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

Abstract

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.

Discovery of familial cerebral cavernous malformation in a Saudi population

“…They have 40% CCM1, 20% CCM2 and another 40% have CCM3 gene mutations 11. Recent studies have concluded that there is incomplete clinical and neuroimaging penetrance in families with a KRIT1 mutation 19. These Saudi patients expand the geographical map of occurrences of FCCM.…”

Discovery of familial cerebral cavernous malformation in a Saudi population

“…They have 40% CCM1, 20% CCM2 and another 40% have CCM3 gene mutations 11. Recent studies have concluded that there is incomplete clinical and neuroimaging penetrance in families with a KRIT1 mutation 19. These Saudi patients expand the geographical map of occurrences of FCCM.…”

A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

“…Studies focused on genotype-phenotype correlations found a high variability of symptoms, even in patients belonging to the same family, and harboring the same mutation (Scimone et al, 2018). Heterogeneity of clinical manifestations and onset age were considered to be associated with the incomplete penetrance of the disease (Battistini et al, 2007).…”

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

“…Here, we presented the largest molecular study in Italian patients with CCM and expanded the previously defined mutational spectrum of KRIT1, CCM2, and PDCD10 in our country (Battistini et al, 2007;Cau et al, 2009;Nannucci et al, 2009;Riant et al, 2013;Spiegler et al, 2014). We also explored the cellular effect of a novel PDCD10 large deletion, which associated with significant reduction of interactions between KRIT1 and CCM2, and impaired autophagy process.…”

Discovery of familial cerebral cavernous malformation in a Saudi population

“…They have 40% CCM1, 20% CCM2 and another 40% have CCM3 gene mutations 11. Recent studies have concluded that there is incomplete clinical and neuroimaging penetrance in families with a KRIT1 mutation 19. These Saudi patients expand the geographical map of occurrences of FCCM.…”

A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

“…Studies focused on genotype-phenotype correlations found a high variability of symptoms, even in patients belonging to the same family, and harboring the same mutation (Scimone et al, 2018). Heterogeneity of clinical manifestations and onset age were considered to be associated with the incomplete penetrance of the disease (Battistini et al, 2007).…”

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

“…Here, we presented the largest molecular study in Italian patients with CCM and expanded the previously defined mutational spectrum of KRIT1, CCM2, and PDCD10 in our country (Battistini et al, 2007;Cau et al, 2009;Nannucci et al, 2009;Riant et al, 2013;Spiegler et al, 2014). We also explored the cellular effect of a novel PDCD10 large deletion, which associated with significant reduction of interactions between KRIT1 and CCM2, and impaired autophagy process.…”

Discovery of familial cerebral cavernous malformation in a Saudi population

“…They have 40% CCM1, 20% CCM2 and another 40% have CCM3 gene mutations 11. Recent studies have concluded that there is incomplete clinical and neuroimaging penetrance in families with a KRIT1 mutation 19. These Saudi patients expand the geographical map of occurrences of FCCM.…”

A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

“…Studies focused on genotype-phenotype correlations found a high variability of symptoms, even in patients belonging to the same family, and harboring the same mutation (Scimone et al, 2018). Heterogeneity of clinical manifestations and onset age were considered to be associated with the incomplete penetrance of the disease (Battistini et al, 2007).…”

A single-center study on 140 patients with cerebral cavernous malformations: 28 new pathogenic variants and functional characterization of a PDCD10 large deletion

“…Here, we presented the largest molecular study in Italian patients with CCM and expanded the previously defined mutational spectrum of KRIT1, CCM2, and PDCD10 in our country (Battistini et al, 2007;Cau et al, 2009;Nannucci et al, 2009;Riant et al, 2013;Spiegler et al, 2014). We also explored the cellular effect of a novel PDCD10 large deletion, which associated with significant reduction of interactions between KRIT1 and CCM2, and impaired autophagy process.…”