Elsevier

The Lancet Neurology

Volume 6, Issue 3, March 2007, Pages 237-244
The Lancet Neurology

Review
Genetics of cavernous angiomas

https://doi.org/10.1016/S1474-4422(07)70053-4Get rights and content

Summary

Cerebral cavernous malformations (CCM) are vascular malformations that can occur as a sporadic or a familial autosomal dominant disorder. Clinical and cerebral MRI data on large series of patients with a genetic form of the disease are now available. In addition, three CCM genes have been identified: CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. These recent developments in clinical and molecular genetics have given us useful information about clinical care and genetic counselling and have broadened our understanding of the mechanisms of this disorder.

Introduction

Cerebral cavernous malformations (CCM) are vascular malformations that are histologically characterised by abnormally enlarged capillary cavities without intervening brain parenchyma.1 From large series studies involving post-mortem examinations or MRI of patients, the prevalence of CCM in the general population has been estimated as 0·1–0·5%;2, 3 most of these malformations were located in the CNS.

Both sporadic and familial forms have been identified. The pattern of inheritance of the familial form is autosomal dominant. The proportion of familial cases has been estimated to be as high as 50% in Hispanic–American patients and close to 10–40 % in other populations.4, 5 Familial cases are characterised by the presence of multiple lesions, whereas sporadic cases usually have a single lesion.

Recent developments in molecular genetics have given us useful information for the clinical management of patients with CCM and their relatives and clues to the mechanisms of this disorder, which will be the focus of this Review.

Section snippets

Familial CCM: clinical and MRI features

Families with several clinically affected patients were first reported by Kufs and colleagues in 1928.6 Thereafter, several additional studies were published but each of them included families with very limited neuroradiological data until Rigamonti and colleagues, in 1988,4 characterised clinical and MRI features of familial CCM in a series of 13 Hispanic–American families—a population in which a strong founder effect was later shown.4, 7, 8, 9, 10, 11 Clinical and MRI features of the first

“Sporadic” cases with multiple lesions

Sporadic cases usually show a single lesion on both TSE and gradient-echo sequences, are not inherited, and do not carry a CCM gene mutation.46, 47, 48, 49 However, some cases have multiple MRI lesions although they do not have any known clinically affected relative and present therefore as sporadic cases. Combined use of clinical and MRI screening together with molecular testing has helped to clarify the situation in these cases.

Clinical and neuroradiological analyses done before the

Pattern of inheritance

The pattern of inheritance in CCM is autosomal dominant with an incomplete clinical and neuroradiological penetrance. In a genetic linkage analysis of the known CCM loci in 20 families Craig and colleagues52 have estimated the clinical penetrance at 88% in CCM1 families, 100% in CCM2, and 63% in CCM3 families. However, a recent analysis done in a large series of families segregating a KRIT1/CCM1 mutation showed a clinical penetrance of about 60%.13 Additional studies done on large series of CCM2

CCM pathogenesis

The mechanisms involved in cerebral blood vessel angiogenesis during development are still poorly defined, therefore hampering the understanding of the mechanisms that lead to cerebrovascular malformations. The identification of the CCM genes has broadened understanding of the mechanisms underlying CCM and recent studies have unravelled some of the function of these genes.68, 69

In situ hybridization studies showed that the three CCM genes have very similar patterns of expression within the CNS,

Conclusions and future directions

The recent identification of the three CCM genes is an important step towards understanding the mechanisms of this disorder. These genes have helped to clarify several features of the disorder, including its incomplete clinical and MRI penetrance, as well as the molecular basis of sporadic cases with multiple lesions. Additional large series studies will now be needed to further assess genotype–phenotype correlations, particularly the prognosis, in relation to the nature of the mutated gene.

Search strategy and selection criteria

References for this Review were identified through searches of PubMed from 1980 until November 2006 with the terms “cerebral cavernous malformations”, “cavernous angiomas”, “CCM1”, “CCM2”, “CCM3”, “KRIT1”, “MGC4607”, and “PDCD10”. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed.

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