ABSTRACT
BACKGROUND: Familial (FHM) and sporadic (SHM) hemiplegic migraine are severe subtypes of migraine associated with transient hemiparesis. For FHM, three genes have been identified encoding subunits of a calcium channel (CACNA1A), a sodium-potassium pump (ATP1A2), and a sodium channel (SCN1A). Their role in SHM is unknown. Establishing a genetic basis for SHM may further the understanding of its pathophysiology and relationship with common types of migraine. It will also facilitate the often difficult differential diagnosis from other causes of transient hemiparesis. METHODS: We systematically scanned 39 well-characterized patients with SHM without associated neurologic features for mutations in the three FHM genes. Functional assays were performed for all new sequence variants. RESULTS: Sequence variants were identified in seven SHM patients: one CACNA1A mutation, five ATP1A2 mutations, and one SCN1A polymorphism. All six mutations caused functional changes in cellular assays. One SHM patient later changed to FHM because another family member developed FHM attacks. CONCLUSION: We show that FHM genes are involved in at least a proportion of SHM patients without associated neurologic symptoms. Screening of ATP1A2 offers the highest likelihood of success. Because FHM gene mutations were also found in family members with "nonhemiplegic" typical migraine with and without aura, our findings reinforce the hypothesis that FHM, SHM, and "normal" migraine are part of a disease spectrum with shared pathogenetic mechanisms.
Subject(s)
Calcium Channels/analysis , Migraine Disorders/genetics , Nerve Tissue Proteins/analysis , Sodium Channels/analysis , Sodium-Potassium-Exchanging ATPase/analysis , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Codon, Nonsense , Genetic Testing , Germany , Humans , Mutation, Missense , NAV1.1 Voltage-Gated Sodium Channel , Netherlands , United StatesABSTRACT
OBJECTIVE: Attacks of familial hemiplegic migraine (FHM) are usually associated with transient, completely reversible symptoms. Here, we studied the ATP1A2 FHM2 gene in a young girl with episodes of both very severe and transient neurological symptoms that were triggered by mild head trauma as well as permanent mental retardation. Her family members suffered from hemiplegic and confusional migraine attacks. METHODS: Mutation analysis of the ATP1A2 gene was performed by direct sequencing of all exons and flanking intronic regions, using genomic DNA of the proband. Functional consequences of the mutation were analyzed by cellular survival assays. RESULTS: We identified a novel G615R ATP1A2 mutation in the proband and several of her family members. Functional analysis of mutant Na,K-ATPase in cellular survival assays showed a complete loss-of-function effect. INTERPRETATION: Permanent mental retardation in children may be caused by ATP1A2 mutations.
Subject(s)
Intellectual Disability/genetics , Migraine with Aura/genetics , Mutation , Sodium-Potassium-Exchanging ATPase/genetics , Arginine/genetics , Blotting, Northern/methods , Blotting, Western/methods , Child , DNA Mutational Analysis/methods , Electroencephalography/methods , Female , Gene Expression/physiology , Glycine/genetics , HeLa Cells , Humans , Intellectual Disability/pathology , Magnetic Resonance Imaging/methods , Migraine with Aura/pathology , Migraine with Aura/physiopathology , Mutagenesis/physiology , Transfection/methodsABSTRACT
Benign familial infantile convulsions (BFIC) is an autosomal dominantly inherited partial epilepsy syndrome of early childhood with remission before the age of 3 years. The syndrome has been linked to loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q in various families. The aim of this study was to identify the responsible locus in four unrelated Dutch families with BFIC. Two of the tested families had pure BFIC; in one family, affected individuals had BFIC followed by paroxysmal kinesigenic dyskinesias at later age, and in one family, BFIC was accompanied by later-onset focal epilepsy in older generations. Linkage analysis was performed for the known loci on chromosomes 1q23, 2q24, 16p12-q12, and 19q. The two families with pure BFIC were linked to chromosome 16p12-q12. Using recombinants from these and other published families, the chromosome 16-candidate gene region was reduced from 21.4 Mb (4.3 cm) to 2.7 Mb (0.0 cm). For the other two families, linkage to any of the known loci was unlikely. In conclusion, we confirm the linkage of pure BFIC to chromosome 16p12-q12, with further refinement of the locus. Furthermore, the lack of involvement of the known loci in two of the families indicates further genetic heterogeneity for BFIC.
