical symptoms of the affected family members with those from the other FHM families linked to mutations in the known genes associated with this disorder. A further two-year follow-up, including clinical response to carbamazepine administered to the proband and the maternal grandmother due to a worsening of the migraine symptoms, is reported. The clinical condition of the proband’s brother, carrying the same mutation and suffering from congenital ventricular and supraventricular extrasystoles, isdiscussed as well.

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Clinical spectrum in three families with familial hemiplegic migraine type 2 including a novel mutation in the ATP1A2 gene

Abstract: Clinical symptoms may last for several weeks in some patients. Patients with FHM2 may also present without hemiplegia. Therefore, the full family history has to be taken into account to establish the diagnosis of FHM.

Cited by 20 publications

References 9 publications

Advances in genetics of migraine

Advances in genetics of migraine

The Expanding Spectrum of Neurological Phenotypes in Children With ATP1A3 Mutations, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia-Parkinsonism, CAPOS and Beyond

Familial Hemiplegic Migraine with an ATP1A4 Mutation: Clinical Spectrum and Carbamazepine Efficacy

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