Genetic heterogeneity in Italian families with familial hemiplegic migraine.
OBJECTIVE
To verify linkage to chromosome 19p13, to detect mutations in the CACNA1A gene, and to correlate genetic results to their clinical phenotypes in Italian families with familial hemiplegic migraine (FHM).


BACKGROUND
FHM is an autosomal dominant disease, classified as a subtype of migraine with aura. Only a proportion of FHM patients have been associated with chromosome 19p13. Among these, four missense mutations within the CACNA1A gene in five unrelated families have been described.


METHODS
A linkage study was performed in 19 patients affected by FHM from five families by studying microsatellite markers associated with the 19p13 region. All familial and seven additional sporadic patients with FHM were analyzed to search for mutations within the CACNA1A gene by applying the double gradient-denaturant gradient electrophoresis technique.


RESULTS
Lod score values did not establish significantly linkage to chromosome 19. However, seven new genetic variants were detected: six were new polymorphisms. The seventh was a missense mutation present in family 1, and it was associated with a hemiplegic migraine phenotype without unconsciousness and cerebellar ataxia. Because this missense mutation is absent in the general population and cosegregates with the disease, it may be a pathologic mutation.


CONCLUSIONS
Genetic heterogeneity of FHM has been shown in familial and sporadic FHM patients of Italian origin. The new missense mutation-G4644T-is associated with milder clinical features compared with typical FHM.
IRCCS H San Raffaele, Laboratorio Biologia Molecolare Clinica, Italy. carrera.paola@hsr.it
P
P
Carrera
M
M
Piatti
S
S
Stenirri
L M
LM
Grimaldi
E
E
Marchioni
M
M
Curcio
P G
PG
Righetti
M
M
Ferrari
C
C
Gelfi
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015220:Calcium Channels / Q000235:genetics*; D002524:Cerebellar Ataxia; D002648:Child; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D004247:DNA / Q000097:blood; D005091:Exons; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006429:Hemiplegia / Q000235:genetics*; D006801:Humans; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008881:Migraine Disorders / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011817:Rabbits; D051381:Rats; D016415:Sequence Alignment; D020864:Calcium Channels, N-Type
D015220:Calcium Channels; D004247:DNA; D005819:Genetic Markers; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C491367:Cacna1a protein, rat