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Original Contribution |

Clinical, Magnetic Resonance Imaging, and Genetic Study of 5 Italian Families With Cerebral Cavernous Malformation FREE

Stefania Battistini, MD, PhD; Raffaele Rocchi, MD; Alfonso Cerase, MD; Alberto Citterio, MD; Laura Tassi, MD; Giuliana Lando, MS; Maria Cristina Patrosso, MS; Rosita Galli, MD; Paola Brunori, MD; Domenica L. Sgrò, MD; Giovanni Pitillo, MD; Giorgio Lo Russo, MD; Alessandro Marocchi, MD; Silvana Penco, MS, PhD
[+] Author Affiliations

Author Affiliations: Department of Neuroscience, Neurology Section, University of Siena (Drs Battistini, Rocchi, and Galli), and Department of Neurosciences, Unit of Diagnostic and Therapeutic Neuroradiology, Azienda Ospedaliera Universitaria Senese (Dr Cerase), Siena, Italy; Departments of Neuroradiology (Dr Citterio) and Neuroscience, Regional Centre for Epilepsy Surgery (Drs Tassi and Lo Russo), and Clinical Chemistry and Clinical Pathology Laboratory, Medical Genetics (Mss Lando and Patrosso and Drs Marocchi and Penco), A. O. Niguarda Ca’Granda Hospital, Milan, Italy; Neurofisiopatology, A. O. Silvestrini, Perugia, Italy (Dr Brunori); Department of Pediatric Sciences, Child Neuropsychiatry Unit, AOU Policlinico “G. Martino,” Messina, Italy (Dr Sgrò); and Child Neuropsychiatry Unit, “F. del Ponte” Hospital, University of Insubria, Varese, Italy (Dr Pitillo).


Arch Neurol. 2007;64(6):843-848. doi:10.1001/archneur.64.6.843.
Text Size: A A A
Published online

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.

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

Setting  University academic teaching hospitals.

Patients  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.

Figures in this Article

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the brain and account for 10% to 20% of all vascular malformations of the central nervous system. They consist of abnormally enlarged capillary cavities without intervening brain parenchyma.1 The prevalence of CCM in the general population has been estimated as close to 0.1% to 0.5%. Their clinical presentation can vary widely, though headaches, seizures, focal neurologic deficit, and hemorrhage are the major symptoms.2 Cutaneous, retinal, hepatic, spinal cord, and vertebral cavernous angiomas have occasionally been reported in patients with CCM.3,4

Cerebral cavernous malformations can occur as either sporadic or autosomal dominant conditions, although with incomplete penetrance and with variable clinical expression, both intrafamilial and interfamilial.2 While sporadic cases most often demonstrate 1 CCM lesion, the familial form frequently is characterized by a high frequency of multiple lesions, the number of which is strongly correlated with patient age, suggesting a dynamic nature of these lesions.5

Three CCM loci have been mapped to chromosomes 7q21-22 (CCM1; Online Mendelian Inheritance in Man [OMIM] 116860), 7p13-15 (CCM2; OMIM 603284), and 3q25.2-27 (CCM3; OMIM 603285),6,7 and 3 types of CCM are recognized on the basis of their underlying molecular genetics. Mutations in the gene KRIT1, encoding Krev-1/rap1 interaction trapped–1 protein (KRIT1), are responsible for CCM18,9 and are found in approximately 40% of inherited cases.10 Sporadic cases with multiple lesions seem to have KRIT1 mutations in approximately the same proportion as familial cases, whereas no KRIT1 mutations have been found in sporadic cases with a single lesion.10 All KRIT1 mutations identified to date are highly stereotyped, leading to premature stop codons, suggesting that KRIT1 loss of function may be the underlying mechanism in patients with CCM.11,12 KRIT1 is a protein of unknown function binding to integrin cytoplasmic domain-associated protein-1α, a protein containing a phosphotyrosine binding domain that also binds to the β1-integrin cytoplasmic domain.13 A second disease gene, MGC4607, encoding the protein malcavernin with a phosphotyrosine binding domain, was identified in families with CCM2.14,15 Mutations in this gene account for about 20% of familial cases, whereas no mutations were found in a cohort of sporadic cases with single and multiple lesions.10 Recently it was shown that KRIT1 and malcavernin interact in a common signaling complex and that loss of this interaction could contribute to CCM pathogenesis.16 Families with CCM3 have recently been shown to have mutations in PDCD10 (programmed cell death 10), a gene up-regulated in the TF-1 premyeloid cell line after apoptosis induction.17 The frequency of PDCD10 mutations identified in families with CCM3 was lower than expected on the basis of linkage,7 suggesting the possibility of a fourth CCM gene.10

Although the disease gene products for all 3 loci have been identified, the pathologic mechanism remains unknown. At least 2 possible mechanisms have been postulated for malformation development: a Knudson second-hit hypothesis and a haploinsufficiency model.18

We performed clinical, neuroradiologic, and genetic analyses in 5 Italian families with familial CCM to further characterize the clinical and neuroimaging features of familial CCM segregating a KRIT1 mutation.

Five unrelated, clinically affected CCM probands (index patients) were consecutively enrolled on the basis of 1 of the 2 following criteria: each proband had at least 1 affected relative and/or had multiple cerebral cavernous angiomas. Diagnosis was based on brain magnetic resonance (MR) imaging features and, when possible, postsurgery histopathologic analysis findings. Detailed clinical and brain MR imaging data were collected for all patients with symptomatic CCM through direct interview and review of medical records. Clinical assessment focused on the occurrence of seizures, cerebral hemorrhage, focal neurologic symptoms, and headache. Subjects who gave written informed consent underwent review of their medical records, brain MR imaging, and blood sampling for genetic analysis, and their medical records were reviewed. Subjects with cavernomas seen on MR images were considered affected and those with no abnormalities seen on MR images were considered unaffected; those who did not undergo MR imaging were classified as “unknown.” The clinical and MR imaging details for 1 kindred (family 1) included in this study were published, in part, before KRIT1 gene identification.19 The current study was approved by the local ethics committee.

The MR imaging was performed on a high-field brain magnet (1.5T) and included standard spin echo and fast turbo spin echo T1- and T2-weighted axial, coronal, and/or sagittal images in all participants. Gradient-echo T2*-weighted axial MR images were obtained in patients with symptoms and in most symptom-free patients.

Genomic DNA was extracted from peripheral blood using standard procedures. In the probands, all 16 coding exons of KRIT1 were amplified with the polymerase chain reaction with a specific subset of 17 primer pairs.12 Direct DNA sequencing was then performed with an automated sequencer (model ABI310, Applied Biosystems, Foster City, Calif). Numbering of nucleotides was according to the full-length KRIT1 complementary DNA (accession number AF296765).

PATIENT CHARACTERISTICS

A cohort of 60 Italian individuals, 15 with symptomatic CCMs and 45 at-risk, symptom-free relatives, was investigated. Pedigrees of the families are shown in Figure 1. Patients with symptomatic CCMs included 11 women and 4 men. The mean ± SD patient age at clinical onset was 15.9 ± 7.5 years (age range, 4-36 years). Among the first clinical manifestations, seizure was reported in 10 patients (67%), recurrent headache in 3 (20%), and cerebral hemorrhage in 2 (13%). At clinical follow-up, 11 patients were totally independent with no permanent neurologic disorders, 1 had 3 symptomatic cerebral hemorrhages, 1 had left-sided hemiparesis, and 2 had intractable seizures.

Place holder to copy figure label and caption
Figure 1.

Pedigrees of families with KRIT1 mutations. A-E, Families 1 through 5, respectively. Filled circles and squares indicate affected, symptomatic individuals; half-filled circles and squares, affected, asymptomatic individuals; open circles and squares, unaffected individuals; question mark inside circles and squares, individuals not known to be affected (no magnetic resonance imaging performed); asterisk, mutation; small open circle, no mutation; arrow, index patient; diagonal line, individual deceased; diamond, sex unknown; and small diamond, in utero death.

Graphic Jump Location
MR IMAGING FINDINGS

Brain MR imaging was performed on 49 individuals, 15 patients with symptomatic CCMs and 34 at-risk, symptom-free relatives (Table 1). Eleven at-risk, symptom-free relatives declined brain MR imaging. Thirty-one subjects, 22 females and 9 males, exhibited cavernous angiomas at MR imaging and were classified as affected; 15 of these had symptomatic CCMs, and 16 had normal findings on neurologic examinations. All but 3 asymptomatic individuals were older than 20 years (mean ± SD age, 40.4 ± 22.3 years; age range, 6-79 years). In 18 symptom-free relatives, no abnormalities were seen on MR images, and they were considered unaffected. Multiple lesions were found in 28 (90.3%) of 31 affected patients, and a single lesion was found in 3 (9.6%) of 31 affected patients aged, respectively, 5, 19, and 26 years, although a correlation between age and number of lesions was not observed in our patients.

Table Graphic Jump LocationTable 1. Clinical, MR Imaging, and Genetic Features in Patients and Relatives
MUTATION ANALYSIS

Fifty-three individuals, 14 with and 39 without symptoms, were screened for KRIT1 gene mutations. Seven individuals, 1 with and 6 without symptoms, refused genetic testing (Table 1). In family 1, a previously described deletion, 1204delAACAA,11,20 was found. A novel 5-base pair (bp) deletion, 1306delTTGAA, was found in family 2, and a novel 2-bp insertion, 658insTT, was identified in family 3. Two nucleotide substitutions were also detected: a previously described splicing mutation,21 Q201E, in family 4, and a new nonsense mutation, Q482X, in family 5. All mutations were heterozygous and introduced a premature stop codon (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Sequence chromatograms of KRIT1 mutations. Mutations are indicated by arrows. A, Family 1: deletion of 5 base pairs (bp) at nucleotide 1204. B, Family 2: deletion of 5 bp at nucleotide 1306. C, Family 3: insertion of 2 bp at nucleotide 658. D, Family 4: C→G substitution at nucleotide 601 (Q201E). E, Family 5: C→T substitution at nucleotide 1444 (Q482X). All changes lead to a premature stop codon through frame shifts (families 1, 2, and 3), aberrant splicing (family 4), or nonsense mutations (family 5).

Graphic Jump Location

Thirty-three KRIT1 mutation carriers, 14 with and 19 without symptoms, and 20 noncarriers without symptoms, were identified. Among the 53 individuals molecularly screened, MR images were available for 42 (Table 1). The mutations identified in the 5 families, and the clinical and MR imaging features in the 31 mutation carriers are given in Table 2.

Table Graphic Jump LocationTable 2. KRIT1 Mutations Identified in Our Families, and Clinical and MR Imaging Features of Mutation Carriers

We describe 5 unrelated Italian families affected with CCM in which 3 novel and 2 previously reported mutations in the KRIT1 gene were identified. All mutations were in the coding sequence, 3 located within the second half of the gene (exons 12, 13, and 14), as in most cases reported in the literature, and 2 in a gene region (exon 8) in which mutations are relatively rare. All mutations introduce a premature termination codon, confirming the stereotypical nature of KRIT1 mutations.12

Six different mutations in the KRIT1 gene have been previously described in Italian families affected with CCM.2,8,12,2224 One of these families has been clinically described in detail, with a syndrome of cerebral angiomas, hepatic hemangiomas, and retinal cavernous angiomas. Segregation of the KRIT1 mutation has been found in members of the family with cerebral or retinal lesions but not hepatic lesions.22

A few KRIT1 mutations have been associated with lesions outside of the brain concurrently with cerebrovascular lesions, suggesting that KRIT1 mutations could cause vascular abnormalities in tissues outside the nervous system.3 In family 1, a large kindred, the proband (III-20) and an affected family member (IV-6) with the mutation on exon 12 (1204delAACAA) had, in addition to cerebral cavernous angiomas, a renal angioma and a retinal angioma, respectively. This mutation has been previously described; however, no detailed clinical information is available.11,20 In the family we observed, only 2 affected members had noncerebral lesions; thus, segregation of the mutation with lesions outside the brain could not be demonstrated.

In our families positive for KRIT1, we observed a distribution of affected individuals consistent with an autosomal dominant mode of transmission, although with a variable phenotypic expression that is both intrafamilial and interfamilial. In family 3, for example, the 6-year-old proband (IV-3), with multiple cerebral cavernomas on MR imaging, had seizures at age 4 years, whereas his mother (III-6, aged 41 years) and a maternal aunt (III-4, aged 38 years) had no symptoms despite multiple cerebral lesions. In family 4, the proband (III-4) had seizures at age 20 years, whereas her affected mother (II-2, aged 79 years) was symptom free.

Among the 33 identified mutation carriers, 19 (57.6%) were, at the time of ascertainment, asymptomatic with normal findings at neurologic examination. This confirms incomplete penetrance of neurologic symptoms associated with CCM, as previously reported in families with the KRIT1 mutation.2,10,25 Among the 31 mutation carriers for whom MR images were available, lesions were detected in 28 (90.3%). Magnetic resonance images showed lesions in 82.3% of asymptomatic mutation carriers (Table 1 and Table 2). Three asymptomatic mutation carriers had normal MR images and were considered unaffected. Two of them did not exhibit any lesions; however, gradient echo MR imaging sequences were not obtained. The first symptom-free mutation carrier was a man (II-1, family 3) who died at age 67 years from a cerebral tumor; no autopsy was performed. The second symptom-free mutation carrier was an 8-year-old girl (IV-10, family 1). Her mother (III-10, aged 44 years) and sister (IV-11, aged 5 years) exhibited lesions on MR imaging. The sister had a cerebral hemorrhage at age 4 years, and both the mother and sister carried the mutation. The third symptom-free mutation carrier was a woman (IV-5, family 1, aged 29 years) who at age 22, before KRIT1 gene identification, underwent MR imaging including a gradient echo sequence that showed no abnormalities.19 She refused to undergo follow-up brain MR imaging to confirm her unaffected status. Thus, based on these observations, it cannot be ruled out that in these 3 symptom-free mutation carriers, considered unaffected, small CCM lesions could be present but undetected or might develop later. On the other hand, another symptom-free mutation carrier (III-10, family 1) had a normal gradient echo MR imaging sequence at age 37 years; a gradient echo MR imaging sequence at age 44 years revealed CCM lesions.

In conclusion, the 5 families with CCMs investigated had a KRIT1 mutation, suggesting that, although the number of families analyzed is small, KRIT1 may account for more than 40% of the genetic form of CCM, as reported in the literature.11 In our series of mutation carriers, clinical penetrance, defined as the percentage of individuals with neurologic symptoms among mutation carriers, was incomplete. In addition, 90.3% of KRIT1 mutation carriers had lesions on MR imaging, suggesting that neuroradiologic penetrance was also incomplete and age dependent. Clinical and neuroradiologic studies and follow-up of larger cohorts of patients carrying the KRIT1 mutation should enable better delineation of the disease penetrance and natural history.

Correspondence: Silvana Penco, MS, PhD, Clinical Chemistry and Clinical Pathology Laboratory, Medical Genetics, A. O. Niguarda Ca’ Granda Hospital, Milan, Italy (Silvana.Penco@ospedaleniguarda.it).

Accepted for Publication: November 16, 2006.

Author Contributions:Study concept and design: Battistini, Brunori, Sgrò, Lo Russo, and Penco. Acquisition of data: Battistini, Rocchi, Cerase, Citterio, Tassi, Galli, Pitillo, Lo Russo, and Penco. Analysis and interpretation of data: Battistini, Rocchi, Tassi, Lando, Patrosso, Marocchi, and Penco. Drafting of the manuscript: Battistini, Lando, and Penco. Critical revision of the manuscript for important intellectual content: Battistini, Rocchi, Cerase, Citterio, Tassi, Patrosso, Galli, Brunori, Sgrò, Pitillo, Lo Russo, Marocchi, and Penco. Statistical analysis: Citterio, Lando, Brunori, and Sgrò. Administrative, technical, and material support: Patrosso, Pitillo, Marocchi, and Penco. Study supervision: Battistini, Rocchi, Tassi, Lo Russo, and Penco.

Financial Disclosure: None reported.

Acknowledgment: We thank the patients for their cooperation.

Zabramski  JMWascher  TMSpetzler  RF  et al.  The natural history of cavernous malformations: results of an ongoing study. J Neurosurg 1994;80422- 432
PubMed
Labauge  PLaberge  SBrunerau  LLevy  CTournier-Lasserve  ESociété Française de Neurochirurgie, Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Lancet 1998;3521892- 1897
PubMed
Retta  SFAvolio  MFrancalanci  F  et al.  Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1. Gene 2004;32563- 78
PubMed
Labauge  PKrivosic  VDenier  CTournier-Lasserve  EGaudric  A Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas. Arch Ophthalmol 2006;124885- 886
PubMed
Rigamonti  DHadley  MNDrayer  BP  et al.  Cerebral cavernous malformations: incidence and familial occurrence. N Engl J Med 1988;319343- 347
PubMed
Dubovsky  JZabramski  JMKurth  J  et al.  Gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4453- 458
PubMed
Craig  HDGuenel  MCepeda  O  et al.  Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation at 7p15-13 and 3q25.2-27. Hum Mol Genet 1998;71851- 1858
PubMed
Laberge-le Couteulx  SJung  HHLabauge  P  et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999;23189- 193
PubMed
Sahoo  TJohnson  EWThomas  JW  et al.  Mutations in the gene encoding KRIT1, a Krev-1/Rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 1999;82325- 2333
PubMed
Revencu  NVikkula  M Cerebral cavernous malformation: new molecular and clinical insights. J Med Genet 2006;43716- 721
PubMed
Verlaan  DJDavemport  WJStefan  HSure  USiegel  AMRouleau  GA Cerebral cavernous malformations: mutations in Krit1Neurology 2002;58853- 857
PubMed
Cavé-Riant  FDenier  CLabauge  P  et al.  Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 2002;10733- 740
PubMed
Zhang  JClatterbuck  RERigamonti  DChang  DDDietz  HC Interaction between Krit1 and icap1α infers perturbation of integrin β1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 2001;102953- 2960
PubMed
Liquori  CLBerg  MJSiegel  AM  et al.  Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 2003;731459- 1464
PubMed
Denier  CGoutagny  SLabauge  P  et al.  Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74326- 337
PubMed
Zawistowski  JSStalheim  LUhlik  MT  et al.  CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformation pathogenesis. Hum Mol Genet 2005;142521- 2531
PubMed
Bergametti  FDenier  CLabauge  P  et al.  Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005;7642- 51
PubMed
Plummer  NWZawistowski  JSMarchuk  DA Genetics of cerebral cavernous malformations. Curr Neurol Neurosci Rep 2005;5391- 396
PubMed
Brunori  PPelliccioli  GCampanella  S  et al.  Multiple cerebral cavernous malformations: study of a family. Riv Neurobiol 1997;43635- 640
Sahoo  TGoenaga-Diaz  ESerebriiskii  IG  et al.  Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 2001;71123- 126
PubMed
Verlaan  DJSiegel  AMRouleau  GA Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation. Am J Hum Genet 2002;701564- 1567
PubMed
Davenport  WJSiegel  AMDichgans  J  et al.  CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology 2001;56540- 543
PubMed
Marini  VFerrera  LDorcaratto  A  et al.  Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test. J Neurol Sci 2003;21275- 78
Guarnieri  VMuscarella  LAAmoroso  R  et al.  Identification of two novel mutations and of a novel critical region in the KRIT1 gene. Neurogenetics 2007;829- 37doi:10.1007/s10048-006-0056-y
PubMed
Denier  CLabauge  PBrunereau  L  et al.  Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 2004;55213- 219
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Pedigrees of families with KRIT1 mutations. A-E, Families 1 through 5, respectively. Filled circles and squares indicate affected, symptomatic individuals; half-filled circles and squares, affected, asymptomatic individuals; open circles and squares, unaffected individuals; question mark inside circles and squares, individuals not known to be affected (no magnetic resonance imaging performed); asterisk, mutation; small open circle, no mutation; arrow, index patient; diagonal line, individual deceased; diamond, sex unknown; and small diamond, in utero death.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Sequence chromatograms of KRIT1 mutations. Mutations are indicated by arrows. A, Family 1: deletion of 5 base pairs (bp) at nucleotide 1204. B, Family 2: deletion of 5 bp at nucleotide 1306. C, Family 3: insertion of 2 bp at nucleotide 658. D, Family 4: C→G substitution at nucleotide 601 (Q201E). E, Family 5: C→T substitution at nucleotide 1444 (Q482X). All changes lead to a premature stop codon through frame shifts (families 1, 2, and 3), aberrant splicing (family 4), or nonsense mutations (family 5).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. KRIT1 Mutations Identified in Our Families, and Clinical and MR Imaging Features of Mutation Carriers
Table Graphic Jump LocationTable 1. Clinical, MR Imaging, and Genetic Features in Patients and Relatives

References

Zabramski  JMWascher  TMSpetzler  RF  et al.  The natural history of cavernous malformations: results of an ongoing study. J Neurosurg 1994;80422- 432
PubMed
Labauge  PLaberge  SBrunerau  LLevy  CTournier-Lasserve  ESociété Française de Neurochirurgie, Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Lancet 1998;3521892- 1897
PubMed
Retta  SFAvolio  MFrancalanci  F  et al.  Identification of Krit1B: a novel alternative splicing isoform of cerebral cavernous malformation gene-1. Gene 2004;32563- 78
PubMed
Labauge  PKrivosic  VDenier  CTournier-Lasserve  EGaudric  A Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas. Arch Ophthalmol 2006;124885- 886
PubMed
Rigamonti  DHadley  MNDrayer  BP  et al.  Cerebral cavernous malformations: incidence and familial occurrence. N Engl J Med 1988;319343- 347
PubMed
Dubovsky  JZabramski  JMKurth  J  et al.  Gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4453- 458
PubMed
Craig  HDGuenel  MCepeda  O  et al.  Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation at 7p15-13 and 3q25.2-27. Hum Mol Genet 1998;71851- 1858
PubMed
Laberge-le Couteulx  SJung  HHLabauge  P  et al.  Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas. Nat Genet 1999;23189- 193
PubMed
Sahoo  TJohnson  EWThomas  JW  et al.  Mutations in the gene encoding KRIT1, a Krev-1/Rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 1999;82325- 2333
PubMed
Revencu  NVikkula  M Cerebral cavernous malformation: new molecular and clinical insights. J Med Genet 2006;43716- 721
PubMed
Verlaan  DJDavemport  WJStefan  HSure  USiegel  AMRouleau  GA Cerebral cavernous malformations: mutations in Krit1Neurology 2002;58853- 857
PubMed
Cavé-Riant  FDenier  CLabauge  P  et al.  Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 2002;10733- 740
PubMed
Zhang  JClatterbuck  RERigamonti  DChang  DDDietz  HC Interaction between Krit1 and icap1α infers perturbation of integrin β1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 2001;102953- 2960
PubMed
Liquori  CLBerg  MJSiegel  AM  et al.  Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 2003;731459- 1464
PubMed
Denier  CGoutagny  SLabauge  P  et al.  Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 2004;74326- 337
PubMed
Zawistowski  JSStalheim  LUhlik  MT  et al.  CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformation pathogenesis. Hum Mol Genet 2005;142521- 2531
PubMed
Bergametti  FDenier  CLabauge  P  et al.  Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 2005;7642- 51
PubMed
Plummer  NWZawistowski  JSMarchuk  DA Genetics of cerebral cavernous malformations. Curr Neurol Neurosci Rep 2005;5391- 396
PubMed
Brunori  PPelliccioli  GCampanella  S  et al.  Multiple cerebral cavernous malformations: study of a family. Riv Neurobiol 1997;43635- 640
Sahoo  TGoenaga-Diaz  ESerebriiskii  IG  et al.  Computational and experimental analyses reveal previously undetected coding exons of the KRIT1 (CCM1) gene. Genomics 2001;71123- 126
PubMed
Verlaan  DJSiegel  AMRouleau  GA Krit1 missense mutations lead to splicing errors in cerebral cavernous malformation. Am J Hum Genet 2002;701564- 1567
PubMed
Davenport  WJSiegel  AMDichgans  J  et al.  CCM1 gene mutations in families segregating cerebral cavernous malformations. Neurology 2001;56540- 543
PubMed
Marini  VFerrera  LDorcaratto  A  et al.  Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test. J Neurol Sci 2003;21275- 78
Guarnieri  VMuscarella  LAAmoroso  R  et al.  Identification of two novel mutations and of a novel critical region in the KRIT1 gene. Neurogenetics 2007;829- 37doi:10.1007/s10048-006-0056-y
PubMed
Denier  CLabauge  PBrunereau  L  et al.  Clinical features of cerebral cavernous malformations patients with KRIT1 mutations. Ann Neurol 2004;55213- 219
PubMed

Correspondence

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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
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Indicate what change(s) you will implement in your practice, if any, based on this CME course.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
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