cerebral cavernous malformation ( ccm ) is a disorder defined by the presence of vascular malformations called cavernomas , histologically characterized by abnormally enlarged capillary cavities without intervening brain parenchyma . ccm represents 513% of all cerebral vascular malformations and its estimated prevalence is about 0.10.5% in the general population . the former usually harbors a single lesion , whereas the latter is characterized by the presence of multiple lesions whose number is correlated with the patient 's age . the proportion of familial cases is estimated to be between 10 and 50% , with an autosomal dominant inheritance and an incomplete penetrance . the average age of onset is about 30 years , but symptoms can also start in early infancy or in old age . the clinical phenotype is highly variable , with seizures , cerebral hemorrhage , focal neurological deficits and headache being the main clinical presentations . mri t2 * -weighted sequences usually show lesions with areas of mixed signal intensity , with a central reticular core and a peripheral rim of decreased signal intensity due to hemosiderin deposition . genetic linkage analysis mapped three ccm loci : ccm1 gene ( krit1 ) at 7q , ccm2 gene ( mgc4607 ) at 7p and ccm3 gene ( pdcd10 ) at 3q [ 5 , 6 ] . in familial cases , a causative mutation is found in 78% of patients , with ccm1 corresponding to more than 50% of mutations . ccm1 encodes for the krev interaction trapped 1 ( krit1 ) protein , which has a role in endothelial junctions and microtubule functions . the proband ( ii-6 ) is a 65-year - old woman . at the age of 55 years brain mri showed bilateral , supra- and infratentorial cavernomas , including the brain stem ( fig 2 ) . eeg at that time displayed bilateral temporal paroxysmal activity , and the epileptic seizures were controlled with levetiracetam 500 mg b.i.d . ccm1/krit 1 coding exons and their intronic boundaries were pcr - amplified and screened with nm_194454.1 as the sequence reference . a novel nucleotide substitution c.1927c > t ( p.gln643 * ) within the exon 17 was found . the proband 's 67-year - old sister ( ii-4 ) experienced isolated tonic - clonic seizures at the age of 61 years imaging investigation revealed a right frontal intracerebral hemorrhage and multiple bilateral supra- and infratentorial cerebral cavernomas . one year thereafter , without evidence of rebleeding , the patient started to have partial complex seizures , controlled with levetiracetam 500 mg b.i.d . after 4 years without symptoms , the patient suffered a new intracerebral hemorrhage in the right temporal lobe . a new brain mri showed progression in the number and size of the cavernomas , a left v cranial nerve schwannoma and a spinal cord cavernoma ( fig 3 ) . genetic analysis using the proband 's mutation as reference displayed the same nucleotide substitution c.1927c > t ( p.gln643 * ) within ccm1 exon 17 . other family members were not evaluated in our hospital , but as far as we know , the oldest sister ( ii-2 ) suffered an intracerebral hemorrhage at the age of 29 that was attributed to a cavernous malformation . in 1 of the proband 's siblings ( iii-6 ) and in both ( iii-3 and iii-5 ) , without any history of neurological disease , i.e. epileptic fits or stroke , brain mri was performed at the age of 31 , 38 and 41 years , respectively , without evidence of any lesion . although the proband 's parents ( i-4 and i-5 ) had no history of any ccm symptoms , one of her father 's brothers ( i-3 ) had a history of refractory seizures since his 4th decade of life . also one of the proband 's father nephews ( iii-10 ) was diagnosed with secondary epilepsy due to an isolated carvernoma at the age of 26 . the proband ( ii-6 ) is a 65-year - old woman . at the age of 55 years brain mri showed bilateral , supra- and infratentorial cavernomas , including the brain stem ( fig 2 ) . eeg at that time displayed bilateral temporal paroxysmal activity , and the epileptic seizures were controlled with levetiracetam 500 mg b.i.d . ccm1/krit 1 coding exons and their intronic boundaries were pcr - amplified and screened with nm_194454.1 as the sequence reference . a novel nucleotide substitution c.1927c > t ( p.gln643 * ) within the exon 17 was found . the proband 's 67-year - old sister ( ii-4 ) experienced isolated tonic - clonic seizures at the age of 61 years . neurological examination revealed a left superior quadrantanopia . imaging investigation revealed a right frontal intracerebral hemorrhage and multiple bilateral supra- and infratentorial cerebral cavernomas . one year thereafter , without evidence of rebleeding , the patient started to have partial complex seizures , controlled with levetiracetam 500 mg b.i.d . after 4 years without symptoms , the patient suffered a new intracerebral hemorrhage in the right temporal lobe . a new brain mri showed progression in the number and size of the cavernomas , a left v cranial nerve schwannoma and a spinal cord cavernoma ( fig 3 ) . genetic analysis using the proband 's mutation as reference displayed the same nucleotide substitution c.1927c > t ( p.gln643 * ) within ccm1 exon 17 . other family members were not evaluated in our hospital , but as far as we know , the oldest sister ( ii-2 ) suffered an intracerebral hemorrhage at the age of 29 that was attributed to a cavernous malformation . in 1 of the proband 's siblings ( iii-6 ) and in both ( iii-3 and iii-5 ) , without any history of neurological disease , i.e. epileptic fits or stroke , brain mri was performed at the age of 31 , 38 and 41 years , respectively , without evidence of any lesion . although the proband 's parents ( i-4 and i-5 ) had no history of any ccm symptoms , one of her father 's brothers ( i-3 ) had a history of refractory seizures since his 4th decade of life . also one of the proband 's father nephews ( iii-10 ) was diagnosed with secondary epilepsy due to an isolated carvernoma at the age of 26 . three genes have been described in the familial cases ( ccm1/krit1 , ccm2/mgc4607 , and ccm3/ pdcd10 ) . although more than 150 distinct mutations have been published , those mutations are highly stereotyped because almost all of them , through different mutation mechanisms , lead to premature termination codons . , the nucleotide substitution c.1927c > t ( p.gln643 * ) within the ccm1 loci exon 17 also encodes a stop codon , responsible for a truncated krit1 protein . this fact , associated with the concordance of the same mutation in 2 family members with multiple cavernous malformations , supports the pathogenic role of the identified mutation . of the patients with ccm who have multiple lesions and no family history , 75% of them have an asymptomatic parent with ccm lesion on brain mri , due to incomplete clinical penetrance . spontaneous de novo mutations can also be responsible for sporadic cases with multiple ccm lesions . as stated above , familial ccm is very heterogeneous , with a significant interfamilial and intrafamilial variability . of the different clinical presentations , seizures are the most frequent , and they can be generalized , partial , or both types , as in our family . ccm lesions are highly epileptogenic due to blood breakdown products like iron surrounding the lesion and the subsequent local gliomatous reaction . intracranial hemorrhage that occurred in patients ii-6 and individuals with ccms experience new bleeding complications at an average rate of 0.71.1% per lesion per year   with an annual symptomatic hemorrhage rate that can reach 6.4% . the risk of clinical manifestations increases with age , being previous gross hemorrhage , infratentorial lesions and female sex , factors associated with future clinical disability . mri t2-weighted gradient - echo sequences were considered to be the gold standard method to access the number and size of the lesions , as their signal evolution . however , this imaging sequence can not fully exclude the presence of the disorder , and the new susceptibility - weighted imaging sequences proved to be more sensitive to detect cavernomas . as mentioned above , ccm familial cases usually present with multiple lesions , in both supra- and infratentorial localizations , as in the present case . less frequently , spinal cord lesions have also been reported , as in patient ii-4 ( fig 3 ) . the association of ccm with extracerebral vascular malformations as well as with other tumors has been reported . as in the present family ( patient ii-4 ; fig 3 ) , ccm can be associated with schwannomas and other intracranial tumors . surgical treatment in ccm seems to be associated with worse outcomes over 5 years compared to conservative treatment . the disease phenotype and genotype characterization , as well as their correlation , are important to establish appropriate therapeutic approaches and clinical surveillance protocols , to define prognosis and to guide genetic counseling . written informed consent was obtained from the proband ( ii-6 ) and patient ii-4 for the publication of this case report and any accompanying images . a copy of the written consent is available for review by the editor of this journal .
introductioncerebral cavernous malformation ( ccm ) is a vascular disorder characterized by the presence of central nervous system cavernomas . in familial forms , 
 mutations in three genes ( ccm1/krit1 , ccm2/mgc4607 and ccm3/pdcd10 ) were identified . 
 we describe a portuguese family harboring a novel ccm1 mutation.case presentationthe proband is a woman who at the age of 55 years started to have complex partial seizures and episodic headache . 
 although nothing was found during her neurological examination , brain mri showed bilateral , supra- and infratentorial cavernomas . 
 she had a sister who , at the age 61 years , suffered a tonic - clonic seizure . 
 neurological examination was normal and imaging investigation demonstrated a right frontal intracerebral hemorrhage and multiple cavernomas . in the following years , she suffered several complex partial seizures and had a new intracerebral hemorrhage located in the right temporal lobe . genetic analysis was performed and a novel nucleotide substitution , i.e. c.1927c > t ( p.gln643 * ) within the exon 17 of the ccm1 gene , was detected in both sisters . 
 the substitution encodes a stop codon , with a consequent truncated krit1 protein , therefore supporting its pathogenic role . 
 further affected family members were detected , suggesting an autosomal dominant pattern of inheritance.conclusionwe report a portuguese family with a novel ccm1 ( krit1 ) mutation 
 c.1927c > t ( p.gln643 * ) 
 . a better knowledge of the phenotype - genotype correlation is needed to improve the management of ccm patients .