Genotype-phenotype correlations in cerebral cavernous malformations patients

Ann Neurol. 2006 Nov;60(5):550-556. doi: 10.1002/ana.20947.


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).

Interpretation: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Brain / pathology
  • Carrier Proteins / genetics
  • Cerebral Hemorrhage / epidemiology
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Diffusion Magnetic Resonance Imaging
  • Female
  • Genotype
  • Hemangioma, Cavernous, Central Nervous System / epidemiology
  • Hemangioma, Cavernous, Central Nervous System / genetics*
  • Hemangioma, Cavernous, Central Nervous System / pathology*
  • Humans
  • KRIT1 Protein
  • Male
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Phenotype
  • Point Mutation / genetics*
  • Proto-Oncogene Proteins / genetics
  • Seizures / epidemiology
  • Severity of Illness Index


  • CCM2 protein, human
  • Carrier Proteins
  • KRIT1 Protein
  • KRIT1 protein, human
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins