Genetics of Cerebral Cavernous Angioma

Abstract

Cerebral cavernous malformations (CCM) are hamartomatous vascular anomalies characterized by densely packed, grossly enlarged immature capillaries without intervening neural tissue. Depending on their location and size (ranging from a few millimeters to several centimeters), the biologically dynamic lesions become symptomatic during the second to fourth decade of life. Clinical symptoms include recurrent headaches, seizures, intracranial hemorrhage, and stroke. There are sporadic and autosomal dominantly inherited forms of CCM. Causal mutations have been demonstrated in three genes, KRIT1, MGC4607, and PDCD10, but additional genes are likely to be discovered. These genes are therefore thought to play a role in angiogenesis. Their specific modes of actions, their contribution to and their likely penetrance in the genesis of CCM are the subject of current investigations. Genetic counseling is strongly advisable for patients with a positive family history and for seemingly sporadic cases with multiple lesions, and genetic testing should be considered on an individual basis. The identification of a mutation enables precise genetic testing of relatives. Given the 50 % a priori risk of autosomal dominant inheritance, the benefits of genetic testing are twofold: a positive test result in a presymptomatic carrier permits close neuroradiological surveillance and timely neurosurgical intervention; a negative test result relieves the proband of unwarranted anxiety and unnecessary medical supervision.

Zusammenfassung

Zerebrale Kavernome sind Blutgefäßanomalien, die aus eng aneinander gelagerten und abnorm dilatierten kapillarähnlichen Strukturen bestehen und wenige Millimeter bis mehrere Zentimeter groß werden. Kavernome manifestieren sich klinisch in der Regel zwischen der 2. bis 4. Lebensdekade. Die Symptomatik reicht von rezidivierenden Kopfschmerzen über epileptische Anfälle bis hin zu Hirnblutungen mit Schlaganfallsymptomatik. Kavernome treten sporadisch oder familiär mit autosomal-dominantem Erbgang auf. Kavernomverursachende Mutationen wurden bisher in drei Genen identifiziert: KRIT1, MGC4607 und PDCD10. Diese Gene sind folglich für die Angiogenese bedeutsam. Eine genetische Beratung und molekulargenetische Diagnostik ist bei Patienten mit positiver Familienanamnese und bei sporadischen Fällen mit multiplen Kavernomen sinnvoll. Die Identifizierung einer Mutation erlaubt eine eindeutige prädiktive genetische Diagnostik in der Verwandtschaft. So haben zum Beispiel Nachkommen eine Wahrscheinlichkeit von 50 %, Träger einer elterlichen Mutation zu sein. Der molekulargenetische Ausschluss einer zuvor nachgewiesenen elterlichen Mutation würde 50 % der Risikopersonen die Angst vor Kavernom-bedingten neurologischen Defiziten nehmen. Nur bei Mutationsträgern ist eine neuroradiologische Überwachung indiziert, um rechtzeitig operativ intervenieren zu können.

Key words

vascular malformations - cerebral cavernous angioma - genetics - genetic counseling and testing

Schlüsselwörter

vaskuläre Fehlbildungen - Kavernome - Genetik - genetische Beratung - molekulargenetische Diagnostik

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