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Open Access Case report

A novel CCM1 mutation associated with multiple cerebral and vertebral cavernous malformations

Silvia Lanfranconi1, Dario Ronchi2, Naghia Ahmed2, Vittorio Civelli3, Paola Basilico12, Nereo Bresolin12, Giacomo Pietro Comi12 and Stefania Corti12*

Author Affiliations

1 Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

2 Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza 35, Milan, 20122, Italy

3 Neuroradiology and Interventional Neuroradiology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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BMC Neurology 2014, 14:158  doi:10.1186/s12883-014-0158-3

Published: 3 August 2014

Abstract

Background

Cerebral cavernous malformations are relatively rare vascular disorders that may affect any part of the central nervous system. This presentation has been associated with heterozygous mutations in CCM1/KRIT1, CCM2/malcavernin and CCM3/PDCD10. We aimed to investigate the genetic defect underlying multiple cerebral and vertebral cavernous malformations in a multigenerational Italian family.

Case presentation

The proband is a 49-year-old man who underwent cerebral MRI in his thirties for persistent haeadache and tingling in his left arm and leg and was diagnosed with multiple supratentorial cavernous angiomas. A right frontal angioma with radiological evidence of a recent bleeding was surgically removed when he was 39 years old and he was thereafter asymptomatic. Magnetic resonance imaging revealed multiple cerebral cavernous malformations in seven members of his familily. Four subjects were asymptomatic. Other family mambers displayed heterogeneous clinical features including seizures and recurrent brain haemorrhages. Sequence analysis in the proband disclosed a novel heterozygous nucleotide substitution (c.263-10A > G) in intron 5 of CCM1. This variant is predicted to create an abnormal acceptor splice site and segregated in affected relatives available for molecular screening. The analysis of CCM1 transcript in proband’s lymphocytes confirmed the partial retention of intron 3 resulting in a premature termination codon.

Conclusions

Our findings demonstrate that c.263-10A > G mutation is associated with cerebral cavernous malformations. A better knowledge of the disease-associated phenotype may lead to an early diagnosis and to an appropriate clinical surveillance in affected patients.

Keywords:
Cerebral Cavernous Malformations; CCM1 protein; Krev interaction trapped 1 protein; Hemangioma; Cavernous; Central Nervous System