Esther E. Kors

Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q‐type calcium channel Cav2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na+,K+‐ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.

Delayed cerebral edema and fatal coma after minor head trauma: Role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine

Trivial head trauma may be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval (“delayed cerebral edema”). Attacks of familial hemiplegic migraine (FHM) can be triggered by minor head trauma and are sometimes accompanied by coma. Mutations in the CACNA1A calcium channel subunit gene on chromosome 19 are associated with a wide spectrum of mutation‐specific episodic and chronic neurological disorders, including FHM with or without coma. We investigated the role of the CACNA1A gene in three subjects with delayed cerebral edema. Two subjects originated from a family with extreme FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema, we found a C‐to‐T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A gene. The mutation was absent in nonaffected family members and 152 control individuals. Haplotype analysis excluded a common founder for both families. Neuropathological examination in one subject showed Purkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the novel S218L mutation in the CACNA1A calcium channel subunit gene is involved in FHM and delayed fatal cerebral edema and coma after minor head trauma. This finding may have important implications for the understanding and treatment of this dramatic syndrome.

Childhood epilepsy, familial hemiplegic migraine, cerebellar ataxia, and a new CACNA1A mutation.

The CACNA1A gene encodes the pore-forming subunit of neuronal P/Q type Ca2+ channels. Mutations in this gene cause a spectrum of neurologic diseases, including familial hemiplegic migraine (FHM) with or without ataxia.1 We report a novel de novo CACNA1A mutation in a Swedish family. Three mutation carriers had FHM and early onset ataxia; additional childhood epilepsy occurred in two . The proband, II-3, is a 54-year-old woman with slowly progressive cerebellar ataxia since childhood and cerebellar atrophy on CT. She was hospitalized at ages 7 and 8 because of decreased consciousness and vomiting for 1 day, starting with a lucid interval after a fall. She experienced four hemiplegic migraine attacks between ages 14 and 30 years and weekly at age 47. Seizures were never observed. Her 32-year-old son (III-5) and 30-year-old daughter (III-6), who have different fathers, showed cerebellar ataxia at age 4. Ataxia is now prominent in both, and brain imaging shows cerebellar atrophy. …

Severe episodic neurological deficits and permanent mental retardation in a child with a novel FHM2 ATP1A2 mutation.

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.

Two de novo mutations in the Na,K-ATPase gene ATP1A2 associated with pure familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine, in which hemiparesis occurs during the aura. The majority of the families carry mutations in the CACNA1A gene on chromosome 19p13 (FHM1). About 20% of FHM families is linked to chromosome 1q23 (FHM2), and has mutations in the ATP1A2 gene, encoding the α2-subunit of the Na,K-ATPase. Mutation analysis in a Dutch and a Turkish family with pure FHM revealed two novel de novo missense mutations, R593W and V628M, respectively. Cellular survival assays support the hypothesis that both mutations are disease-causative. The identification of the first de novo mutations underscores beyond any doubt the involvement of the ATP1A2 gene in FHM2.

Recent findings in headache genetics

Purpose of reviewThe progress in headache genetics, especially migraine genetics, recently jumped ahead with some major discoveries. Recent findingsFamily and epidemiological studies further strengthen the genetic contribution to migraine and two recent observations gave new molecular insights in the disease. Studies on the genetics of familial hemiplegic migraine revealed, in addition to the previously identified familial hemiplegic migraine type 1 gene CACNA1A on chromosome 19, the familial hemiplegic migraine type 2 gene ATP1A2, encoding the α2-subunit of sodium/potassium pumps. Recent genome screens in families with migraine identified susceptibility loci on chromosomes 4, 6, 11 and 14. SummaryThe findings in familial hemiplegic migraine confirm that dysfunction in ion transport is a key factor in migraine pathophysiology and might help us in the elucidation of migraine molecular pathways. The identification of several migraine susceptibility loci underline its genetically complex nature.

Calcium channel mutations and migraine

&NA; An increasing number of mutations in the CACNA1A gene have been identified, which are associated with a broad clinical spectrum, including familial hemiplegic migraine. Transfection studies and mouse model analyses are currently being undertaken to study the correlation between CACNA1A mutations and disease. Curr Opin Neurol 15:311‐316.

Episodic ataxia type 2: Three novel truncating mutations and one novel missense mutation in the CACNA1A gene

Abstract. We analysed the CACNA1A gene, located on chromosome 19p13, in three unrelated families and one sporadic case with episodic ataxia type 2 (EA–2). In two of the families and the sporadic patient, novel truncating mutations, which disrupt the reading frame and result in a premature stop of the CACNA1A protein, were identified in exons 14, 16 and 26. In the remaining family, a novel missense mutation (H253Y) was found. Of the twenty two EA–2 mutations identified thus far, including those of the present study, seventeen are truncating mutations and five are missense mutations, all resulting in an EA–2 clinical phenotype.

The 3p21.1-p21.3 hereditary vascular retinopathy locus increases the risk for Raynaud's phenomenon and migraine

Previously, we described a large Dutch family with hereditary vascular retinopathy (HVR), Raynauds phenomenon and migraine. A locus for HVR was mapped on chromosome 3p21.1-p21.3, but the gene has not yet been identified. The fact that all three disorders share a vascular aetiology prompted us to study whether the HVR haplotype also contributed to Raynauds phenomenon and migraine in this family. Whereas the parent-child transmission disequilibrium test (TDT) did not reach significance, the sibling TDT revealed that the HVR haplotype harbours a susceptibility factor for Raynauds phenomenon and migraine. Identification of the HVR gene will improve the understanding of the pathophysiology of HVR, Raynauds phenomenon and migraine.

Premature stop codons in a facilitating EF-hand splice variant of CaV2.1 cause episodic ataxia type 2

Premature stop codons in CACNA1A, which encodes the alpha(1A) subunit of neuronal P/Q-type (Ca(V)2.1) Ca(2+) channels, cause episodic ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca(V)2.1-mediated Ca(2+) currents. We identified three novel heterozygous stop codon mutations associated with EA2 in an alternately spliced exon (37A), which encodes part of an EF-hand motif required for Ca(2+)-dependent facilitation. One family had a C to G transversion (Y1854X). A dinucleotide deletion results in the same premature stop codon in a second family, and a further single nucleotide change leads to a different truncation (R1858X) in a de novo case of EA2. Expression studies of the Y1854X mutation revealed loss of Ca(V)2.1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca(V)2.1 channels.