Novel CCM1 (KRIT1) Mutation Detection in Brazilian Familial Cerebral Cavernous Malformation: Different Genetic Variants in Inflammation, Oxidative Stress, and Drug Metabolism Genes Affect Disease Aggressiveness.
Adult
Anticonvulsants
/ therapeutic use
Brazil
DNA Glycosylases
/ genetics
DNA-(Apurinic or Apyrimidinic Site) Lyase
/ genetics
Female
Frameshift Mutation
Genotype
Hemangioma, Cavernous, Central Nervous System
/ complications
Humans
Inflammation
/ genetics
KRIT1 Protein
/ genetics
Lipopolysaccharide Receptors
/ genetics
Magnetic Resonance Imaging
Mothers
Oxidative Stress
/ genetics
Phenotype
Seizures
/ drug therapy
Severity of Illness Index
Superoxide Dismutase
/ genetics
Toll-Like Receptor 4
/ genetics
CCM1 (KRIT1)
Cerebral cavernous malformation
Drug metabolism
Inflammation
Oxidative stress
Journal
World neurosurgery
ISSN: 1878-8769
Titre abrégé: World Neurosurg
Pays: United States
ID NLM: 101528275
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
18
01
2020
revised:
18
02
2020
accepted:
19
02
2020
pubmed:
3
3
2020
medline:
22
8
2020
entrez:
2
3
2020
Statut:
ppublish
Résumé
Cerebral cavernous malformations (CCMs) are vascular capillary anomalies with a dysfunctional endothelial adherent junction profile, depicting hemorrhage and epilepsy as the main clinical features. With the advent of an increasingly personalized medicine, better comprehension of genetic mechanisms behind CCM represents an important key in the management of the patients and risk rating in relatives. In this context, genetic factors that might influence clinical expressiveness of CCM need to be identified. A 33-year-old woman harboring multiple CCM lesions with a CCM1 mutational profile already being treated conservatively for a right mesial temporal lobe CCM presented with refractory seizures. Magnetic resonance imaging showed no bleeding in the lesion, and the patient was submitted to complete resection of the CCM. Histopathology of the CCM samples depicted an extensive inflammatory reaction and colocalization of CD20+ and CD68+ cells. Genetic analyses of the patient and her mother demonstrated a novel CCM1 (KRIT1) frameshift mutation (c.1661_1662insT; p.Leu554PhefsTer14). Furthermore, variants in CD14 (rs778588), TLR-4 (rs10759930), SOD2 (rs4880), APEX1 (rs1130409), and OGG1 (rs1052133), known as polymorphisms related to disease aggressiveness, were detected in the patient and not in her oligosymptomatic mother harboring the same CCM1 mutation. Heterogeneity of clinical manifestations among individuals with familial CCM with the same genotype adds mechanistic involvement of modifier factors as phenotypic markers. We describe a novel CCM1/KRIT1 familial mutation in which the coexistence of genetic variants in inflammation and oxidative stress may be related to variable expressiveness of the disease.
Sections du résumé
BACKGROUND
Cerebral cavernous malformations (CCMs) are vascular capillary anomalies with a dysfunctional endothelial adherent junction profile, depicting hemorrhage and epilepsy as the main clinical features. With the advent of an increasingly personalized medicine, better comprehension of genetic mechanisms behind CCM represents an important key in the management of the patients and risk rating in relatives. In this context, genetic factors that might influence clinical expressiveness of CCM need to be identified.
CASE DESCRIPTION
A 33-year-old woman harboring multiple CCM lesions with a CCM1 mutational profile already being treated conservatively for a right mesial temporal lobe CCM presented with refractory seizures. Magnetic resonance imaging showed no bleeding in the lesion, and the patient was submitted to complete resection of the CCM. Histopathology of the CCM samples depicted an extensive inflammatory reaction and colocalization of CD20+ and CD68+ cells. Genetic analyses of the patient and her mother demonstrated a novel CCM1 (KRIT1) frameshift mutation (c.1661_1662insT; p.Leu554PhefsTer14). Furthermore, variants in CD14 (rs778588), TLR-4 (rs10759930), SOD2 (rs4880), APEX1 (rs1130409), and OGG1 (rs1052133), known as polymorphisms related to disease aggressiveness, were detected in the patient and not in her oligosymptomatic mother harboring the same CCM1 mutation.
CONCLUSIONS
Heterogeneity of clinical manifestations among individuals with familial CCM with the same genotype adds mechanistic involvement of modifier factors as phenotypic markers. We describe a novel CCM1/KRIT1 familial mutation in which the coexistence of genetic variants in inflammation and oxidative stress may be related to variable expressiveness of the disease.
Identifiants
pubmed: 32113992
pii: S1878-8750(20)30394-6
doi: 10.1016/j.wneu.2020.02.119
pii:
doi:
Substances chimiques
Anticonvulsants
0
KRIT1 Protein
0
KRIT1 protein, human
0
Lipopolysaccharide Receptors
0
TLR4 protein, human
0
Toll-Like Receptor 4
0
Superoxide Dismutase
EC 1.15.1.1
superoxide dismutase 2
EC 1.15.1.1
DNA Glycosylases
EC 3.2.2.-
oxoguanine glycosylase 1, human
EC 3.2.2.-
APEX1 protein, human
EC 4.2.99.18
DNA-(Apurinic or Apyrimidinic Site) Lyase
EC 4.2.99.18
Types de publication
Case Reports
Langues
eng
Sous-ensembles de citation
IM
Pagination
535-540.e8Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.