Abstract
The mutation detection rate for familial cerebral cavernous malformations (CCM) is extremely high, being about 90 % if direct sequencing of the three genes, CCM1, CCM2, and CCM3, is used in conjunction with quantitative analyses to detect larger CCM1-3 deletions/duplications. We here report on an individual who had presented with more than 30 cerebral and spinal cavernous malformations, two intracranial meningiomas, and disease manifestation only in the mid-forties. A CCM1 missense variant of unclear relevance was found during the first sequencing step. Thereafter, direct sequencing of all three CCM genes revealed the typical pathogenic loss-of-function mutation c.598C > T/p.Q200* in the CCM3 gene. Our results demonstrate that mutation analyses of all three CCM genes in the index patient regardless of previous identification of an unclassified CCM1 variant is crucial for reliable predictive testing of at-risk relatives.
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Acknowledgments
The authors thank the patient for her cooperation. Juliane Najm and Stefanie Spiegler are funded by EU grant EnVision (FP7-REGPOT-2010-1, Grant no. 264143).
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Juri Kivelev, Helsinki, Finland
The amount of incidental CM cases has been increased gradually throughout the world. There is no doubt about the reasons of this phenomenon: the availability of neuroimaging tools is getting better all the time. In such environment, we are transferring more and more towards prophylactic medicine, which, however, imposes new demands on practitioners' everyday clinical work.
In terms of population screening and prophylactic treatment, the work of Schröder et al. is very important, since the authors emphasize the complexity of decision making process when dealing with familial CMs. Most of these patents are prone to have multiple lesions with significant risk of de novo CM formation. Thus, a prophylactic surgery in such cases might be very controversial. This was also shown in our previous investigations (1), where the long-term outcome in operated and conservatively-treated patients with multiple CMs occurred to be the same.
These findings confirm the need of new noninvasive reliable diagnostic tools, which may predict the clinical course of CM. Genetic screening is definitely the future of medicine; and with widespread availability of simple laboratory testing, the financial aspects are not anymore limiting its use in daily practice.
But the ethical aspects do.
Is it worth to check the presence of some particular CCM mutation in asymptomatic children? Is it reasonable to impose such a severe psychological pressure on CM patients with familial history, while the risks of clinical manifestations are quite low, and, even when occur, the symptoms are rarely invaliding? These questions are appropriately highlighted in the report of Schröder et al. Furthermore, authors accurately discussed very important practical issue: the attitude of the insurance companies and employers to the fact of pathological gene confirmation in clinically unaffected patients what might affect significantly the patients' personal life in the future.
In congruence with authors, we think that a decision to perform genetic screening in families affected by CM should be very studious; delicateness, logicality, and patience are key factors of effective cooperation.
References
1 Kivelev J, Niemelä M, Kivisaari R, Dashti R, Laakso A, Hernesniemi J. Long-term outcome of patients with multiple cerebral cavernous malformations. Neurosurgery 65(3):450–455, 2009
Felix Rosenow, Karl Martin Klein, Marburg, Germany
Schröder et al. report an illustrative case with familial cavernous malformations. During sequence analysis of the gene CCM1, a missense variant of unclear relevance was found. The authors continue to sequence CCM2 and CCM3 and identify a clearly pathogenic truncation mutation in CCM3. This case nicely illustrates that not every sequence change is a pathogenic mutation and careful consideration of each variant and possibly sequencing of additional genes is necessary to identify the causative mutation. This is of paramount importance for predictive genetic testing of at-risk relatives.
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Schröder, W., Najm, J., Spiegler, S. et al. Predictive genetic testing of at-risk relatives requires analysis of all CCM genes after identification of an unclassified CCM1 variant in an individual affected with cerebral cavernous malformations. Neurosurg Rev 37, 161–165 (2014). https://doi.org/10.1007/s10143-013-0478-6
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DOI: https://doi.org/10.1007/s10143-013-0478-6