In the genetic forms of hemiplegic migraine, three genes have been identified: CACNA1A coding for a calcium channel located on chromosome 19, ATP1A2 coding for a sodium/potassium pump on chromosome 1 and SCN1A coding for a sodium channel located on chromosome 2.
In certain cases, however, the mutation appears de novo in a patient although neither of the parents is a carrier. These are sporadic but genetic forms of the disease.
All FHM families in which there is a cerebellar ataxia are linked to chromosome 19; in approximately 50% of cases, the disease is linked to a mutation in position 666 in the CACNA1A protein (T666M); in other cases, the mutations reported in the literature to date are located in the parts of the gene coding for segments S4, S5 or S6 or the P-loop in CACNA1A.
In families suffering from pure FHM without ataxia , approximately one-third are linked to chromosome 19 (and the mutations reported in the literature to date are also located in the part of the gene coding for segments S4, S5 or S6 or the P-loop in CACNA1A). Other families (some 20% of cases) are linked to chromosome 1 (the ATP1A2 gene) and data available at the present time shows that the mutations observed in these patients are mainly nonsense mutations spread over the entire ATP1A2 gene. The percentage of forms linked to a mutation of the SCN1A gene is not known but the initial data indicates that this gene is very rarely implicated in FHM.
To meet the demand from clinicians confronted with atypical forms of FHM, our laboratory has introduced routine sequencing of the areas of the CACNA1A gene implicated in FHM (exons coding for segments S4, S5 and S6 and the P-loop) and comprehensive sequencing of the ATP1A2 gene. Because of the existence of other FHM genes which have not yet been identified, the proposed molecular screening does not provide 100% sensitivity and patients and families should be informed of this fact.
In our experience of diagnostic practice over the past 5 years, we have not revealed any mutation in the CACNA1A and ATP1A2 genes in patients who have their first hemiplegic migraine attack after the age of 20 and who have no relatives similarly affected.
The essentially missense nature of the mutation (replacement of one amino acid by another) sometimes makes it difficult to interpret the results and the distinction between a pathogen mutation and a benign polymorphism. Evidence of the "de novo" character of this amino acid change (change present in the patient but absent from the 2 parents) or its presence in the parent affected may then be a very important factor in reaching a conclusion. This is why we always request blood samples from both parents of an affected child.
The SCN1A gene (implicated in certain forms of epilepsy) can be screened in the genetics laboratory in the Pitié Salpétrière Hospital.