|Familial hemiplegic migraine with prolonged coma and cerebellar atrophy: CACNA1A T666M mutation in a Korean family.|
|Jump to Full Text|
|PMID: 22969264 Owner: NLM Status: MEDLINE|
|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 (1997C→T, T666M) in exon 16 of the CACNA1A gene. Familial hemiplegic migraine should be considered in patients with episodic neurological dysfunction with cerebellar atrophy.|
|Kyung-Ho Choi; Jang Su Kim; Seo-Young Lee; Suk-won Ryu; Sam Su Kim; Seung-hwan Lee; Sunghun Kim; Hee-Kwon Park|
Related Documents :
|24873084 - High prevalence of anterolateral ligament abnormalities in magnetic resonance images of...
25021744 - Pth-055 uss small bowel for crohn's disease - single centre experience in medium size...
23111694 - Registry for the evaluation of the prognostic value of a novel integrated imaging appro...
24360724 - Vulnerable atherosclerotic carotid plaque evaluation by ultrasound, computed tomography...
16715954 - Fdg pet scan in a primitive neuroectodermal tumor.
7949564 - Successful medical treatment of a spinal histoplasmoma.
|Type: Case Reports; Journal Article Date: 2012-08-22|
|Title: Journal of Korean medical science Volume: 27 ISSN: 1598-6357 ISO Abbreviation: J. Korean Med. Sci. Publication Date: 2012 Sep|
|Created Date: 2012-09-12 Completed Date: 2013-01-16 Revised Date: 2013-07-11|
Medline Journal Info:
|Nlm Unique ID: 8703518 Medline TA: J Korean Med Sci Country: Korea (South)|
|Languages: eng Pagination: 1124-7 Citation Subset: IM|
|Department of Neurology, College of Medicine, Kangwon National University Hospital, Chuncheon, Korea.|
|APA/MLA Format Download EndNote Download BibTex|
Asian Continental Ancestry Group
Atrophy / genetics, metabolism
Calcium Channels / genetics*
Cerebellum / blood supply, pathology*
Coma / diagnosis*
Magnetic Resonance Imaging
Migraine with Aura / diagnosis*, genetics
Republic of Korea
Tomography, X-Ray Computed
|0/CACNA1A protein, human; 0/Calcium Channels|
Journal ID (nlm-ta): J Korean Med Sci
Journal ID (iso-abbrev): J. Korean Med. Sci
Journal ID (publisher-id): JKMS
Publisher: The Korean Academy of Medical Sciences
© 2012 The Korean Academy of Medical Sciences.
Received Day: 07 Month: 2 Year: 2012
Accepted Day: 25 Month: 5 Year: 2012
Print publication date: Month: 9 Year: 2012
Electronic publication date: Day: 22 Month: 8 Year: 2012
Volume: 27 Issue: 9
First Page: 1124 Last Page: 1127
PubMed Id: 22969264
|Familial Hemiplegic Migraine with Prolonged Coma and Cerebellar Atrophy: CACNA1A T666M Mutation in a Korean Family|
|Jang Su Kim2*|
|Sam Su Kim4|
1Department of Neurology, College of Medicine, Kangwon National University Hospital, Chuncheon, Korea.
2Department of Laboratory Medicine & Genetics, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Korea.
3Department of Laboratory Medicine, College of Medicine, Kangwon National University Hospital, Chuncheon, Korea.
4Department of Radiology, College of Medicine, Kangwon National University Hospital, Chuncheon, Korea.
5Department of Neurology, College of Medicine, Inha University Hospital, Incheon, Korea.
Address for Correspondence: Sunghun Kim, MD. Department of Neurology, Kangwon National University Hospital, 156 Baengnyeong-ro, Chuncheon 200-722, Korea. Tel: +82.33-258-2430, Fax: +82.33-258-2103, firstname.lastname@example.org
[equal] *Kyung-Ho Choi and Jang Su Kim contributed equally to this work.
Familial hemiplegic migraine (FHM) is a rare form of migraine with aura that involves motor aura (hemiparesis) and an autosomal dominant classical migraine subtype. It can manifest with various neurological symptoms that are indistinguishable from stroke or seizure. 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). In Korea, genetically confirmed HM has not been reported. Here, 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. Subsequently, he became stuporous. Hemiparesis was not observed throughout the episode. 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. 1). Conventional MRI and diffusion-weighted imaging (DWI) performed when global aphasia developed showed only cerebellar atrophy (Fig. 2A). 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. 2B). 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. 3). A cerebrospinal fluid study revealed no abnormalities.
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 (1997C→T, T666M) in the exon 16 of the CACNA1A gene.
He recovered gradually over the following 4 days. Mild dysarthria and gait disturbance, which had existed before the event, were detected by repeated neurological examinations. Repeated PWI performed 10 days after recovery returned to normal. 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.
There are three known types and corresponding loci of FHM. 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, more than 30 mutations have been identified in the CACNA1A gene. The mutation that causes the T666M 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 T666M 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). Coma affected up to a third of patients with FHM1 (3). One percent of FHM sufferers had no headache, with otherwise typical attacks (13). Aura might persist for weeks (14). 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). Symptom progression exceeding the vascular territory is a differentiating item from ischemia.
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. No cases were identified genetically. We postulate that there can be heterogeneous pathophysiological abnormalities in these cases. 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.
This study is supported by 2011 Kangwon National University Hospital Grant.
|1.||Thomsen LL,Eriksen MK,Roemer SF,Andersen I,Olesen J,Russell MB. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteriaBrainYear: 20021251379139112023326|
|2.||Ducros A,Denier C,Joutel A,Cecillon M,Lescoat C,Vahedi K,Darcel F,Vicaut E,Bousser MG,Tournier-Lasserve E. The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal calcium channelN Engl J MedYear: 2001345172411439943|
|3.||Russell MB,Ducros A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and managementLancet NeurolYear: 20111045747021458376|
|4.||Sa-Kong Y,Lee BH,Bae SN,Lee KW,Nam SO. A case of familial hemiplegic migraineJ Korean Child Neurol SocYear: 200311367371|
|5.||Kim JM,Kim JS,Ki CS,Jeon BS. Episodic ataxia type 2 due to a deletion mutation in the CACNA1A gene in a Korean familyJ Clin NeurolYear: 2006226827120396531|
|6.||Koh SH,Kim HT,Kim SH,Lee GY,Kim J,Kim MH. Spinocerebellar ataxia type 6 and episodic ataxia type 2 in a Korean familyJ Korean Med SciYear: 20011680981311748369|
|7.||Romaniello R,Zucca C,Tonelli A,Bonato S,Baschirotto C,Zanotta N,Epifanio R,Righini A,Bresolin N,Bassi MT,et al. A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutationJ Neurol Neurosurg PsychiatryYear: 20108184084320682717|
|8.||Pietrobon D,Striessnig J. Neurobiology of migraineNat Rev NeurosciYear: 2003438639812728266|
|9.||Mullner C,Broos LA,van den Maagdenberg AM,Striessnig J. Familial hemiplegic migraine type 1 mutations K1336E, W1684R, and V1696I alter Cav2.1 Ca2+ channel gating: evidence for beta-subunit isoform-specific effectsJ Biol ChemYear: 2004279518445185015448138|
|10.||Vincent M,Hadjikhani N. The cerebellum and migraineHeadacheYear: 20074782083317578530|
|11.||Headache Classification Subcommittee of the International Headache SocietyThe International Classification of Headache Disorders: 2nd editionCephalalgiaYear: 200424Suppl 1916014979299|
|12.||Bradshaw P,Parsons M. Hemiplegic migraine, a clinical studyQ J MedYear: 196534658514252427|
|13.||Kirchmann M. Migraine with aura: new understanding from clinical epidemiologic studiesCurr Opin NeurolYear: 20061928629316702837|
|14.||Thomsen LL,Ostergaard E,Olesen J,Russell MB. Evidence for a separate type of migraine with aura: sporadic hemiplegic migraineNeurologyYear: 20036059560112601098|
|15.||Butteriss DJ,Ramesh V,Birchall D. Serial MRI in a case of familial hemiplegic migraineNeuroradiologyYear: 20034530030312669159|
|16.||Hsu DA,Stafstrom CE,Rowley HA,Kiff JE,Dulli DA. Hemiplegic migraine: hyperperfusion and abortive therapy with intravenous verapamilBrain DevYear: 200830869017614229|
|17.||Kumar G,Topper L,Maytal J. Familial hemiplegic migraine with prolonged aura and multimodality imaging: a case reportHeadacheYear: 20094913914218624711|
|18.||Oberndorfer S,Wober C,Nasel C,Asenbaum S,Lahrmann H,Fueger B,Grisold W. Familial hemiplegic migraine: follow-up findings of diffusion-weighted magnetic resonance imaging (MRI), perfusion-MRI and [99mTc] HMPAO-SPECT in a patient with prolonged hemiplegic auraCephalalgiaYear: 20042453353915196295|
|19.||Prodan CI,Holland NR,Lenaerts ME,Parke JT. Magnetic resonance angiogram evidence of vasospasm in familial hemiplegic migraineJ Child NeurolYear: 20021747047212174974|
|20.||Zifkin B,Andermann E,Andermann F,Kirkham T. An autosomal dominant syndrome of hemiplegic migraine, nystagmus, and tremorAnn NeurolYear: 198083293327436378|
Keywords: CACNA1A Gene, Cerebellar Atrophy, Familial Hemiplegic Migraine, T666M.
Previous Document: Ceftiaxone-induced neurotoxicity: case report, pharmacokinetic considerations, and literature review...
Next Document: Oncogenic microRNA 17-92 cluster is regulated by epithelial cell adhesion molecule and could be a po...