Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation.
BACKGROUND
Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in seizures, hemorrhage, recurrent headaches, and focal neurologic deficits. These CCMs can occur as sporadic or autosomal dominant conditions, although with incomplete penetrance and variable clinical expression. Three CCM loci have been identified, on chromosomes 7q21-22 (CCM1; Online Mendelian Inheritance in Man [OMIM] 116860), 7p13-15 (CCM2; OMIM 603284), and 3q25.2-27 (CCM3; OMIM 603285), and 3 genes have been cloned, KRIT1 on CCM1, MGC4607 on CCM2, and PDCD10 on CCM3. Mutations in KRIT1 account for more than 40% of CCMs.


OBJECTIVE
To describe the results of a comprehensive evaluation of 5 Italian families affected with CCM.


METHODS
Clinical, magnetic resonance imaging, and KRIT1 gene analysis.


METHODS
University academic teaching hospitals.


METHODS
Fifteen patients with CCM diagnosed according to defined criteria and 45 at-risk, symptom-free relatives.


RESULTS
Three novel and 2 described mutations were found in KRIT1. The families included 33 KRIT1 mutation carriers, 57.6% of whom had no symptoms. Magnetic resonance imaging revealed CCM lesions in 82.3% of symptom-free mutation carriers.


CONCLUSIONS
The data confirm both incomplete clinical and neuroimaging penetrance in families with the KRIT1 mutation. This consideration is important in genetic counseling. Moreover, the data emphasize both the importance of magnetic resonance imaging in the diagnosis of CCM and the potential for DNA-based diagnosis to identify subjects at risk.
Battistini
Stefania
S
Department of Neuroscience, University of Siena, Italy.
Rocchi
Raffaele
R
Cerase
Alfonso
A
Citterio
Alberto
A
Tassi
Laura
L
Lando
Giuliana
G
Patrosso
Maria Cristina
MC
Galli
Rosita
R
Brunori
Paola
P
Sgrò
Domenica L
DL
Pitillo
Giovanni
G
Lo Russo
Giorgio
G
Marocchi
Alessandro
A
Penco
Silvana
S
D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D002493:Central Nervous System Diseases / Q000209:etiology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020786:Hemangioma, Cavernous, Central Nervous System / Q000150:complications / Q000175:diagnosis* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007558:Italy; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins