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Review
Genetics of migraine
The Genetics of Migraine
Anne Ducros, Elisabeth Tournier-Lasserve, and Marie-Germaine Bousser
The search for genes involved in the pathophysiology of
migraine poses major difficulties. First, there is no
objective diagnostic method to assess the status of the
individuals studied. Second, migraine is a polygenic
multifactorial disorder. Familial hemiplegic migraine (FHM)
is the only known autosomal dominant subtype of
migraine. In half the families with FHM who have been
studied, there are mutations in the calcium-channel gene
CACNA1A, located on chromosome 19. In other families, a
locus has been mapped on chromosome 1. The role of
these loci in typical migraine is still unknown. A
susceptibility locus for migraine with aura has been
located on chromosome 19 (but is distinct from
CACNA1A) and a genome-wide linkage analysis has
mapped a susceptibility locus on chromosome 4. Another
locus for migraine may be on the X chromosome. Finally,
many positive association studies have been published,
but few have been replicated.
Lancet Neurology 2002; 1: 285–93
Migraine is a primary headache disorder consisting of
recurrent attacks of disabling pain that last from a few hours
to a few days.1 Typically, patients with migraine are perfectly
well between attacks. Migraine is very common, affecting
about 15% of the western populations.2–5 The mechanisms of
migraine are far from being completely understood. Familial
aggregation has long been known and was even classically
used as a diagnostic criterion. During the past 10 years, the
genetics of migraine has become an important research
topic with the major goal being the identification of
susceptibility genes that may give clues to the mechanisms
underlying this disorder and may help to develop new
diagnostic and therapeutic strategies.
Why is it so difficult to identify migraine genes?
Genetic studies face difficulties directly related to some of the
characteristic features of migraine. First, researchers must
establish the clinical status of each person studied—ie, find
out whether the individual is affected or not. In the absence
AD is at the Headache Emergency Department, Lariboisière
Hospital. AD and ETL are both at INSERM Unit EMI 99-21, Faculté
de Médecine Lariboisière. MGB is at the Department of Neurology,
Lariboisière Hospital, Paris, France.
Correspondence: Dr Anne Ducros, Urgences Céphalées, Hôpital
Lariboisière, 2 rue Ambroise Paré, 75475 Paris Cedex 10, France.
Tel +33 1 4995 6537; fax +33 1 4995 2481;
email [email protected]
THE LANCET Neurology Vol 1 September 2002
of any biological or radiological marker, the diagnosis of
migraine is purely clinical. The International Headache
Society (IHS) classification (panel), published in 1988,1
IHS diagnosis criteria for migraine without aura, migraine with
aura, and two varieties of migraine with aura (migraine with typical
aura and FHM)1
Migraine without aura
At least five attacks meeting the criteria below:
Headache attacks lasting between 4 h and 72 h (untreated or
unsuccessfully treated)
Headache with at least two of the following characteristics:
Unilateral location
Pulsating quality
Moderate or severe intensity
Aggravation by walking up stairs or similar routine physical activity
During headache at least one of the following:
Nausea and/or vomiting
Photophobia and phonophobia
At least one of the following:
History and physical and neurological examinations do not suggest a
disorder causing secondary headaches
History and physical and neurological examinations suggest a disorder
causing secondary headaches, but it is ruled out by appropriate
investigations
Such a disorder is present, but migraine attacks do not occur for the
first time in close temporal relation to the disorder
Migraine with aura
At least two attacks meeting the criteria below:
At least three of the following four characteristics:
One or more fully reversible aura symptoms indicating focal cerebral
cortical and/or brain stem dysfunction
At least one aura symptom that develops gradually over more than
4 min or two or more symptoms that occur in succession
No aura symptom lasts more than 60 min; if more than one aura
symptom is present, duration is proportionally increased
Headache follows aura with a free interval of less than 60 mins (it may
also begin before or simultaneously with the aura)
At least one of the following:
History and physical and neurological examinations do not suggest a
disorder causing secondary headaches
History and physical and neurological examinations suggest a disorder
causing secondary headaches, but it is ruled out by appropriate
investigations
Such a disorder is present, but migraine attacks do not occur for the
first time in close temporal relation to the disorder
Migraine with typical aura
Meets criteria for migraine with aura (above) including all four of the
following criteria:
Homonymous visual disturbances
Unilateral paresthesias and/or numbness
Unilateral weakness
Aphasia or unclassifiable speech difficulty
Familial hemiplegic migraine
Meets criteria for migraine with aura
The aura includes some degree of hemiparesis and may be prolonged
At least one first-degree relative has identical attacks
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Review
Genetics of migraine
distinguishes different varieties of migraine, the two most
frequent being migraine without aura and migraine with
aura. Attacks of migraine without aura are characterised by
moderate to severe head pain which is often unilateral,
pulsating, and aggravated by routine physical activity (panel).
The headache lasts from 4 h to 72 h and is associated with
nausea, vomiting, photophobia, and phonophobia. Attacks
of migraine with aura are characterised by transient
neurological signs preceding or accompanying the headache
phase. These “aura” symptoms develop gradually and last
from a few minutes to up to an hour (panel). Visual
symptoms, including the classical scintillating scotoma, are
the most frequent, followed by sensory disturbances, speech
difficulties, and, rarely, motor symptoms. Migraine is
characterised by the repetition of such attacks in the absence
of any underlying disorder causing secondary headaches.
According to the IHS criteria, at least five attacks of migraine
without aura or two attacks of migraine with aura are
required to classify a person as affected.
Recurrent migraine attacks may be part of the
clinical range of several organic cerebral disorders such
as arteriovenous malformations,6 mitochondrial encephalopathies (including mitochondrial encephalopathy with
lactic acidosis and stroke-like episodes [MELAS]),7,8
antiphospholipid antibody disease,9 and some cerebral
arteriopathies including cerebral autosomal dominant
arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).10,11 Moreover, a migrainous
attack may be triggered by various acute vascular events such
as cervical-artery dissection, cerebral-venous thrombosis, or
cerebral infarction. In patients affected by such disorders,
migraine attacks are symptomatic of the underlying
problem. However, symptomatic migraine attacks are often
difficult to distinguish from those of a primary migraine
disorder. Are the mechanisms of symptomatic migraine
attacks different from those of primary migraine attacks? Or
is it just that patients with these organic cerebral disorders
have a lower threshold for developing migraine attacks?
As described above, the IHS classification distinguishes
different types of migraine. Migraine without aura is more
common than migraine with aura in the general population
(6–10% vs 3–6%). Some patients have attacks of only one
type—with or without aura—but about a third experience
both types of attacks during their life. We do not yet know
whether migraine with and without aura are two clinical
forms of the same disease, or whether they represent two
distinct disorders. There are also other less common types of
migraine. Several genetic studies have focused on familial
hemiplegic migraine (FHM), a rare type of migraine with
aura, because it is the only form in which a monogenic
mendelian mode of inheritance has been clearly
established.12,13 A typical attack is characterised by unilateral
motor weakness associated with at least one other aura
symptom such as sensory disturbances within the zone of
motor deficit, visual symptoms, or aphasia.13–16 Bilateral
motor and sensory symptoms are reported by about a
quarter of patients.16,17 The aura phase lasts for 1–2 h and is
followed by a migrainous headache. The mean age at onset is
lower (at about 11 years) than in other types of
286
migraine.16,18,19 Moreover, severe attacks of confusion or even
coma with prolonged hemiplegia, fever, and meningismus
are reported by a third of the patients with FHM at least
once in their life.16,20–23 Finally, some patients may have
permanent neurological signs between attacks, mostly
nystagmus and ataxia.15,16,22,24 These features have led to the
distinction between families with pure hemiplegic migraine
(80%) and those with hemiplegic migraine and cerebellar
symptoms (20%), in which at least one family member has
nystagmus or ataxia.13,25,26 FHM is characterised by large
clinical variability in the severity and frequency of attacks
among individuals belonging to different families but also
within the same family.13,15,16 Besides familial cases, some
sporadic cases of hemiplegic migraine with cerebellar
symptoms have also been reported.16,27 Whether FHM has
the same pathophysiological mechanisms as other types of
migraine with aura is not known.
Classification of individuals as “affected” or “unaffected”
for genetic studies does not reflect the important clinical
heterogeneity of migraine. Indeed, the frequency and
severity of attacks show much variability from one patient to
another. Let us consider, for example, a family in which the
40-year-old daughter has had one or two severe attacks of
migraine without aura with intractable headache and
vomiting every month, lasting 3 days at a time, since the age
of 12. The 65-year-old mother has had only two mild and
short attacks of migraine with visual aura in her fifties. The
daughter is affected by migraine without aura and the
mother by migraine with aura, but do they suffer from the
same disorder?
Finally, several other factors have to be taken into
account in genetic studies of migraine. The high prevalence
of migraine (8–25% of the population)2,3 could lead, purely
by chance, to a significant part of the observed familial
aggregation. Women are twice as likely to be affected as men,
which also has to be taken into account in segregation
studies.4,5
Is migraine a genetic condition?
In addition to genetic factors, familial aggregation of a
pathological disorder may be due to environmental factors
and may also, as previously mentioned, occur purely by
chance in very common diseases. A major step in the study
of migraine genetics was thus to show the existence of
genetic factors by the means of genetic epidemiological
surveys.28
Twin studies have been used to assess the respective roles
of genetic and environmental factors. These studies are
based on the comparison of concordance rates between
monozygotic and dizygotic twins. All twin studies done so
far show that migraine has a genetic component in addition
to environmental factors.29–36 The most recent of these
studies was the only one that was carried out in a large
population and used the IHS diagnosis criteria. In this
Danish twin study including 1013 monozygotic and 1667
dizygotic twin-pairs, the pairwise concordance rate was
significantly higher among monozygotic than dizygotic twin
pairs for migraine without aura (28 vs 18%, p<0·05)34 and
for migraine with aura (34 vs 12%, p<0·001).36
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Genetics of migraine
Family studies provide information about the effect of
genetic factors and the potential mode of inheritance. Many
studies have produced controversial results owing to
methodological biases such as the lack of homogeneous
diagnostic criteria before 1988, the lack of separation between
migraine without aura and migraine with aura, the use of a
questionnaire instead of direct interview of the probands, the
lack of a direct interview of the relatives, and the selection of
probands from specialised centres.37–41 However, all of these
studies concluded that genetic factors are implicated in
migraine. The proportion of familial cases was estimated to be
between 34% and 90%, and all possible transmission patterns
were proposed, apart from X-linked inheritance.
Two family studies addressing all methodological
concerns have been published. Russell and Olesen42 studied
the relative risk of migraine without aura and migraine with
aura in all first-degree relatives and spouses of 44 probands
selected out of 4000 representative individuals from the
general Danish population. Compared with the general
population, first-degree relatives of probands with migraine
without aura had a relative risk of 1·86 (95% CI 1·56 to 2·16)
of migraine without aura and first-degree relatives of
probands with migraine with aura had a relative risk of 3·79
(95% CI 3·21 to 4·38) of migraine with aura.42 Stewart and
colleagues43 undertook a population-based study in Maryland
(USA) to analyse the relative risk of migraine without aura
and migraine with aura in all first-degree relatives of 73
migrainous probands and 72 matched controls. Compared
with controls, first-degree relatives of probands with migraine
had a relative risk of 1·50. However, this increase in risk was
not statistically significant (95% CI 0·94 to 2·40) and no
difference was observed when migraine without aura and
migraine with aura were analysed separately. When the
researchers considered only the 26 probands with important
disability due to migraine, they found a 2·17-fold significantly
increased risk of migraine in first-degree relatives (95% CI
1·22 to 3·87).43
With regard to the mode of inheritance, the results
of a large Danish population-based segregation analysis,
including 126 families with migraine without aura and
127 families with migraine with aura, showed that both types
of migraine have a non-mendelian multifactorial mode of
inheritance.44 Analysis of the Danish twin-study data also
favoured a model combining additive genetic and
environmental factors.34–36 In addition, analysis of 31 families
with a high risk of migraine without aura also suggested
multifactorial inheritance.45
Together, these data indicate that both migraine without
aura and migraine with aura are complex diseases caused by a
combination of genetic and environmental factors. Several
studies have suggested that genetic factors may be more
important in migraine with aura than in migraine
without.35,36,42 The possible number of genetic susceptibility
loci is unknown. FHM is the only monogenic variety of
migraine.12,13
Strategies in the quest for migraine genes
In non-mendelian diseases, the identification of diseasecausing mutations can be achieved by different methods. In
THE LANCET Neurology Vol 1 September 2002
families, linkage analysis to candidate genes or markers can
be used to map a susceptibility locus, followed by detection
of the pathogenetic mutation and positional cloning. Modelfree or non-parametric linkage analyses have to be used in
migraine because classic parametric linkage analyses require
the definition of a precise genetic model, and such a
definition is inaccurate in non-mendelian disorders.
Association studies, which do not have such difficult
methodological considerations, can be performed in
homogeneous populations.46 These studies compare the
frequency of alleles of a polymorphic genetic marker
between patients and healthy controls. In the absence of
methodological shortcomings, a significant difference means
that the polymorphism is located within the susceptibility
gene or is in linkage disequilibrium with the susceptibility
gene. However, association studies do not provide any
indication of the normal function of the tested gene or of its
abnormal function in the pathophysiology of the disease
being studied.46
By contrast, genetics provides powerful tools for the
identification of genes causing mendelian disorders. Several
research teams have thus focused their efforts on the
localisation and identification of the genes involved in FHM,
since these genes may also be good candidates for the much
more frequent migraine types, migraine with aura and
migraine without aura.
Genetic heterogeneity of FHM
FHM is genetically heterogeneous.12,14,25,26,47–49 Joutel and coworkers47 localised the first gene on the short arm of
chromosome 19 in 1993. In 1996, Ophoff and colleagues12
identified this gene as CACNA1A, which encodes the ␣1A
subunit of the neuronal P/Q type voltage-gated calcium-ion
channel. CACNA1A is implicated in about 50% of families
with FHM and in all families with FHM and permanent
cerebellar symptoms.14–16,25,26 In 1997, a second gene was
mapped to chromosome 1q; significant linkage with markers
located on 1q31 was found in a large American family48 and
significant linkage to more centromeric markers located at
1q21-q23 was found in three French families.49 From present
evidence, we do not know whether one gene or two distinct
genes for FHM are located on chromosome 1q. The
chromosome 1 locus is implicated in a few families
(10–20%) of those affected by pure FHM.49 Finally, 30–40%
of families show no linkage to these first two loci, which
suggests the existence of at least one other FHM gene.49
CACNA1A, ␣1A subunit, and P/Q-type channels
CACNA1A, the only known FHM gene, encodes the main
subunit of the P/Q type voltage-gated calcium channel.12
These channels are large multimeric proteins located within
the cell membrane; in the centre is a pore that opens in
response to membrane depolarisation, letting calcium ions
flow into the cell.50,51 In neurons, they have a major role in
the control of neuronal excitability and neurotransmitter
release. Each channel is formed by a main ␣1 subunit
associated with four auxiliary subunits (␣2, ␤, ␥, and ␦).50,51
The ␣1 subunit forms the ionic pore that includes the
structures that bring about voltage sensitivity and ionic
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R195K
R192Q
S218L
Genetics of migraine
V1457L
V714A K1336E
R583Q
T666M
D715E
V1696I
Y1385C
R1668W
L1682P
W1684R
I1811L
CACNA1A mutations causing FHM. A schematic structure of the ␣1A
pore-forming subunit of the P/Q type voltage-gated calcium channels is
shown. This subunit is located in the neuronal membrane and contains
four repeat domains. Each domain includes six membrane-spanning
segments (S1 to S6) and a so-called P-loop between the fifth and sixth
segments. The four S4 segments form the voltage sensor of the channel,
the four S5 and S6 segments build the ionic pore, and the four P-loops
line the inner part of this pore. Positions of the 15 mis-sense mutations
identified in FHM are indicated. Mutations causing pure hemiplegic
migraine are represented by red circles and mutations causing
hemiplegic migraine with permanent cerebellar symptoms are
represented by green stars.
selectivity. All ␣1 subunits have the same structure (figure).
There are at least ten genes (CACNA1A, B, C, D, E, F, G, H, I,
and S) coding for distinct ␣1 subunits.50–52 Depending on the
␣1 subunit type, a calcium channel has distinct
pharmacological and kinetic properties generating different
types of calcium currents: L, N, P/Q, R, or T.50,51,53 The ␣1A
subunit is the main subunit of P/Q type neuronal calcium
channels, which are expressed in central neurons and in
peripheral neurons at the neuromuscular junction.50,54 As a
result of alternative splicing, ␣1A subunits can generate two
distinct types of calcium currents: the slow inactivating
P-type currents that are the major calcium currents in
cerebellar Purkinje cells, and the fast inactivating Q-type
currents that play a major part in the control of
neurotransmitter release.55
CACNA1A is a large gene containing 47 exons.12 Exon 47
contains a polymorphic CAG repeat, which is predicted to
code for a polyglutamine stretch in a subset of the known
human transcripts.56 Thus far, 15 CACNA1A mutations have
been identified in 31 families with FHM (24 affected by
FHM with cerebellar symptoms and seven by pure FHM)
and in two sporadic cases affected by hemiplegic migraine
with cerebellar symptoms (table 1).12,16,19,27,57–63 Five of these
mutations are recurrent—ie, they have been detected in two
or more unrelated families.12,16,19,57,59,60,62,63 The commonest
mutation, T666M, has been detected in 12 unrelated families
and in one sporadic case.12,16,59,60,63 All 15 mutations are missense mutations, causing a substitution of one amino acid of
the 2550 that constitute the predicted protein. The
mutations are located in important functional domains of
the subunit, near the ionic pore or within the voltage sensor
(figure). Nine of the 15 mutations, including the five
recurrent ones, are associated with hemiplegic migraine with
cerebellar symptoms.
Different CACNA1A mutations have been identified in
two other autosomal dominant neurological disorders:
episodic ataxia type 2 (EA2)12 and spinocerebellar ataxia type
6 (SCA6).56 EA2, like FHM, is a paroxysmal neurological
disorder causing recurrent attacks of major instability with
lack of coordination. Attacks are often provoked by exercise
or emotion and last between 15 min and a few hours.
Acetazolamide is effective in preventing attacks in most
patients. During attack-free intervals, clinical examination
commonly discloses permanent cerebellar signs (nystagmus
and/or ataxia). Most of the mutations identified in patients
with EA2 are predicted to result in a truncation of the
putative protein.12,64,65 SCA6 is a progressive cerebellar disease
Table 1. CACNA1A mutations identified in FHM
Mutation
S218L
R583Q
D715E
Y1385C
Reference
62
57
16
12
60
16
63
16
16
27
R1668W
L1682P
W1684R
I1811L
16
61
16
12
Family (or case)
2 families
1 family
3 families
1 family
1 family
9 families
1 family
1 sporadic case
1 family
1 sporadic case
(de novo mutation)
1 family
1 family
1 family
2 families
R192Q
R195K
V714A
K1336E
V1457L
R1668W
V1696I
12
16
12
16
58
16
16
1 family
1 family
1 family
1 family
1 family
1 family
1 family
T666M
288
Exon
5
13
Nucleotide change
TCG→TTG
CGA→CAA
␣1A subunit domain
IS4-S5
IIS4
Cerebellar symptoms
+
+
16
ACG→ATG
II P loop
+
17
26
GAC→GAG
TAC→TGC
IIS6
IIIS5
+
+
32
32
32
36
CGG→TGG
CTN→CCN
TGG→CGG
ATC→CTC
IVS4
IVS4
IVS4-S5
IVS6
+
+
+
+
4
4
17
25
27
32
33
CGA→CAA
AGG→AAG
GTG→GCG
AAA→GAA
GTG→TTG
CGG→TGG
GTC→ATC
IS4
IS4
IIS6
IIIS3-S4
III P loop
IVS4
IVS5
-
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Genetics of migraine
characterised by an adult-onset statokinetic ataxia caused by
small expansions of the CAG repeat contained within exon
47 of CACNA1A.56,66
Consequences of CACNA1A mutations
Several methods can be used to understand the mechanisms
leading from the different CACNA1A mutations to the
observed phenotypes.
Seven CACNA1A mutations causing FHM have been
studied electrophysiologically by comparison of the
calcium currents between cells expressing the wild-type
gene and cells expressing the mutant gene.67–69 All the
mutations modify the density and the gating properties of
P/Q-type currents. FHM mutations are thus “gain of
function” mutations with the abnormal protein producing
altered calcium currents. No difference was observed
between the mutations causing pure FHM and the
mutations causing FHM with cerebellar symptoms.
However, the conditions in vitro are unlikely to reflect the
complexity of the situation in vivo. On the other hand, EA2
mutations are “loss of function” mutations with the
mutated protein incapable of generating any current when
expressed in heterologous cells.70,71
Knockout mice that do not carry the Cacna1a gene
are born with a severe ataxia and die within a few days.72
Mice carrying different mutations within Cacna1a
display distinct phenotypes called tottering,73 leaner,73 or
rocker,74 which are characterised by various paroxysmal
manifestations (absence epilepsy and motor attacks) and
are in all cases associated with a permanent cerebellar
ataxia of variable severity. Tottering mice show abnormal
control of acetylcholine release at the neuromuscular
junction.54 Moreover, the different mutants display several
anatomical abnormalities, including abnormal arborisation
of Purkinje cells, abnormal migration of granular cells,
and abnormalities of the locus coeruleus.73,74 These
abnormalities suggest that P/Q-type channels may be
implicated not only in the control of neurotransmitter
release but also in neuronal development.
Genotype–phenotype correlations in FHM
FHM is characterised by striking clinical variability. Age
at onset, frequency, duration, and features of attacks may
vary from one patient to another, even among affected
members from a given family who all carry the same
mutation in the same gene.16,19 This variability suggests
complex interactions between the consequences of the
mutation and environmental factors or modifying genetic
factors.
Several studies have shown that the various FHM
genotypes have a role in producing this clinical variability.
In a study of five families, the clinical features of 46 patients
from three families with linkage to chromosome 19 were
compared with those of 20 patients from two unlinked
families.15 Patients from the families with chromosome 19
linkage had a higher frequency of attacks with loss of
consciousness (39% vs 15%) and head-trauma triggered
attacks (70% vs 40%) than unlinked families.15 In a study of
17 families, the clinical and genetic features of FHM were
THE LANCET Neurology Vol 1 September 2002
compared between three groups of families: ten with
linkage to chromosome 19 (94 patients), three with linkage
to chromosome 1 (24 patients), and four unlinked families
(24 patients).75 Two major differences were shown: first, the
penetrance of FHM was lower in chromosome-1-linked
families than in the other group and second, permanent
cerebellar symptoms were present in a subset of
chromosome-19-linked families and absent in all the other
family groups.75
The detailed clinical analysis of a large series of 117
individuals with CACNA1A mutations causing FHM has
allowed better delineation of the clinical range of this type
of migraine with aura.16 FHM caused by CACNA1A
mutations is characterised by a high penetrance of
hemiplegic migraine attacks (86%), in which the motor
aura is always associated with sensory, language, or visual
aura symptoms. However, in contrast to other varieties of
migraine with aura in which visual symptoms are present in
about 99% of patients, a quarter of patients with FHM do
not have visual symptoms.76 FHM is also characterised by
the frequency of bilateral motor signs during aura (about
30% of patients), severe attacks with impairment of
consciousness (30% of patients), an early age at onset (close
to 11 years), and by the importance of minor head trauma
as a triggering factor. Finally, permanent cerebellar signs
are found in about 80% of patients with mutations
belonging to families who have hemiplegic migraine with
cerebellar symptoms. Altogether, these characteristics
suggest that FHM due to CACNA1A mutations is a very
unusual variety of migraine with aura.
In addition, striking correlations have been found
between the genotype and phenotype. The frequency of
symptoms was studied in 85 patients with the three most
frequent mutations linked to FHM with cerebellar signs:
T666M (55 patients), R583Q (16 patients), and D715E (14
patients).16 Patients with the T666M mutation had the
highest penetrance of hemiplegic migraine (98%), severe
attacks with coma (50%), and nystagmus (86%). Patients
with the R583Q mutation had the highest penetrance of gait
ataxia (81%) in the absence of any nystagmus, and those
with the D715E mutation had the lowest penetrance of
hemiplegic migraine attacks (64%).16
The various studies of CACNA1A mutations in FHM
have provided several important insights. First, the
mutations causing FHM with cerebellar symptoms
are distinct from those causing pure FHM, and all recurrent
mutations cause FHM with cerebellar symptoms.16,19
This genotype–phenotype correlation strongly suggests
that mutations causing FHM with cerebellar symptoms
have particular pathogenetic consequences in cerebellar
neurons, whereas mutations causing pure FHM do not
have such deleterious effects. Second, other important
genotype–phenotype correlations have been demonstrated,
suggesting that the existence of distinct CACNA1A
mutations may explain, at least partly, the clinical
variability of FHM.16,19 Finally, mutations have been
detected in two sporadic cases, including a de novo
mutation; thus, sporadic hemiplegic migraine is due to
CACNA1A mutations in at least some cases.16,27
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Genetics of migraine
Are FHM genes implicated in migraine without
aura and/or migraine with aura?
CACNA1A is the first gene for which an involvement in a
subtype of migraine has been demonstrated. CACNA1A and
the other FHM genes represent good candidate genes for
migraine with aura and migraine without aura. Indeed,
several clinical features support the hypothesis that migraine
without aura and migraine with aura could also be
neurological channelopathies, the main factor being
paroxysmal presentation with attacks lasting a few hours to a
few days. Several groups have tried to implicate CACNA1A or
other ion channel genes indirectly in migraine with aura and
migraine without aura. Subtle subclinical cerebellar
abnormalities have been discovered by the analysis of hand
reaching movements in patients with migraine.77 This
impairment was more pronounced in patients with aura than
those without. By means of single-fibre electromyography,
subclinical abnormalities of neuromuscular transmission
have been shown in a subset of patients with migraine with
aura.78,79 Single-endplate abnormalities were significantly
more frequent in a group of patients affected by migraine
with prolonged aura than in a group of healthy volunteers.80
These studies do not show that CACNA1A is involved in
migraine without aura or migraine with aura, but they do
provide important information about the existence of mild
subclinical permanent neurological abnormalities in a
subgroup of patients with migraine that could be used as
objective markers to constitute homogeneous groups of
patients for genetic studies.
The involvement of CACNA1A in the more frequent
types of migraine has been analysed by linkage and
association studies with contradictory results.81–88 None of the
positive studies provided a direct analysis of the CACNA1A
gene to detect pathogenetic mutations. As a consequence,
these studies showed only that a susceptibility locus for
migraine with or without aura might be located nearby or
within the 19p13 region, without direct evidence that
CACNA1A was the susceptibility gene. Nyholt and coworkers82 published a linkage study in a large family affected
by migraine with aura showing positive linkage results with
19p13 markers. Subsequently, the same group reported that
sequencing of the 47 exons of CACNA1A in two patients
from this family did not reveal any mutations.87 In a second
step, they conducted a linkage analysis in 82 pedigrees and a
large case-control association study but did not detect any
linkage or association between CACNA1A polymorphisms
and migraine in these groups.87
Jones and colleagues88 analysed families affected by
migraine with aura for cosegregation of the disease with six
chromosome-19p13 markers. Positive lod scores were
obtained by use of multipoint model-free linkage analysis as
well as a dominant affected-only model with all six tested
markers. The maximum lod score (model-free lod=4·28) was
obtained close to marker D19S592, which is located about 10
cM telomeric to CACNA1A. This study reinforces the
positive results previously obtained by several groups and is
consistent with the presence of a susceptibility locus for
migraine on 19p close to, but distinct from, the CACNA1A
gene.81–83
290
On the basis of these studies, CACNA1A is most likely not
a major susceptibility gene for migraine with aura and
migraine without aura. Some explanations for this
conclusion are as follows. First, as discussed above, FHM
resulting from CACNA1A mutations differs from typical
migraine in its unusual genetic and clinical features,
including a high penetrance of hemiplegic migraine attacks
and a frequent association with permanent clinically obvious
cerebellar symptoms.16 Second, CACNA1A is implicated in
less than 40% of families with pure FHM.14,16,25,26,48,49,58,75 The
genes causing pure FHM (ie, without cerebellar signs) may be
better candidate genes for migraine with aura and migraine
without aura. However, none of the previously cited studies
have definitively ruled out the possibility that CACNA1A may
contribute to migraine with aura, at least in a small subset of
patients and families. Three of the 16 families with migraine
with aura studied by Jones and colleagues88 had higher lod
scores with markers from the CACNA1A locus than with
markers located telomeric to CACNA1A. These families may
therefore show linkage to CACNA1A. Further data are
needed to clarify the relations between CACNA1A and
migraine with aura.88
Genes encoding ion-channel subunits are major
candidates for other FHM genes and remain good candidates
for migraine with aura and migraine without aura. The
chromosome 1q FHM gene (or genes) remains unidentified.
Moreover, nothing is known about the involvement of the
chromosome 1q FHM locus in migraine with aura and
migraine without aura, and a third FHM gene has yet to be
mapped.
Are other loci or genes implicated in migraine
with or without aura?
Nyholt and colleagues89,90 have analysed X-chromosome
markers in three large Australian pedigrees. They found
positive non-parametric lod scores with Xq24–28 markers in
two of these families.89,90 According to these researchers, this
locus may be involved in the higher female prevalence of this
disorder. Further studies, including a much larger panel
of families, are necessary to confirm the role of an
X-chromosome locus in migraine susceptibility.
As previously discussed, Jones and colleagues88 have
shown that chromosome 19p13 contains a susceptibility
locus for migraine with aura that seems to be distinct from
the FHM locus. Subsequently, the same group found a
significant association between migraine and five different
single-nucleotide polymorphisms within the insulin
receptor gene (INSR) located on 19p13.91 This association
was found in two large case-control populations collected
independently, including a total of 827 cases and 765
controls. Positive association was mainly accounted for by
the results obtained in patients with migraine with aura and
in one of the two populations. The five single-nucleotidepolymorphism alleles associated with migraine had no effect
on INSR transcription, translation, protein expression, and
INSR-mediated functions.91 This study did not exclude the
possibility that the five polymorphisms in INSR could be in
linkage disequilibrium with another gene close to INSR. The
nature of INSR gene involvement in migraine remains to be
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Review
Genetics of migraine
elucidated and present evidence does not allow us to consider
INSR as a migraine gene.
Recently Wessman and colleagues92 published the first
genome-wide linkage analysis in migraine with aura, which
led to the mapping of a susceptibility locus on chromosome
4q24.92 This large study included 50 Finnish families with
vertical transmission of migraine with aura consistent with
dominant inheritance. The Finnish population is genetically
homogeneous owing to a small number of founders. The
researchers analysed only families affected by migraine with
aura because of data suggesting that genetic factors may be
more important in migraine with aura than in migraine
without aura. Moreover, only individuals affected by
migraine with aura were considered to avoid heterogeneity
and eventual phenocopies that might have been introduced
by inclusion of migraine without aura. Statistically significant
linkage was found with the marker D4S1647 by parametric
two-point linkage analysis on the assumption of a dominant
mode of transmission, as well as multipoint parametric and
non-parametric analyses.92 The chromosome 4q24 locus was
the only one to give significant linkage results in this panel of
families. In addition, non-significant nominal evidence of
linkage (ie, positive lod scores <3, p>0·001) was found with
other markers, including markers on 19p13.2, 1q42.2, and Xp
(but not Xq). The 19p13 marker that gave a positive lod score
is located telomeric to CACNA1A, and the 1q42 marker that
gave a positive lod score is located telomeric to both FHM
loci (1q21–23 and 1q31). The results of this study strongly
suggest a susceptibility locus for migraine with aura on 4q24.
Lea and colleagues93 recently published a linkage study in
a large family affected by typical migraine. They reported
significant linkage using a chromosome 1q31 marker located
within the locus for FHM. These researchers also conducted a
linkage analysis of 82 pedigrees and a case-control association
study, which produced positive linkage results (maximum
lod score of 1·24, p=0·008) and significant association results
(p=0·010). These observations will need to be confirmed by
other researchers but they reinforce the hypothesis that pure
FHM genes may be good candidates for migraine with or
without aura.
Finally, many association studies have been performed in
migraine.94 Positive associations have been found between
migraine and polymorphisms within genes encoding
the dopamine D2 receptor,95,96 the human serotonin
transporter,97,98 catechol-O-methyltransferase,99 endothelin
type A,100 dopamine ␤-hydroxylase,101 and 5,10-methylenetetrahydrofolate reductase.102 These various candidate
polymorphisms have been chosen on the basis of the
Search strategy and selection criteria
aura
Migraine subtype
FHM with cerebellar symptoms
Pure FHM
Pure FHM
Migraine with aura
Chromosome
19p13
19p13
1q21–23
1q31
19p13.2
Migraine with aura
Migraine with aura
4q24
Xq
Gene
CACNA1A
CACNA1A
Unknown
Distinct from
CACNA1A?
INSR?
Unknown
Unknown
hypothesis that the genes containing them encode proteins
that are thought to be involved in migraine. However, further
studies are needed to find out whether the alleles associated
with migraine have any biological effect. Moreover, most of
these studies are single reports and await replication.
Summary
Migraine is a complex polygenic multifactorial disorder in
which genetic factors interact with environmental factors.
Several studies have suggested that genetic factors may be
more important in migraine with aura than in migraine
without aura. The number of different susceptibility loci and
genes is still unknown (table 2). FHM, which is the only
known monogenic variety of migraine, is caused by
mutations in the calcium channel gene CACNA1A located on
chromosome 19p13 in about 50% of families. In those
families, FHM is thus a neuronal channelopathy. However,
CACNA1A is most likely not a major susceptibility gene for
the other types of migraine. Other FHM genes, responsible
for pure FHM, may be better candidate genes for migraine
with aura and migraine without aura. Recent data suggest
that a susceptibility locus for migraine with aura is located on
19p13, telomeric to CACNA1A. Another susceptibility locus
for migraine with aura has been mapped on 4q24 by a
genome-wide linkage analysis in 50 Finnish families. Finally,
a migraine susceptibility locus may reside on Xq. Several
associations have been found between polymorphisms within
various candidate genes and migraine, but the significance of
these findings is still unclear. Future objectives in migraine
genetics are: to identify other FHM genes and to analyse their
role in migraine with aura and migraine without aura; to
identify the susceptibility gene or genes for migraine with
aura located within the 19p13 locus and to find out whether
CACNA1A is implicated; and to replicate the 4q24 significant
linkage results in migraine with aura in a non-Finnish
population and identify the underlying susceptibility gene.
Authors’ contributions
Data for this review were identified by searches of Medline and
references from relevant articles using the search terms
“migraine”, “hemiplegic migraine”, “familial”, “genetics”,
“association study”, “polymorphism”, “linkage”, “gene”, and
“calcium channel”. Many articles were also identified through
searches of the extensive files of the authors. Abstracts were
included only when they related directly to previous published
work. In addition to papers published in English, a few papers
published in French were reviewed.
THE LANCET Neurology Vol 1 September 2002
Table 2. Susceptibility loci identified in FHM and in migraine with
AD wrote this review with assistance from MGB. ETL and MGB
critically evaluated the review at its various stages.
Conflict of interest
We have no conflict of interest.
Role of the funding source
The authors are supported by the Assistance Publique des Hopitaux de
Paris and by INSERM. No funding body had a role in the preparation of
the review or in the decision to submit it for publication.
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Review
Genetics of migraine
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