A G301R Na+/K+ -ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs.
Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na+/K+ -ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.
Department of Neurological Sciences, 1st Medical School, La Sapienza University, Rome, Italy.
Maria
M
Spadaro
Simona
S
Ursu
Frank
F
Lehmann-Horn
Liana
L
Veneziano
Veneziano
V
Liana
Giovanni
G
Antonini
Antonini
A
Giovanni
Paola
P
Giunti
Giunti
G
Paola
Marina
M
Frontali
Karin
K
Jurkat-Rott
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000473:pathology*; D002648:Child; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D020325:Migraine with Aura / Q000175:diagnosis / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*; D013696:Temperature; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon; D014057:Tomography, X-Ray Computed
D005819:Genetic Markers; C498531:ATP1A2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase