A case of familial hemiplegic migraine associated with a novel ATP1A2 gene mutation

Hemiplegic migraine constitutes an unusual form, characterized by periodic attacks of migraine with a motor component (hemiplegia). Familial forms are dominantly inherited, and are attributable to mutations in genes encoding proteins involved in ion transportation, including ATP1A2, which codes for the α-2 isoform of the sodium-potassium adenosine triphosphatase, a P-type cation transport adenosine triphosphatase, and responsible for the so-called familial hemiplegic migraine type 2. We describe a 9-year-old boy affected by familial hemiplegic migraine, with a novel ATP1A2 gene mutation (c.1799T>C p.V600A) in exon 13. Long-term treatment with flunarizine resulted in a good clinical response and the prevention of further attacks.     

A novel missense ATP1A2 mutation in a Finnish family with familial hemiplegic migraine type 2

Familial hemiplegic migraine (FHM), a rare autosomal dominant subtype of migraine with aura, has been linked to two chromosomal loci, 19p13 and 1q23. Mutations in the Na⁺,K⁺-ATPase 2 subunit gene, ATP1A2, on 1q23 have recently been shown to cause familial hemiplegic migraine type 2 (FHM2). We sequenced the coding regions of this gene in a Finnish chromosome 1q23-linked FHM family with associated symptoms such as coma and identified a novel A1033G mutation in exon 9. This mutation results in a threonine-to-alanine substitution at codon 345. This residue is located in a highly conserved N-terminal region of the M4–5 loop of the Na⁺,K⁺-ATPase. Furthermore, the T345A mutation co-segregated with the disorder in our family and was not present in 132 healthy Finnish control individuals. For these reasons it is most likely the FHM-causing mutation in this family.     

CACNA1A gene de novo mutation causing hemiplegic migraine, coma, and cerebellar atrophy

Familial hemiplegic migraine is caused by CACNA1A missense mutations in 50% of families, including all families with cerebellar ataxia. A patient with healthy parents, who experienced prolonged attacks of migraine with hemiplegia, coma, and seizures, is reported. The patient also had mental retardation, permanent cerebellar ataxia with cerebellar atrophy, and right-sided brain atrophy. This patient carried a de novo Tyr 1385 Cys mutation in the CACNA1A gene and illustrates a novel phenotype associated with CACNA1A mutations.     

Sporadic hemiplegic migraine and epilepsy associated with CACNA1A gene mutation

Familial hemiplegic migraine (FHM) is a clinically and genetically heterogeneous disease most commonly linked to CACNA1A gene mutation. Epilepsy rarely occurs in FHM and is seen predominantly with specific CACNA1A gene mutations. Here we report a sporadic case of FHM1 linked to S218L CACNA1A gene mutation with the triad of prolonged hemiplegic migraine, cerebellar symptoms, and epileptic seizures. Epilepsy in this syndrome follows the pattern of isolated unprovoked seizures occurring only during childhood and hemiplegic migraine-provoked seizures occurring during adulthood. Clinical and electrographic status epilepticus can occur during prolonged migraine attacks. We suggest that patients with seizures, ataxia, and hemiplegic migraine be genetically tested for FHM. Patients with prolonged hemiplegic migraine attacks and confusion should be tested with continuous EEG recording to ascertain whether electrographic status is occurring, as intensive antiepileptic treatment not only resolves status but immediately stops hemiplegic migraine and improves associated neurological deficits.     

A novel GABRG2 mutation associated with febrile seizures

Mutations in the gene encoding the gamma2 subunit of the gamma-aminobutyric acid type A receptor (GABRG2) have been reported to cause childhood absence epilepsy (CAE), febrile seizures (FS), and generalized epilepsy with FS plus (GEFS+). The authors analyzed GABRG2 in 47 unrelated patients with CAE, FS, and GEFS+ and identified a novel mutation that cosegregated with FS. Electrophysiologic studies demonstrated altered current desensitization and reduced benzodiazepine enhancement in mutant receptors.     

Familial basilar migraine associated with a new mutation in the ATP1A2 gene

Basilar migraine (BM), familial hemiplegic migraine (FHM), and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by motor symptoms, which are absent in BM. Mutations in CACNA1A and ATP1A2 have been found in FHM. The authors detected a novel mutation in the ATP1A2 gene (R548H) in members of a family with BM, suggesting that BM and FHM may be allelic disorders.     

A de novo mutation in sporadic nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy is sometimes due to mutations in CHRNA4. The commoner presentation of sporadic nocturnal frontal lobe epilepsy has not been associated with genetic defects. A 30-year-old woman diagnosed as having sporadic nocturnal frontal lobe epilepsy was found to have a de novo Ser252Leu CHRNA4 mutation. A pattern is emerging of site-specific mutation within the second transmembrane domain of CHRNA4 in association with autosomal dominant nocturnal frontal lobe epilepsy and sporadic nocturnal frontal lobe epilepsy in families with different ethnic backgrounds.     

Mild epileptic phenotype associates with de novo eef1a2 mutation: Case report and review

BackgroundMutations in the elongation factor 1 alpha 2 (EEF1A2) gene have been recently shown to cause epileptic encephalopathy (MIM # 616409 EIEE33) associated with neurodevelopmental disorders such as intellectual disability, autistic spectrum disorder, hypotonia and dysmorphic facial features. EEF1A2 protein is involved in protein synthesis, suppression of apoptosis, regulation of actin function and cytoskeletal structure. To date, only sixteen patients with EEF1A2 mutations have been reported.Case reportWe described a new case, a boy with severe intellectual disability with absent speech, autistic spectrum disorder, mild dysmorphic facial features, failure to thrive and epilepsy associated to a de novo heterozygous missense mutation in EEF1A2 (c.364G>A; p.Glu122Lys) identified by next generation sequencing; it was already reported in other studies. Most clinical features are shared by all individuals with EEF1A2 mutation, but unlike others reports our patient showed a mild epileptic phenotype: epilepsy developed in late infancy and was well-controlled with antiepileptic drugs. Moreover, at the onset of epilepsy, interictal wake/sleep electroencephalograms showed typical pattern that disappeared with age.ConclusionThis report focused that EEF1A2 mutations should be considered not only in patients with epileptic encephalopathy, but also in those with less severe epilepsy. A typical EEG pattern may be a biomarker for EEF1A2 mutation, but further investigations and longitudinal clinical observations are required.