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Clinical features of cerebral cavernous malformations patients with KRIT1 mutations.

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Clinical Features of Cerebral Cavernous
Malformations Patients with
KRIT1 Mutations
Christian Denier, MD,1,2 Pierre Labauge, MD,1,3 Laurent Brunereau, MD,4 Florence Cavé-Riant, MD,2
Florence Marchelli, MD,1 Minh Arnoult,1 Michaelle Cecillon,1 Jacqueline Maciazek,1
Anne Joutel, MD, PhD,1,2 Elisabeth Tournier-Lasserve, MD,1,2
and the Société Française de Neurochirurgie and the Société de Neurochirurgie de Langue Française
Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral
hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being characterized by the presence
of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been
identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed
in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers.
Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom-free. Mean age at clinical
onset was 29.7 years (range, 2–72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (ⴞ7.2) and on gradient echo sequences 19.8
(ⴞ33.2). Twenty-six mutation carriers harbored only one lesion on T2-weighted MRI, including 4 mutation carriers,
aged from 18 to 55 yr-old, who presented only one CCM lesion both on T2-weighted and on highly sensitive gradient
echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr-old, did not have any detectable lesion
both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation
carriers aged 50 or more are symptom-free. The presence of only one lesion, even when using gradient echo MRI
sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when
using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be
overlooked in some mutation carriers presenting as sporadic cases with a unique lesion.
Ann Neurol 2004;55:213–220
Cerebral cavernous malformations (CCMs/OMIM
116860) are vascular malformations, mostly located in
the central nervous system and characterized by abnormally enlarged capillary cavities without intervening
brain parenchyma.1 From a large series based on necropsy and/or magnetic resonance imaging (MRI), their
prevalence in the general population has been estimated to be close to 0.1 to 0.5%.2,3 Most common
symptoms include seizures (38 –51% of cases), cerebral
hemorrhages (11–32%), and focal neurological deficits
(12– 45%).4
Cavernous angiomas can occur as a sporadic or an
From 1INSERM E365, Lariboisière Medical School, Paris; 2Cryogenetics Laboratory, Hôpital Lariboisière, Assistance Publique-Hôpitaux
de Paris; 3Neurology Department, CHU Montpellier Nimes; and
Radiology Department, CHU de Tours, Tours, France.
Received Jul 29, 2003, and in revised form Sep 4. Accepted for
publication Sep 4, 2003.
autosomal dominant condition. The frequency of the
familial form has been estimated as high as 50% in
Hispano-American CCM patients5 and close to 10 to
20% in white patients (E. Tournier-Lasserve, unpublished data). Usually, sporadic cases harbor only one
CCM lesion, whereas familial cases are characterized by
the presence of multiple lesions whose number is
strongly correlated to patients’ age.5,6 “Sporadic” cases
harboring multiple lesions have been shown to be affected by an hereditary form of the disease because
75% of them have an asymptomatic parent with CCM
lesions on brain MRI, due to the incomplete clinical
Address correspondence to E. Tournier-Lasserve, INSERM E365,
Faculté de médecine Lariboisière, 10, avenue de Verdun, 75010
Paris, France. E-mail:
The main clinical investigators are listed in the Appendix on page
© 2003 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
penetrance of this condition.5,6 A spontaneous de novo
mutation of KRIT1/CCM1 gene also has been reported in one apparently sporadic CCM patient with
multiple lesions.7
Previous genetic linkage analyses identified three
CCM loci on 7q (CCM1), 7p (CCM2), and 3q
(CCM3). The proportions of families linked to these
loci have been estimated to be close to 40% (CCM1),
20% (CCM2), and 40% (CCM3).8,9 The sole CCM
gene identified so far, CCM1, encodes Krit1, a 736 –
amino acid protein containing four ankyrin domains
and a Four point 1 (4.1) protein/Ezrin/Radixin/Moesin
domain.10,11 This protein has been shown to interact
in vitro with Rap1A, a small GTPase and icap1␣, a
modulator of ␤1 integrin signal transduction pathway.12–14
So far, 74 distinct KRIT1 mutations causing
CCMs have been published including 42 from our
laboratory.7,10,11,15–21 They are highly stereotyped because all of them lead to premature termination
codons, suggesting that these mutations have the same
consequence at the protein level and that Krit1 haploinsufficiency, through mRNA decay, is the most likely
pathophysiological mechanism involved in CCM1 patients.22 Interestingly, a highly recurrent KRIT1 mutation has been detected in Hispano-American CCM patients in whom a strong founder effect was reported.23
Several clinical and neuroradiological studies conducted before CCM1/KRIT1 gene identification helped
to delineate some of the main features of this condition, namely, its autosomal dominant pattern of inheritance, its incomplete clinical penetrance, and the high
frequency of multiple lesions. These studies also
showed the intrafamilial and interfamilial variability of
familial CCM.5,6,24 Despite the high number of
KRIT1 mutations reported so far, the phenotypes associated with the presence of a KRIT1 mutation in CCM
patients have not yet been documented in a large series
of white patients.
We consecutively recruited 153 CCM probands who
had at least one affected relative with CCM and/or
presented multiple cerebral cavernous angiomas.
KRIT1 gene mutation screening of these 153 probands
led to the identification of 64 mutation carriers. We
genotyped herein 313 family members of these 64
KRIT1-positive index patients and report the clinical
and neuroradiological features of the 202 KRIT1 mutation carriers identified within these families.
Patients and Methods
Patients and Families
Twenty-eight French University Neurosurgery centers participated in this study which was approved by the local ethics
committee. A total of 153 unrelated clinically affected CCM
index patients were consecutively enrolled on the basis of one
of the two following criteria: to have at least one affected
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relative and/or to have multiple cerebral cavernous angiomas.
Detailed clinical and neuroimaging information was collected
for all index patients through direct interview and reviewing
of medical charts. Clinical assessment included information
on cerebral hemorrhages, focal neurological symptoms, seizures, and headaches (when occurring in the absence of any
hemorrhage detectable on cerebral imaging). Hemorrhage diagnosis was based on the assessment of clinical symptoms
and MRI and was confirmed in most cases by neurosurgery.
CCM diagnosis was based on cerebral MRI features and/or
pathological analysis.
Pedigrees were established with the help of the proband of
each family. In addition to clinical information provided by
the probands on their relatives, all symptomatic and
symptom-free at-risk relatives who provided their written informed consent were directly interviewed by one of us (P.L.)
using a standardized procedure.
MRI data were retrospectively collected for all symptomatic patients. Symptom-free subjects who gave their informed
consent underwent cerebral sagittal T1-weighted and axial
T2-weighted MRI. In addition, most of these symptom-free
patients underwent MRI gradient-echo sequences investigation. MRI data were independently reviewed by P.L. and
We considered as “affected” all subjects showing cavernous angiomas on cerebral MRI whatever their clinical status.
This group included symptomatic and symptom-free subjects. We considered as “healthy” all subjects with a normal
MRI. Those who did not undergo MRI screening were classified as “unknown.” Clinical and MRI information for 22
of the 64 families included in this study had been reported
in part elsewhere before KRIT1 gene identification.6
Molecular Analysis
Genomic DNA from each index patient and all consenting
relatives was extracted from peripheral blood using standard
procedures. Genomic DNA from 100 unrelated healthy
white French subjects was available as a control group. A
combination of single-strand conformation polymorphism
(SSCP) and sequencing have been used to screen the 16 coding exons and exon–intron boundaries of KRIT1 gene in all
153 probands as described elsewhere.20 Molecular screening
data of 121 of these probands were reported previously.20
Thirty-two additional probands were screened herein using
the same procedure. This screening led us to identify a deleterious mutation in 64 of these 153 probands, a proportion
which is in agreement with previously reported linkage data.9
All these mutations led to a premature stop codon through
nonsense, splicing, or frameshift mutations, strongly suggesting that the consequences of these mutations at the protein
level would be similar (Fig 1).20
Fig 1. Genealogical trees of families with KRIT1 mutations.
The pedigrees are numbered (Cn) and KRIT1 mutations are
indicated. Numbering of KRIT1 nucleotides (nt) is according
to the full-length KRIT1 cDNA (accession number
AF296765), beginning nucleotide numbering at the A of the
ATG initiator codon. MRI ⫽ magnetic resonance imaging;
CCM ⫽ cerebral cavernous malformation.
Figure 1
Denier et al: Cerebral Cavernous Malformations
Table 1. Clinical and Neuroradiological Features in 202 KRIT1 Mutations Carriers
All Subjects
N ⫽ 202
Symptomatic subjects
Age of patients (yr)
Mean ⫾ SD
Age of onset (yr)
Mean ⫾ SD
No. of CCM lesions
On T2-weighted MRI ⫾ SD
On gradient-echo sequence ⫾ SD
Mean age at MRI (yr)
Types of first clinical manifestations (%)
Cerebral hemorrhages–no/total no
Seizures–no. total no.
Others–no. total no.
Asymptomatic subjects
Age of patients (yr)
Mean ⫾ SD
Number of CCM lesions
On T2-weighted MRI ⫾ SD
On gradient-echo sequence ⫾ SD
Mean age at gradient-echo MRI
N ⫽ 98
N ⫽ 104
N ⫽ 126
N ⫽ 62
N ⫽ 64
41.8 ⫾ 17.9
40.7 ⫾ 18.4
42.9 ⫾ 17.4
29.7 ⫾ 16.6
27.5 ⫾ 16
32.1 ⫾ 17
5.0 ⫾ 6.7 (n ⫽ 79)a
18.2 ⫾ 28 (n ⫽ 37)
36.8 ⫾ 17.2
4.0 ⫾ 3.6 (n ⫽ 39)
15.1 ⫾ 16.2 (n ⫽ 17)
36.4 ⫾ 17.4
6.0 ⫾ 8.7 (n ⫽ 40)
20.8 ⫾ 35.3 (n ⫽ 20)
37.3 ⫾ 17.2
32% (n ⫽ 111)
N ⫽ 76
29% (n ⫽ 58)
N ⫽ 36
34% (n ⫽ 53)
N ⫽ 40
46.8 ⫾ 17.3
47 ⫾ 18.3
46.6 ⫾ 16.7
4.8 ⫾ 8.0 (n ⫽ 53)
21.1 ⫾ 37.4 (n ⫽ 43)
42.8 ⫾ 19.8
6.7 ⫾ 11 (n ⫽ 24)
24.1 ⫾ 40.6 (n ⫽ 17)
41 ⫾ 17.5
3.2 ⫾ 3.7 (n ⫽ 29)
19.2 ⫾ 35.8 (n ⫽ 26)
44.2 ⫾ 14.5
The number between brackets indicates the number of individuals for whom data were available.
SD ⫽ standard deviation; CCM ⫽ cerebral cavernous malformations; MRI ⫽ magnetic resonance imaging.
Based on these data, SSCP analysis was used herein to
genotype all available and consenting members of the 64
KRIT1-positive families including 126 symptomatic CCM
patients, 187 at-risk asymptomatic relatives, and 64 spouses.
In addition to SSCP screening, genomic DNA sequencing
was used for confirmation of “mutation carrier” status in all
symptom-free patients with a normal MRI.
Statistical Analysis
Student t and ␹2 tests were utilized for comparison of age at
inclusion, age of onset, and number of CCM lesions on
MRI. A p value less than 0.05 was considered significant.
Plus or minus values are means ⫾ SD.
Clinical and Neuroradiological Features of the 202
KRIT1 Mutation Carriers
A total of 202 KRIT1 mutation carriers was identified
including the 64 probands and 138 relatives. Among
mutation carriers, there were 98 men and 104 women.
Mean age at inclusion was similar in men and women
and close to 40 years old (Table 1). Among these mutation carriers, 126 were symptomatic. There was no
difference when comparing the clinical manifestations
present in the probands and their clinically affected relatives, and therefore these two groups were considered
as a whole (data not shown).
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Mean age at clinical
onset was 29.7 ⫾ 16.6 years (range, 2–72). Mean age
at clinical onset was slightly higher in women, but this
difference did not reach statistical significance (see Table 1). Grouping of patients according to clinical age
of onset in three age groups (0 –24, 25– 44, and ⱖ45
years) showed that half of the patients presented their
first neurological symptoms before 25 years of age and
20% after 45 years old (Table 2). Interestingly, comparison of male/female proportions within these three
age groups showed a significant deviation toward a
higher age of onset in women ( p ⬍ 0.05). This later
age of onset in women was not associated with a propensity to a particular type of initial clinical event.
group of the 126 symptomatic patients, seizures were
the initial events in 55% of the patients; 47% of the
patients had generalized seizures, 43% had partial seizures, and 10% had both types. Cerebral hemorrhage
was the second most common event (32%). At time of
inclusion, 15% of the patients had presented more
than one hemorrhagic event (two to four symptomatic
hemorrhages). For patients who did not present with
seizures or hemorrhage, initial symptoms were focal
signs (9%) and headache (4%). Mean age of onset of
patients in whom seizures were the initial event was
Table 2. Comparison of Male/Female Age Range at Clinical
Onset in KRIT1 Mutation Carriers
Age Groups (yr)a
ⱖ 45
Symptomatic men (N ⫽ 58)b
Symptomatic women (N ⫽ 53)
All symptomatic patients
(N ⫽ 111)
Comparison of the proportions of males and females within these
three age groups showed a significant deviation toward a higher age
of onset in females ( p ⬍ 0.05).
The number between brackets indicates the number of individuals
for whom data were available.
slightly higher than in patients with hemorrhage
(28.5 ⫾ 15.2 years old as compared with 24.4 ⫾ 15.2
years old in patients whose first event was hemorrhage), but this difference was not statistically significant. These two groups of patients did not differ for
the number of CCM lesions. At last, in addition to
cerebral lesions, 10 patients from 5 of these 64 families
showed cutaneous hyperkeratotic vascular lesions that
have been reported previously to be associated with cerebral cavernous angiomas.24
Clinical disability at time of inclusion was assessed
according to neurological handicap: 89% of the whole
group of symptomatic patients were fully independent,
10% were handicapped, and 1% were bedridden.
Comparison of sex ratio, symptoms at clinical onset,
and mean number of lesions did not show any difference between independent and disabled patients. For
the 61 patients in whom seizures were the initial event,
the grade of epilepsy disability was evaluated according
to patient’s response to anticonvulsant drugs: 91%
were controlled by anticonvulsants, whereas 9% had
intractable epilepsy. We did not detect any difference
for age or number of lesions between these two groups
of epileptic patients.
T2-weighted standard MRI sequences were available
for 132 KRIT1 mutation carriers (including 79 symptomatic subjects) and gradient-echo sequences for 80
(37 symptomatic subjects).
Classically, familial CCM patients have multiple
CCM lesions, whereas nonfamilial sporadic cases harbor only one CCM lesion. In this panel, 80% of
KRIT1 mutation carriers had multiple lesions on T2weighted sequences and 90% multiple lesions on
highly sensitive gradient-echo sequence MRI investigations. The average number of lesions per subject was
4.9 ⫾ 7.2 on standard MRI and 19.8 ⫾ 33.2 on
gradient-echo sequences ( p ⬍ 0.001). There was no
significant difference in the number of lesions in subjects with and without symptom on both T2-weighted
MRI sequences (5.0 ⫾ 6.7 vs 4.8 ⫾ 8.0) and gradientecho MRI sequences (18.2 ⫾ 28.0 vs 21.1 ⫾ 37.4; see
Table 1).
Of 132 mutation carriers for whom MRI investigation was available, 26 subjects (20%) harbored only
one lesion on T2-weighted MRI (mean age at MRI,
29.4 ⫾14.8 years; range, 5–50). Among them, 12 subjects underwent gradient-echo sequence MRI, which
disclosed multiple lesions in eight cases; the last four
subjects, one man and three women, aged, respectively,
18, 34, 34, and 55 years old, were all symptom-free
and presented only one CCM lesion both on T2weighted and on gradient-echo sequences MRI (see
Fig 1).
At last, eight symptom-free mutation carriers had a
normal T2-weighted MRI (see next paragraph).
There was a strong correlation between age and
number of lesions on T2-weighted and gradient-echo
sequences. Among subjects younger than 45 years old,
the average number of lesions on T2-weighted sequences was 3.3 ⫾ 3.4 (range, 0 –19; n ⫽ 85), whereas
it was 8.0 ⫾10.7 in subjects aged 45 years and older
(range, 0 – 43; n ⫽ 47; p ⬍ 0.001). On gradient-echo
sequences, the mean number of lesions was 10.6 ⫾
20.2 in subjects younger than 45 years (range, 0 –130;
n ⫽ 51), whereas it was 35.9 ⫾ 44.3 in subjects older
than 45 years (range, 0 –154; n ⫽ 29; p ⬍ 0.001).
Among the 249 sampled at-risk relatives of
the 64 probands carrying a KRIT1 mutation, 138 were
mutation carriers, including 62 symptomatic subjects
and 76 symptom-free subjects. Comparison of symptomatic and asymptomatic subjects for mean age at inclusion and sex ratio did not show any significant difference.
Among these 76 symptom-free mutation carriers, 53
underwent an MRI investigation; CCM lesions were
detected in 45 of them. Among the eight symptom-free
subjects who did not show any CCM lesions on T2weighted imaging, two subjects, a 44-year-old man and
a 67-year-old woman, showed on gradient-echo sequences MRI, respectively, nine and three hyposignals
strongly suggestive of type IV lesions according to
Zabramski’s classification25; of the six remaining
symptom-free subjects, five subjects underwent
gradient-echo sequence MRIs that were strictly normal.
In addition to carrying the mutation identified within
their affected family members, these five symptom-free
KRIT1 mutation carriers had been previously shown to
carry the disease CCM1-linked haplotype within their
respective families10 (data not shown). These five subjects included a 27-year-old man and four women aged
29, 33, 35, and 48 years old (Figs 1 and 2).
Denier et al: Cerebral Cavernous Malformations
Fig 2. Incomplete clinical and neuroradiological penetrance in
a KRIT1 mutation carrier. (top) Part of the genealogical tree
of Family C005 is shown: men (squares), women (circles),
healthy with a normal magnetic resonance image (MRI):
(open symbols), clinically affected: (filled symbols), and
symptom-free patients with CCM lesions on MRI: (half-filled
symbols). The numbering in this part of Family C005 is
according to the single-strand conformation polymorphism
(SSCP) gel lanes. The proband of this family harbors a C to
T nucleotide substitution at nucleotide 1943 within exon 17
which emerged as an abnormal SSCP conformer (lane 3). All
members of the family showing CCM lesions (Patients 3, 5, 6,
8) carry the same abnormal conformer that was detected in
the proband and that was absent in healthy subjects with the
exception of Subject 2, a 48-year-old female mutation carrier
whose MRI, including gradient-echo sequences, was strictly
normal (bottom panel, showing cerebral gradient-echo sequences MRI of Subjects 2 [normal MRI] and 8 [CCM temporal lesion]).
Before CCM gene mapping and CCM1/KRIT1 gene
identification, several studies allowed establishment of
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some of the major clinical and neuroimaging features
of familial cavernous angiomas, namely, its autosomal
dominant pattern of inheritance, its incomplete clinical
penetrance, and the multiplicity of cerebral CCM lesions. Another major feature of this genetically heterogenous condition is its clinical variability both within
a given family and from one family to another. The
features associated with KRIT1 mutations had not yet
been assessed in a large series of patients. Herein, we
characterized the clinical and neuroimaging features of
this condition in 64 families in which segregates a mutation within the KRIT1/CCM1 gene, all these mutations being highly stereotyped and leading to a premature termination codons and most likely to Krit1
Clinical penetrance in familial CCM was reported to
be incomplete. In our panel of KRIT1-positive families,
clinical penetrance was also incomplete. The proportion
of symptomatic subjects among mutation carriers in this
panel was 62%. Importantly for genetic counseling, only
half of the sampled mutation carriers subjects aged 50
years or older at inclusion had neurological symptoms
that were CCM related (58%). These proportions
should be considered as a maximum estimate because
not all asymptomatic subjects have been genotyped.
Neuroimaging penetrance of CCM was considered
previously to be much higher and complete or almost
complete. So far, only four obligate transmitters of the
disease with a normal T2-weighted MRI scan have
been reported6,26,27; sensitive gradient-echo MRI scan
was not performed in those patients and, indeed, to
our knowledge, there is no published case of an obligate asymptomatic carrier with a normal gradient-echo
MRI. Molecular screening allowed us to establish that
neuroimaging penetrance is also incomplete, even
when using the highly sensitive gradient-echo sequence
investigation. Indeed, 5 of our 76 asymptomatic mutation carriers, the oldest one being 48 years old, did not
show any lesion on gradient-echo MRI.
Previous studies have shown that most patients affected with familial CCM harbor multiple cerebral lesions, and that apparently isolated patients showing
multiple lesions are in reality affected with an hereditary form of the disease. In this panel, at least 13% of
KRIT1 mutation carriers had only one CCM lesion on
T2-weighted sequences and 2% had only one lesion on
gradient-echo sequences. These data, combined with
the incomplete clinical penetrance of this disorder,
strongly suggest that the familial nature of cavernous
angiomas may be overlooked in some patients.
Additional information was drawn from male/female
KRIT1 mutation carriers comparison. The proportions
of affected subjects and the nature of the clinical manifestations were similar in these two groups except for a
higher proportion of women in the age groups of patients with a late onset (after 45 years old). Although
these data need confirmation in a second panel of families, they raise interesting questions. Previous studies
including mostly sporadic cases suggested that men
have an earlier age of onset.2,28,29 Other studies suggested the role of hormonal factors which may influence the biological behavior of cavernous angiomas in
women, in particular, during pregnancy and under
hormonal treatment.2,29 –32 So far, to our knowledge,
influence of menopause on cerebral cavernous angiomas evolution has not been studied. Studies of larger
cohorts of female patients carrying a KRIT1 mutation
should allow to better delineate the natural history of
the disease regarding main hormonal events.
At last, a follow-up of this cohort of genotyped patients and further genetic studies should also help in
the future to delineate environmental factors or modifying genes explaining the intrafamilial and interfamilial variability of familial CCM.
The main clinical investigators were Drs Barbieux-Vaquez,
Canaple, Le Gars (Amiens), de Bray, Fournier, Guy, PenissonBesnier (Angers), Bergouignan (Bayonne), Beuriat (Beaune),
Thibaut (Berck), Bizette, Czorny, Godard, Jacquet (Besançon), Comoy, David, Parker, Said (Bicêtre), Castel, Guerin,
Loiseau (Bordeaux), Houtteville, Khoury, Viader (Caen), Attané, Tannier (Carcassonne), Bréchard (Chalons/Saone), Carriere, Chazal, Clavelou (Clermont-Ferrand), Nivelon (Dijon),
Benabid, Perret (Grenoble), Latinville (La Rochelle), Born
(Liège), Christiaens, Combelles, Lejeune, Louis, Pasquier
(Lille), Moreau (Limoges), Fischer, Froment, Guyotat, Mortelese, Sindou (Lyon), Robert, Sauvage, Savet (Macon), Attarian,
Gomez, Lena (Marseille), Richard (Montbéliard), Cesari,
Coubes, Idee, Frerebeau (Montpellier), Rey (Narbonne), Carriere (Nimes), Hepner, Lescure, Vespignani, Weber (Nancy),
Martin, Mussini, Resche (Nantes), Borg, Grellier, Thomas,
Lonjon (Nice), Masson, Redondo, Rey (Paris, Beaujon), Delalande (Paris), Georges, Lot, Hagueneau, Sarrazin, Silhouette
(Paris, Lariboisière), Zerah, Renier, Pierre-Kahn (Paris,
Necker), Baulac, Capelle, Arthuis, Clemenceau, Faillot, Fohano, Philippon (Paris, La Salpétrière), Gil, Lapierre, Neau
(Poitiers), Rousseaux, Gaillard (Reims), Carsin, Dufour, Guegan, Seigneuret, Scarabin (Rennes), Drouin-Garraud, Rossi,
Frebourg, Freger (Rouen), Brunon, Garnier, Michel (SaintEtienne), Esposito, Metraut (Strasbourg), Aesch, Maheut
Lourmière, François, Jan, Velut (Tours), Arrue, Bousquet,
Chaix, Clanet, Fabre, Geraud, Lazorthes, Manelfe, Tremoulet
(Toulouse), and Joyeux (Valence).
This work was supported by an INSERM/AFM/MESR grant
(French National Institute for Health and Medical Research/French
Association against Myopathies/French Research Ministry,
AAE00013HSA, E.T.L.). C.D. is a recipient of a fellowship from
Poste Accueil INSERM.
We thank all families for their participation. We are also indebted
to all members of the Société Française de Neurochirurgie and Société de Neurochirurgie de Langue Française who participated in
this study.
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features, patients, mutation, clinical, krit, malformations, cavernous, cerebral
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