A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.
OBJECTIVE
To search for mutations in the calcium channel gene CACNA1A and to study the genotype-phenotype correlation in a family with a severe familial hemiplegic migraine (FHM) phenotype and a slowly progressive cerebellar ataxia.


BACKGROUND
CACNA1A gene mutations on chromosome 19 are involved in approximately 50% of FHM families. The association of FHM and cerebellar ataxia has been reported in a small number of FHM families, all linked to chromosome 19.


METHODS
The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days. She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI. Linkage analysis was performed and the whole CACNA1A gene, 47 exon-intron boundaries, was analyzed by double gradient-denaturing gradient gel electrophoresis (DG-DGGE).


RESULTS
Genetic studies suggested linkage to chromosome 19p13, and DG-DGGE analysis detected a heteroduplex fragment in exon 13 of the CACNA1A gene. By direct sequencing, a G-to-A substitution resulting in an arginine to glutamine change at codon 583 in the second putative voltage sensor domain of the channel alpha1A-subunit, was identified, possibly representing the disease-causing mutation. The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia.


CONCLUSIONS
The combination of episodic dysfunction and permanent deficit could depend on the variety of functions of calcium channels and their distribution in the nervous system.
Institute of Neurological Sciences, University of Siena, Italy. battistinis@unisi.it
S
S
Battistini
S
S
Stenirri
M
M
Piatti
C
C
Gelfi
P G
PG
Righetti
R
R
Rocchi
F
F
Giannini
N
N
Battistini
G C
GC
Guazzi
M
M
Ferrari
P
P
Carrera
D000086:Acetazolamide / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000473:pathology; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003292:Convulsants / Q000627:therapeutic use*; D005091:Exons; D005260:Female; D006429:Hemiplegia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007438:Introns; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011817:Rabbits; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D020864:Calcium Channels, N-Type
D000086:Acetazolamide; D015220:Calcium Channels; D003292:Convulsants; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type