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

Gustavo da Fontoura Galvão; Elielson Veloso da Silva; Fabrícia Lima Fontes-Dantas; Ricardo Castro Filho; Soniza Alves-Leon; Jorge Marcondes de Souza

doi:10.1016/j.wneu.2020.06.170

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

World Neurosurg. 2020 Oct:142:481-486.e1. doi: 10.1016/j.wneu.2020.06.170. Epub 2020 Jun 29.

Authors

Gustavo da Fontoura Galvão¹, Elielson Veloso da Silva², Fabrícia Lima Fontes-Dantas³, Ricardo Castro Filho⁴, Soniza Alves-Leon⁵, Jorge Marcondes de Souza⁶

Affiliations

¹ Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil; Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil.
² Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil; Fluminense Federal University, Post-Graduation Program in Neurology and Neuroscience, Rio de Janeiro RJ, Brazil.
³ Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil.
⁴ Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil.
⁵ Federal University of the State of Rio de Janeiro, Translational Neuroscience Laboratory, Post-Graduation Program in Neurology, Rio de Janeiro RJ, Brazil; Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurology, Rio de Janeiro RJ, Brazil.
⁶ Federal University of Rio de Janeiro, University Hospital Clementino Fraga Filho, Department of de Neurosurgery, Rio de Janeiro RJ, Brazil. Electronic address: [email protected].

PMID: 32615293
DOI: 10.1016/j.wneu.2020.06.170

Abstract

Background: 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.

Case description: 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).

Conclusions: 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.

Keywords: CCM1 (KRIT1); CCM2 (MGC4607); Cerebral cavernous malformation; Epilepsy.

Publication types

Case Reports

MeSH terms

Carrier Proteins / genetics*
Drug Resistant Epilepsy / etiology
Hemangioma, Cavernous, Central Nervous System / complications
Hemangioma, Cavernous, Central Nervous System / genetics*
Humans
KRIT1 Protein / genetics*
Magnetic Resonance Imaging
Middle Aged

Substances

CCM2 protein, human
Carrier Proteins
KRIT1 Protein
KRIT1 protein, human

Supplementary concepts

Familial cerebral cavernous malformation