The identification of the three CCM
genes represents an important step towards the elucidation of the molecular basis of CCM. In addition, large prospective studies of genotype–phenotype association can now be undertaken. This would allow evaluation of clinical penetrance, age at onset, frequency and severity of symptoms, evolution, and response to treatment, all pivotal factors for designing accurate patient care guidelines. Other interesting questions could be addressed. What is the percentage of familial CCM and what is the frequency of de novo germline mutations? Is the KRIT1
associated hyperkeratotic cutaneous capillary‐venous malformation also present in patients with mutations in the MGC4607
or the PDCD10
genes, suggesting an important function in cutaneous angiogenesis for all three proteins? Is there a significant co‐occurrence of CCMs with developmental venous anomalies as suggested,45
and if so, what is the basis for this? Do all CCM families have a mutation in one of the three known genes, or do others exist? Twelve families in the screening carried out by Bergametti et al
did not harbour a mutation in any of the three CCM genes.26
Large deletions and non‐sensitivity of the techniques used could explain this, but it also opens the door for the existence of a fourth gene, as recently suggested by Liquori et al
Another aspect for deeper investigation is the aetiology of sporadic CCM: are they caused by genetic or environmental factors or both? If genetic in origin, are the causative genes the same as in the familial forms? Sporadic patients with multiples lesions seem to harbour KRIT1
mutations in approximately the same proportion as familial cases.46,47
These mutations are either de novo or inherited from an asymptomatic parent. If this is also true for malcavernin and PDCD10
, multiple CCMs can be postulated to have a genetic aetiology. Thus sporadic cases with multiple lesions need to be considered as familial cases, which is of major importance for patient care and genetic counselling. In contrast, sporadic cases with only one malformation may indeed differ in aetiology, with no increase in risk for progeny. Based on these data, we suggest a clinico‐genetic risk evaluation scheme (fig 3).
Figure 3Scheme for evaluation of genetic risk.
The pathogenic mechanism leading from the heterozygous germline mutation to CCM formation is poorly understood. Two major hypotheses have been put forward: haploinsufficiency and paradominant inheritance. The latter has been favoured and could explain several CCM features: the localised nature and the number of lesions (usually one in sporadic cases versus multiple in familial cases) and the age at the first symptom (earlier in familial cases). Moreover, this mechanism has been shown to be true for a patient with another inherited multifocal vascular malformation, glomuvenous malformation.48
Gault and coworkers also identified two truncating biallelic mutations in KRIT1
in one CCM patient with multiple lesions, although two previous screens had failed to detect somatic mutations in 20 and 72 patients, respectively (including familial and sporadic ones).49,50,51
While the techniques used may not have been sensitive enough, other mechanisms are likely to contribute to CCM pathogenesis.52
One explanation is trans‐heterozygosity, in which case a patient with a germline mutation in the CCM1
gene would have a somatic mutation in CCM2
gene and so forth. This could explain intrafamilial clinical variability. This can now be tested in CCM lesions, as well as in the Ccm
murine model, but may need laser capture dissection to enrich the subpopulation of cells with second hit.
As patients with a familial CCM history present similar neurological symptoms, one could assume that the three CCM
genes are involved in a common functional pathway. Indeed, it has been shown that KRIT1 interacts with malcavernin, and there is evidence that loss of this interaction contributes to the CCM pathogenesis.29
In this scenario, the CCM3
gene product, suspected to be involved in apoptosis, should be a member of this complex or play a role in a KRIT1/malcavernin pathway. As KRIT1 and malcavernin are suggested to be involved in β1 integrin signalling through ICAP1, with possible downstream signalling via p38MAPK, and as PDCD10 was identified as a gene involved in apoptosis, it may be that the CCM pathway functions in cell adhesion governed survival. If the CCM
genes have such a role in vascular endothelial cells or neural cells or both, the enlarged endothelial lined cerebral vascular channels could result from inhibited apoptosis. This would be similar to what has been proposed for cutaneous venous malformations, which are caused by TIE‐2 point mutations that lead to increased Akt activity.53,54
As CCM1, CCM2, and CCM3 seem to be expressed in neurones rather than in blood vessels, the vascular phenotype should result from a defect in signalling between these two juxtaposed structures. Interestingly, it has been shown that vascular and neuronal development are closely linked with several proteins—for example, neuropilin and VEGF, having a functional role in both (reviewed by Carmeliet55
). Moreover, some studies have shown the importance of neuronal invasion of primary capillary plexus for its proper remodelling and maturation (reviewed by Eichmann et al56
). Supplementary in vitro and in vivo studies on the three CCM proteins are clearly needed: co‐immunoprecipitation and co‐localisation studies implicating CCM3
, and the generation of conditional homozygous, heterozygous, and compound heterozygous mutant mice. This should yield further fundamental insights, especially as to whether the primary defect is vascular or neuronal. Despite the lack of detailed mechanistic understanding of CCM formation, the important discoveries that have been made enable precise molecular diagnosis in patients with a family history or with multiple lesions, testing that should now be taken into clinical practice to allow more appropriate follow up, treatment, and genetic counselling.