familial hemiplegic migraine ( fhm ) is a rare form of migraine with aura that involves motor aura ( hemiparesis ) and an autosomal dominant classical migraine subtype .
the prevalence of hemiplegic migraine ( hm ) was reported as at least 0.002% for the sporadic form and at least 0.003% for the familial form in denmark ( 1 ) .
we present the first korean family with fhm due to mutation in the cacna1a gene .
a 43-yr - old right - handed man presented to the department of emergency of kangwon national university hospital with suddenly noticed right hemianopia , dysphasia , and dizziness on march 11 , 2010 . when he arrived at the emergency room , global aphasia and vomiting developed .
four and 5 yr before the admission , he had three episodes of right hemiparesis lasting a few hours . at those times , he was evaluated for a suspicion of transient ischemic attack , but without any risk factors for cerebral ischemia mri showed cerebellar atrophy .
thus , he underwent genetic tests for mutations in the sca1 , 2 , 3 , 6 , 7 , 8 , and drpla genes , which were all negative .
he had occasional headaches , the nature of which could not be recalled because those were trivial .
his family history revealed that his mother had suffered from headache and frequent transient hemiparesis , from her 30s to 50s ( fig .
conventional mri and diffusion - weighted imaging ( dwi ) performed when global aphasia developed showed only cerebellar atrophy ( fig .
ct angiography performed during the coma , 3 hr after the current symptom onset , showed mild vasodilation of the intracranial blood vessels and increased vascularity in the left hemisphere ( fig .
perfusion - weighted imaging ( pwi ) showed elevated cerebral blood flow ( cbf ) ( fig . 2c ) .
eeg revealed persistent low - voltage arrhythmic delta activity over the left hemisphere ( fig .
a genetic study of fhm was performed using the samples from the patient and his mother , after obtaining their informed consents .
genomic dna was extracted from the peripheral blood using an instagene matrix kit ( bio - rad , ca , usa ) , according to the manufacturer 's instructions .
the entire coding region of the cacna1a gene on chr 19p13 was amplified via polymerase chain reaction using primer sets described previously and a rotor - gene 6000 thermal cycler .
direct dna sequencing was performed using a bigdye terminator cycle sequencing kit ( applied biosystems , usa ) on an abi prism 3130 genetic analyzer ( applied biosystems ) .
the gene mutation analysis performed in the patient and his mother led to the identification of a heterozygous point mutation ( 1997ct , t666 m ) in the exon 16 of the cacna1a gene .
mild dysarthria and gait disturbance , which had existed before the event , were detected by repeated neurological examinations .
eeg gradually improved , but still showed a small amount of arrhythmic slowing in the left hemisphere , even after 10 days .
we prescribed verapamil preventively and there have been no further attacks for the past 30 months .
fhm1 , which accounts for approximately 50% of fhm cases , is caused by mutations in the cacna1a gene , which encodes the alpha-1 subunit of a high - voltage - gated p / q type calcium channel ( cav2.1 ) ( 2 ) . in familial and sporadic hm ,
the mutation that causes the t666 m substitution is the most common and accounts for 40% of unrelated fhm1 cases ( 3 ) .
previously , only one korean family with symptoms that were suggestive of hm was reported , but without a genetic study ( 4 ) .
a few korean families with different mutations in cacna1a have been reported ; however , they all exhibited episodic ataxia type 2 ( 5 , 6 ) .
cav2.1 channels are located in the presynaptic terminals and in the somatodendritic membranes throughout the brain and play a role in controlling neurotransmitter release .
the various mutations found in this calcium channel gene cause a wide spectrum of symptoms .
fhm1 is associated with mostly missense mutations , whereas ea2 and sca6 are associated with truncating mutations and expansion of a cag repeat , respectively ( 7 ) .
their effects on channel function were suggested to be a gain of function for the fhm1 mutation and a loss of function for the ea2 mutation ( 8) .
however , the phenotypes of fhm1 , ea2 , and sca6 can coexist in a family member ( 7 ) and in single patient ( 9 ) , suggesting that these allelic disorders form a broad disease spectrum .
two thirds of fhm patients experience the cerebellar sign and about 30% of them exhibit cerebellar atrophy ( 10 ) .
this channel varies in type within different brain regions , and the cav2.1 channels are mostly expressed in cerebellar purkinje cells , which account for the progressive cerebellar sign in fhm1 , ea2 , and sca6 ( 8) . the t666 m mutation is particularly associated with the cerebellar symptom and the high incidence of coma ( 2 ) .
the episode of fhm presented here had distinctive features that did not fulfill the ihs diagnostic criteria ( 11 ) , as the patient exhibited prolonged coma without hemiplegia and the absence of subsequent headache .
a review of published cases showed that 38% of hm cases had no attack of hemiplegia ( 12 ) .
one percent of fhm sufferers had no headache , with otherwise typical attacks ( 13 ) .
our patient showed different symptoms between attacks , but left - hemispheric symptoms were always present .
unilateral symptoms may switch between attacks , or the same side may always be affected ( 3 ) .
symptom variability among patients and attacks in a patient may be explained by genetic heterogeneity together with the probable presence of environmental and genetic modifying factors ( 2 , 3 ) .
symptom progression in the order of visual , sensory , motor , aphasic , and basilar disturbances is the common process ( 3 ) , which can be explained by a cortical spreading depression ( csd ) from the visual cortex ( 8) .
eeg during hm attacks usually shows attenuation or slow activities in the symptomatic hemisphere , which differentiates this condition from nonconvulsive seizures . the eeg abnormality outlasting
the symptom in this patient could be the evidence of permanent sequelae of migraine , as well as cerebellar atrophy .
cerebral hemodynamics in fhm has been reported anecdotally by angiography , pwi , or single photon emission computed tomography ( spect ) .
most cases showed vasodilation or hyperperfusion during aura , which can differentiate this condition from ischemia ( 15 - 18 ) .
however , vasoconstriction was reported in a few cases ( 19 , 20 ) . neither the severity of symptoms nor the time point of evaluation explained this discordance .
in addition , many modifying factors may be involved in trigeminovascular activation secondary to electrophysiological dysfunction of neurons .
this is the first report of fhm in a korean family and the only report of perfusion imaging in a genetically identified case .
because fhm is a rare disease , without a suspicion of hm , patients may be misdiagnosed as having transient ischemia , epilepsy , or even conversion disorder .
symptom progression exceeding the vascular territory from the initial visual symptom , absence of hypoperfusion , and electrical suppression differentiate hm from other episodic neurological disorders .
fhm should be one of the differential diagnoses of episodic neurological dysfunction and cerebellar atrophy .
 we report the first korean patient with familial hemiplegic migraine type 1 , with clinical and multimodal imaging findings . a 43-yr - old man was admitted for right hemianopia and aphasia , followed by coma . 
 mri showed only cerebellar atrophy . 
 ct angiography showed mild vasodilation of intracranial blood vessels and increased vascularity in the left hemisphere and perfusion - weighted imaging showed elevated cerebral blood flow . 
 gene analysis of the patient and his mother led to the identification of a heterozygous point mutation ( 1997ct , t666 m ) in exon 16 of the cacna1a gene . 
 familial hemiplegic migraine should be considered in patients with episodic neurological dysfunction with cerebellar atrophy . 
INTRODUCTION
CASE DESCRIPTION
DISCUSSION