Genotype-phenotype correlations in cerebral cavernous malformations patients.
OBJECTIVE
To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers.


METHODS
A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed.


RESULTS
A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety-four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2-weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient-echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient-echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05).


CONCLUSIONS
Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient-echo sequence lesions with age differs between CCM1 and CCM2 patients.
Denier
Christian
C
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.|Service de Neurologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Paris.
Labauge
Pierre
P
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.|Service de Neurologie, Centre Hospitalier Universitaire de Nïmes, Nïmes.
Bergametti
Françoise
F
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.|Université Denis Diderot Paris7.
Marchelli
Florence
F
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.
Riant
Florence
F
Assistance Publique-Hôpitaux de Paris, Laboratoire de Cytogénétique, Hôpital Lariboisière, Paris.
Arnoult
Minh
M
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.|Université Denis Diderot Paris7.
Maciazek
Jacqueline
J
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.
Vicaut
Eric
E
Unité de Recherche Clinique, Hôpital Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris.
Brunereau
Laurent
L
Service de Radiologie, Centre Hospitalier Universitaire de Tours, Paris, France.
Tournier-Lasserve
Elisabeth
E
Institut National de la Sante et de la Recherche Médicale U740, Faculté de Médecine Lariboisière, Paris.|Université Denis Diderot Paris7.|Assistance Publique-Hôpitaux de Paris, Laboratoire de Cytogénétique, Hôpital Lariboisière, Paris.
D000293:Adolescent; D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002543:Cerebral Hemorrhage / Q000453:epidemiology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D038524:Diffusion Magnetic Resonance Imaging; D005260:Female; D005838:Genotype; D020786:Hemangioma, Cavernous, Central Nervous System / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012640:Seizures / Q000453:epidemiology; D012720:Severity of Illness Index
C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins