Original articleNovel Mutation Confirms Seizure Locus SCN1A is Also Familial Hemiplegic Migraine Locus FHM3
Introduction
Migraine is an extremely common complex polygenic trait, into which a window has recently been opened. Studies on familial hemiplegic migraine (rare inherited Mendelian dominant forms of migraine) provide insights into migraine pathophysiology [1], [2]. Analysis of the normal and pathogenic alleles of genes underlying such rare genetic syndromes is a promising route to the discovery of critical molecular targets that are involved in common disease and against which new drugs can be developed [3].
Familial hemiplegic migraine has been clearly associated with missense mutations in at least two genes: CACNA1A, encoding the α1 subunit of the neuronal P/Q Ca++ channel and giving rise to familial hemiplegic migraine 1 (OMIM #141500), and ATP1A2, encoding the α2 isoform of the major subunit of the Na,K-ATPase and giving rise to familial hemiplegic migraine 2 (OMIM #602481). Together, these two genes account for most cases of familial hemiplegic migraine [2], [4], [5].
The type 2 mutations produce hypomorphic kinetic alterations in Na/K pump function [6], [7], but it remains controversial whether the type 1 mutations are hypermorphic [8] or hypomorphic [9].
The range of disease phenotypes produced by alleles at both of these familial hemiplegic migraine loci is broad, but clearly includes seizures and ataxia, as well as migraine [1], [2], [3], [4], [5], [10], [11], [12]. Alleles of the CACNA1A gene at the familial hemiplegic migraine 1 locus cause a spectrum of diseases, including episodic ataxia type 2 and spinocerebellar ataxia type 6. Also included are many individuals comorbid with familial hemiplegic migraine, ataxia, or seizures. Likewise, ATP1A2 alleles at the familial hemiplegic migraine 2 locus cause a spectrum of diseases, including comorbidity with benign familial infantile convulsions and ataxia.
Recently, the neuronal voltage-gated sodium channel gene SCN1A has also been implicated as a familial hemiplegic migraine locus. An extended disease-associated haplotype covering more than 12 million bases of chromosome 2q24 was detected in three, likely closely related, families segregating the classical familial hemiplegic migraine syndrome [13]. The SCN1A rare mutation G1489K was found within this extended disease haplotype, and the homologous mutation in a related gene, SCN5A was shown to alter channel function, making this mutation a promising etiological candidate for familial hemiplegic migraine-3 [13]. This remains to be proven, however, given the large size of the shared haplotype, the inability to directly express the pathogenic allele for functional analysis, and the existence of only this single pathogenic haplotype, which would be estimated to contain at least 10,000 additional polymorphic variants (taking the HapMap typical frequency of 1/1200 bp).
Mutations of SCN1A, however, have been unambiguously shown to be pathogenic. They were first observed to cause the epilepsy syndrome generalized epilepsy with febrile seizures plus type 2 (OMIM #600235), and now at least a dozen pathogenic alleles causing variants of this syndrome have been recognized, all being missense mutations creating amino acid replacements that do not perturb the critical ion pore region of the channel [14], [15]. Shortly thereafter a rare, very severe dominant seizure syndrome that is also initially associated with febrile seizures but progresses to a malignant myoclonic seizure phenotype, called severe myoclonic epilepsy of infancy (OMIM #607208), proved to be allelic with generalized epilepsy with febrile seizures plus type 2 [16]. Dozens of alleles have now been identified, most being new mutations in SCN1A, and the vast majority being functional null alleles (e.g., frameshift, nonsense), but also including missense mutations within the critical pore domain of the channel [15].
This report presents a three-generation family exhibiting both the broad phenotypic spectrum of the dominant syndromes produced at this locus and also the second SCN1A allele associated with a migraine syndrome similar to those caused at the two other familial hemiplegic migraine loci, securing the assignment of SCN1A itself, not a linked gene, as the familial hemiplegic migraine-3 locus.
Section snippets
Patient 1
A female patient of nonconsanguineous mixed European, French Canadian, Native American, and Mexican ancestry presented at 4 years of age with a history of uncontrolled jerking of the limbs and trunk. The movements were not noticed at birth, but had been observed by the family since at least 2 years of age. The jerking movements were exacerbated by fine motor activity and walking. She has had no recognized seizures. There was no delay of early developmental milestones, however she has been
Results
Both patients were found to be heterozygous for the same novel DNA sequence variant of the SCN1A gene. The novel variant allele was a C→G transversion at nucleotide position 3521, resulting in a threonine-to-serine amino acid change encoded by codon 1174 (T1174S). This is a rare, novel allele not present in the NCBI SNP database (http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=6323) and apparently not previously reported. It occurs in a highly conserved region of the SCN1A protein, with the
Discussion
The novel T1174S allele, and the range of disease phenotypes produced in this three-generation family, exhibits the broad phenotypic spectrum of dominant neuronal hyperexcitability syndromes that even a single allele of this sodium channel gene can produce. The difference in phenotype of patient 1 and 2, although potentially attributable to the well-recognized variant presentation of migraine in children [17], is nonetheless substantial, even though they share the same major pathogenic allele
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2016, Seminars in Pediatric NeurologyCitation Excerpt :It has also been hypothesized that epileptic discharges may lead to lowering of the cortical spreading depression threshold or lead to activation of the trigeminovascular system and subsequent onset of migraine.54-56 There is a growing interest in exploring genetic polymorphisms on chromosome 9, 12, and 14, as well as mutations related to ion channels such as CACNA1A, ATP1A2, and SCN1A, lending susceptibility to both migraine and epilepsy.55,57-64 Nonetheless, the strong association between headache, especially migraine, and epilepsy highlights the importance for the neurologist to always elicit headache history in patients with epilepsy, identify common triggers, and tailor lifestyle modification and pharmacologic management that addresses both.
From focal epilepsy to dravet syndrome –heterogeneity of the phenotype due to SCN1A mutations of the p.Arg1596 amino acid residue in the nav1.1 subunit
2015, Neurologia i Neurochirurgia PolskaCitation Excerpt :Clinical spectrum of SCN1A mutations ranges from febrile seizures and quite benign febrile seizures plus (FS or FS+, MIM 604403), genetic epilepsy with febrile seizures plus (GEFS+, MIM 604403) to severe epilepsy syndromes such as Dravet syndrome (DS, MIM 607208) and intractable childhood epilepsy with generalized tonic–clonic seizures (ICE-GTC) [1]. SCN1A mutations have been also found in single patients with other epilepsy syndromes (e.g. West syndrome [2], Lennox–Gastaut syndrome [3], Rasmussen encephalitis [4] and Panayiotopoulos syndrome [5]) and in rare cases of Familial Hemiplegic Migraine (FHM, MIM 6096345) [6] and Familial Autism [7]. So far more than 1200 different mutations in the SCN1A gene have been identified [according to SCN1A Mutation Database, http://www.gzneurosci.com/scn1adatabase/].
When is a child with status epilepticus likely to have Dravet syndrome?
2014, Epilepsy ResearchCitation Excerpt :The inheritance of SCN1A variants was checked whenever possible, and was mostly de novo in DS patients, except in one boy who had a missense variant (T1174S) inherited from his asymptomatic mother. This variant was already reported in patients with a wide range of phenotypes, including 3 female members of a family with severe migraines (Gargus and Tournay, 2007), and a girl with DS for whom genetic analyses evidenced two variants, one of which, the T1174S, being transmitted by her asymptomatic mother (Le Gal, personal communication). It has also been reported in one unaffected control (cited in SCN1A variant database).
SCN1A Mutation—Beyond Dravet Syndrome: A Systematic Review and Narrative Synthesis
2021, Frontiers in Neurology