ORPHA: 569; DO: 0111183;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q24.3 | Migraine, familial hemiplegic, 3 | 609634 | Autosomal dominant | 3 | SCN1A | 182389 |
A number sign (#) is used with this entry because familial hemiplegic migraine-3 (FHM3) is caused by heterozygous mutation in the SCN1A gene (182389) on chromosome 2q24.
Mutations in the SCN1A gene also result in generalized epilepsy with febrile seizures plus (GEFS+; 604233).
Familial hemiplegic migraine-3 (FHM3) is a severe subtype of migraine with aura characterized by some degree of hemiparesis during the attacks (Dichgans et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of FHM, see FHM1 (141500).
Dichgans et al. (2005) reported 3 unrelated families of European origin with a form of autosomal dominant FHM. Age at onset ranged from 6 to 15 years, and the episodes were associated with variable features of nausea, vomiting, photophobia, and phonophobia. Three patients also had seizures during infancy.
Le Fort et al. (2004) reported a Swiss family in which FHM segregated with what the authors termed 'elicited repetitive daily blindness' (ERDB). The 43-year-old proband reported 3 to 10 daily episodes of transient blindness since infancy. The episodes were commonly provoked by sudden changes of light intensity, orthostasis, or pressure on the eyelid; unilateral stimulation provoked an ipsilateral response, and bilateral stimulation provoked a response of both eyes. He also had episodes of classic FHM since adolescence, with unilateral sensory symptoms and weakness followed by migraine headaches. There was no temporal relationship between the FHM episodes and the ERDB. Three additional family members with ERDB also had FHM, and 2 members of a previous generation reportedly had FHM in isolation. The FHM in this family was unremarkable in itself, but was distinguished by its association with ERDB and childhood epilepsy. During childhood, the proband and his youngest daughter had idiopathic epilepsy with partial complex seizures and secondary generalization, which converted with time into FHM.
Vahedi et al. (2009) reported a 3-generation French family with FHM3. The proband was an 18-year-old woman with FHM since age 6. She also had episodes of elicited repetitive daily blindness since age 6 that occurred independently from the FHM attacks. Pupillary reflexes were absent during the ERDB episodes, but normal between episodes. Her mother and sister had FHM without EDRB episodes.
The transmission pattern of FHM3 in the family reported by Dichgans et al. (2005) was consistent with autosomal dominant inheritance.
By genomewide linkage analysis of 3 families with FHM, Dichgans et al. (2005) identified a disease locus on chromosome 2q24 (maximum multipoint lod score of 5.9 between markers D2S2330 and D2S399). Haplotype analysis suggested a founder effect, and the candidate interval was refined to a 12.6-Mb region. The locus was designated FHM3 (Goadsby and Kullmann, 2005).
In affected members of 3 European families with FHM3, Dichgans et al. (2005) identified a heterozygous mutation in the SCN1A gene (182389.0012).
In affected members of 2 unrelated families with FHM3 associated with elicited repetitive daily blindness, Vahedi et al. (2009) identified respective heterozygous mutations in the SCN1A gene (182389.0021 and 182389.0022). One of the families had been reported by Le Fort et al. (2004). Vahedi et al. (2009) noted that ERDB has features of spreading depression, with propagation of the darkness from the periphery to the center and a refractory period.
Dichgans, M., Freilinger, T., Eckstein, G., Babini, E., Lorenz-Depiereux, B., Biskup, S., Ferrari, M. D., Herzog, J., van den Maagdenberg, A. M. J. M., Pusch, M., Strom, T. M. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet 366: 371-377, 2005. [PubMed: 16054936] [Full Text: https://doi.org/10.1016/S0140-6736(05)66786-4]
Goadsby, P. J., Kullmann, D. M. Another migraine gene. Lancet 366: 345-346, 2005. [PubMed: 16054921] [Full Text: https://doi.org/10.1016/S0140-6736(05)66787-6]
Le Fort, D., Safran, A. B., Picard, F., Bochardy, I., Morris, M. A. Elicited repetitive daily blindness: a new familial disorder related to migraine and epilepsy. Neurology 63: 348-350, 2004. [PubMed: 15277634] [Full Text: https://doi.org/10.1212/01.wnl.0000130251.59422.b4]
Vahedi, K., Depienne, C., Le Fort, D., Riant, F., Chaine, P., Trouillard, O., Gaudric, A., Morris, M. A., LeGuern, E., Tournier-Lasserve, E., Bousser, M.-G. Elicited repetitive daily blindness: a new phenotype associated with hemiplegic migraine and SCN1A mutations. Neurology 72: 1178-1183, 2009. [PubMed: 19332696] [Full Text: https://doi.org/10.1212/01.wnl.0000345393.53132.8c]