First Report of Concomitant Pathogenic Mutations Within MGC4607/CCM2 and KRIT1/CCM1 in a Familial Cerebral Cavernous Malformation Patient

• Published in: World neurosurgery Vol. 142; pp. 481 - 486.e1
• Main Authors: da Fontoura Galvão, Gustavo, Veloso da Silva, Elielson, Fontes-Dantas, Fabrícia Lima, Filho, Ricardo Castro, Alves-Leon, Soniza, Marcondes de Souza, Jorge
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2020
• Subjects: Carrier Proteins - genetics; CCM1 (KRIT1); CCM2 (MGC4607); Cerebral cavernous malformation; Drug Resistant Epilepsy - etiology; Epilepsy; Hemangioma, Cavernous, Central Nervous System - complications; Hemangioma, Cavernous, Central Nervous System - genetics; Humans; KRIT1 Protein - genetics; Magnetic Resonance Imaging; Middle Aged; SWI; MRI; Epilepsy; Cerebral cavernous malformation; CCM2 (MGC4607); CCM; CCM1 (KRIT1)
• ISSN: 1878-8750; 1878-8769
• DOI: 10.1016/j.wneu.2020.06.170

Familial cerebral cavernous malformations (CCM) are among the most common vascular malformations of the central nervous system (CNS) and are linked to mutations on the specific genes CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10. We present the first report in the literature of a pharmaco-resistant epileptic patient harboring co-occurring pathogenic mutations within CCM2/MGC4607 and CCM1/KRIT1.
A 51-year-old patient first presented at age of 33 years with episodes of seizures. Magnetic resonance imaging including a susceptibility-weighted imaging sequence had shown multiple cerebral cavernous malformation lesions. She had partial response of symptoms and remained in routine follow-up needing progressive pharmacological improvement. Direct sequencing allowed the detection of 1 nonsense pathogenic mutation in CCM2/MGC4607 (c.118C>T; p.Arg40Ter) and 1 unclassified frameshift insertion variant in CCM1/KRIT1 (c.1687_1688insT; p.Tyr563LeufsTer5).
Although the CCM2/MGC460 variant seems to be the major contributor for the patient’s CCM phenotype, the mutated CCM1/KRIT1 seems to act as a booster to CCM overall pathogenicity.