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Mutation Analysis of the CACNA1A Calcium Channel Subunit Gene in 27 Patients With Sporadic Hemiplegic Migraine
Gisela Terwindt, MD, PhD;
Esther Kors, MD;
Joost Haan, MD, PhD;
Frans Vermeulen;
Arn van den Maagdenberg, PhD;
Rune Frants, PhD;
Michel Ferrari, MD, PhD;
for the International Hemiplegic Migraine Research Group
Arch Neurol. 2002;59:1016-1018.
ABSTRACT
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Background Familial hemiplegic migraine is a rare autosomal dominant subtype of
migraine with aura that in half of the families is caused by mutations in
the CACNA1A gene on chromosome 19p13. In sporadic
hemiplegic migraine (SHM), that is, hemiplegic migraine without affected family
members, the contribution of the CACNA1A gene is
unknown.
Objective To investigate the involvement of the CACNA1A
calcium channel subunit gene in SHM.
Methods We screened 27 patients with SHM for mutations in the CACNA1A gene by a combination of single-strand conformational polymorphism
analysis and sequence analysis.
Results One patient with SHM also had ataxia, nystagmus, and cerebellar atrophy
on computed tomography and carried a T666M mutation. Another patient with
SHM who had no cerebellar signs carried an R583Q mutation. No mutations or
interictal neurological abnormalities were found in the remaining 25 patients
with SHM.
Conclusions Most patients with SHM do not have a CACNA1A
mutation. The results of this study, combined with the findings reported in
the literature, show that the presence of cerebellar symptoms in addition
to the hemiplegic attacks increases the chance of finding a CACNA1A mutation. In addition, to our knowledge, we have found a first
patient with SHM without cerebellar signs with a mutation.
INTRODUCTION
FAMILIAL HEMIPLEGIC migraine (FHM) is a rare autosomal dominantly inherited
subtype of migraine with aura.1 Patients with
FHM have attacks of migraine with aura that are also associated with hemiparesis.
Otherwise, the symptoms of the headache and the aura phase are similar to
those of nonhemiplegic migraine with aura, but may last much longer. At least
3 different genes have been implicated in FHM: the CACNA1A calcium subunit gene on chromosome 19p13 in half of the families with
FHM,2 an unknown gene on chromosome 1 in a
few families, and at least a third one, as a few families could not be linked
to either chromosome 19 or chromosome 1.3-4
In sporadic hemiplegic migraine (SHM) (ie, hemiplegic migraine without
a history of affected family members), the cause is unknown. In 2 of 3 patients
with SHM who have cerebellar signs that have been analyzed for mutations in
the CACNA1A gene, a mutation was found; a T666M mutation
in a patient with SHM who had cerebellar ataxia, and a Y1384C mutation in
a woman with mental retardion who had recurrent prolonged attacks of hemiplegic
migraine, coma, and seizures associated with permanent cerebellar ataxia and
atrophy.5 Eight patients with SHM who had no
cerebellar signs were analyzed, but no mutation was found.6-8
In the present study we performed a mutation analysis of the coding exons
of the CACNA1A gene by single-strand conformational
polymorphism analysis in 27 patients with SHM.
PATIENTS AND METHODS
As part of our ongoing mutation analysis of the CACNA1A gene, we studied 27 patients who had migraine with aura associated
with hemiparesis. They originated from Western Europe, mostly the Netherlands,
and one was from the United States. All available first-degree relatives were
interviewed and their condition was diagnosed according to the criteria of
the International Headache Society.1 In all
patients with SHM, polymerase chain reaction products of all 47 exons of the CACNA1A gene were screened for sequence aberrations by
single-strand conformational polymorphism analysis.2, 9
RESULTS
Eight patients had no family member who had any type of migraine headache,
while 19 patients had at least one first-degree relative who experienced migraine
headache but none associated with hemiparesis (Table 1). Table 1 summarizes
the clinical characteristics of the hemiplegic migraine attacks of the patients
with SHM. The total duration of the migraine attacks varied between minutes
and days, and even up to weeks in 2 patients. The paresis lasted between minutes
and days, and weeks in 1 patient. In 2 patients the attacks fulfilled the
criteria for basilar migraine.1 Two patients
reported loss of consciousness during attacks, 1 patient reported confusion,
and 2 patients reported attacks triggered by minor head trauma. Mutation analysis
of the CACNA1A gene was unremarkable in 25 patients.
One patient carried a T666M mutation (family 27). This 78-year-old woman had
migraine attacks with aphasia, pyrexia, hemianopsia, and hemiparesis starting
at the age of 14 years. In between attacks the patient showed gaze-evoked
horizontal nystagmus and upgazed paresis, dysarthria, and mild limb and gait
ataxia; cerebral computed tomography revealed cerebellar atrophy. Another
patient carried an R583Q mutation (patient 26). This 16-year-old boy had had
5 migraine attacks with aphasia, hemiparesis, and confusion with a duration
of half an hour followed by headache. No cerebellar signs were present.
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Clinical Characteristics and Family History of Migraine of 27 Patients
With Sporadic Hemiplegic Migraine*
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COMMENT
We found a CACNA1A mutation in 2 of 27 patients with SHM. These findings
are consistent with the results of other smaller studies showing mutations
in the CACNA1A gene in 2 of 3 patients with SHM who
have permanent cerebellar ataxia, and no mutations in 8 patients without ataxia.6-8
We used single-strand conformational polymorphism analysis, which is
a reasonable sensitive (70%-90%) method for screening genes for point mutations
as long as the fragments are not longer than 200 bases.10
However, other types of mutations like microdeletions or macrodeletions are
undetectable by single-strand conformational polymorphism. To investigate
this, other techniques such as Southern blotting and/or pulsed-field gel electrophoresis
should be used. However, the genomic size of the CACNA1A gene, 350 kilobases, makes it hard to apply these alternative methods
in a standard (and rapid) mutation screening. The promotor region or other
regulatory elements were not analyzed, as at this moment, these have not been
identified. Other studies in sporadic cases of specific genetic disorders
give similar results as our study; a positive test rate is usually low, ranging
from 2% to10%.11
The patient in our study carrying the T666M mutation was distinctive
from the others by showing permanent cerebellar ataxia and atrophy on computed
tomographic scanning. Unfortunately, no DNA and direct information of the
parents were available. The other mutation found in our study (R583Q), however,
was found in a patient who did not have cerebellar symptoms. This R583Q mutation
was reported previously in 4 families with FHM and associated ataxia.8, 12 The mean age of onset of the ataxia
is 40 years, ranging from 11 to 78 years.8
The patient with SHM in our study is only 16 years old; it is possible that
he will develop these symptoms.
Clinical analysis of the symptoms of the aura in patients with FHM suggests
an extensive overlap with basilar migraine.13
Only 2 of our patients with SHM had attacks fulfilling the criteria for basilar
migraine. Unconsciousness during attacks and provocation of attacks by mild
head trauma are not uncommon features of 19p13-linked families with FHM.14-15 In contrast, only 2 patients with
SHM in this study reported these features. Thus, both genetic and clinical
data suggest that FHM and SHM might be pathophysiologically different.
AUTHOR INFORMATION
Accepted for publication January 7, 2002.
Author contributions: Study concept and design (Drs Terwindt, Haan, Frants, and Ferrari); acquisition
of data (Drs Terwindt, Kors, van den Maagdenberg, and Ferrari
and Mr Vermeulen); analysis and interpretation of data (Drs Terwindt, Kors, Haan, van den Maagdenberg, and Ferrari and Mr Vermeulen); drafting of the manuscript (Drs Terwindt, Kors,
Haan and van den Maagdenberg and Mr Vermeulen); critical revision of
the manuscript for important intellectual content (Drs Kors,
Haan, van den Maagdenberg, Frants, and Ferrari); obtained funding (Drs Frants and Ferrari); administrative, technical, and
material support (Dr van den Maagdenberg and Mr Vermeulen); study supervision (Drs Haan, van den Maagdenberg,
Frants, and Ferrari).
This work was supported by nr 903-52-291 from the Netherlands Organization
of Scientific Research, The Hague, and The Migraine Trust, London, England.
| International Hemiplegic Migraine Research
Group
Members of the International Hemiplegic Migraine Research Group included
the aforementioned authors and following persons: Neurologische
Klinik der Ruhr-Universität, Bochum, Germany: J. Federlein, MD; Neurologische Universitätsklinik Regensburg, Regensburg,
Germany: A. May, MD, PhD; Charing Cross Hospital,
London, England: R. C. Peatfield, MD; Canisius Wilhelmina
Hospital, Nymegen, the Netherlands: E. F. J. Poels, MD; Headache Center, Henry Ford Hospital and Health Sciences Center, Detroit,
Mich: N. M. Ramadan, MD; Hospital de la Citadelle,
Liège, Belgium: J. Schoenen, MD, PhD; Klinikum
Grosshadern, München, Germany: A. Straube, MD, PhD; and
Leeds, England: P. F. Taylor, MD.
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Corresponding author: Michel Ferrari, MD, PhD, Department of Neurology,
Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, the Netherlands
(e-mail: M.D.Ferrari{at}lumc.nl).
From the Department of Neurology (Drs Terwindt, Kors, Haan, and Ferrari)
and Department of Human Genetics, Leiden University Medical Centre (Mr Vermeulen
and Drs van den Maagdenberg and Frants), Leiden, the Netherlands; and the
Department of Neurology, Rijnland Hospital, Leiderdorp, the Netherlands (Dr
Haan).
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