title: Spectrum of genotype and clinical manifestations in cerebral cavernous malformations.
abstract: OBJECTIVE
  Cerebral cavernous malformations (CCMs) are focal dysmorphic blood vessel anomalies predisposing individuals to hemorrhagic stroke and epilepsy. CCMs are sporadic or inherited as autosomal dominant disease with three known genes. The hypothesis that genetic heterogeneity would account for the remarkable variability in CCM manifestations was tested.
  
  
  METHODS
  CCM cases were prospectively enrolled. Germline CCM1 gene mutations were sought in 89 CCM samples. Associations with clinical manifestations and lesion characteristics were made among 41 symptomatic familial cases, including one cohort of 26 cases with CCM1 mutations and a second cohort of 15 cases without identifiable CCM1 mutations. The 15 cases were screened for CCM2 and CCM3 mutations.
  
  
  RESULTS
  CCM1 mutations were found in 34 out of 50 subjects with familial disease and in none of 39 sporadic CCM cases. CCM2 and CCM3 mutations were found in three out of 10 families screened without CCM1 mutations. Clinical manifestations in 22 Hispanic-American cases with identical CCM1 mutations were highly variable. Fewer CCM1 patients experienced hemorrhage than others with familial disease (P = 0.0139 for all cases and P = 0.0442 for symptomatic cases). Adjusting for sex and age improved the logistic regression model, suggesting decreased numbers of patients with hemorrhage in CCM1 familial disease (P = 0.003 for all cases and P = 0.014 for symptomatic cases). Hemorrhage differences were not related to size or number of lesions.
  
  
  CONCLUSIONS
  Factors in addition to CCM1 germline mutation contribute to CCM clinical manifestations. However, this evidence suggests that familial cases with CCM1 mutations may have less severe clinical manifestations than other familial cases.
authors.affiliation: Department of Neurosurgery, University of Colorado at Denver and Health Sciences Center, Denver, Colorado 80262, USA. Judith.Gault@uchsc.edu
authors.forename: Judith
authors.initials: J
authors.lastname: Gault
authors.forename: Stephan
authors.initials: S
authors.lastname: Sain
authors.forename: Ling-Jia
authors.initials: LJ
authors.lastname: Hu
authors.forename: Issam A
authors.initials: IA
authors.lastname: Awad
mesh_terms: D000328:Adult; D003120:Colorado / Q000453:epidemiology; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D005838:Genotype; D020786:Hemangioma, Cavernous, Central Nervous System / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D000075927:KRIT1 Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015995:Prevalence; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors
chemical_list: D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins