Edited by: Paul Pavlidis, University of British Columbia, Canada
Reviewed by: Jun Zhang, Texas Tech University Health Sciences Center, United States; Claudia Vianna Maurer-Morelli, Universidade Estadual de Campinas, Brazil
This article was submitted to Neurogenomics, a section of the journal Frontiers in Neurology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Familial cerebral cavernous malformations (CCMs) are autosomal dominant disorders characterized by hemorrhagic strokes, recurrent headache, epilepsy, and focal neurological deficits. Genetic variants in
Cerebral cavernous malformations (CCMs) are vascular anomalies characterized by densely packed tortuous microvessels outlined with deficient interstitial brain parenchyma. They are the second most prevalent type of vascular malformation, accounting for 10–15% of all vascular malformations in the central nervous system (CNS). These dysplastic capillaries are mainly present in the brain and spine cord, but they may also affect the skin and liver, with increased propensity to leak and rupture, causing hemorrhagic strokes, recurrent headache, epilepsy, and focal neurological deficits (
In this study, we described the clinical and neuroradiological findings in two Chinese families with CCMs and identified two novel genetic variants in
Two pedigrees of the two Chinese families with CCMs were enrolled. This study was approved by the Institutional Review Board of Zhejiang University School of Medicine, and written informed consent was received from all subjects or their family members. The detailed medical history of the family members from the two pedigrees was obtained. Brain MRIs, including susceptibility-weighted images (SWI) and video-electroencephalography (VEEG), were performed in some cases.
Blood samples were collected from all members of these two families, and genomic DNA was extracted using commercial kits and then stored at −20°C. Exome sequencing was performed for
The proband II:1 (Figure
CCM lesions in Family One detected by SWI-MRI. The proband's SWIs (II:1) revealed dot and patchy low intensity lesions on temporal lobe, cerebellum and thalamus (upper row). SWI (II:2) showed 2 popcorn-like lesions in left occipital region and right temporal pole, which were very dark, suggesting chronic bleeding.
The proband's younger sister II:2 complained of chronic intensified and aggravated headaches for over 10 years. T2-weighted images of MRI showed 2 popcorn-like lesions in left occipital region and right temporal pole, and these lesions were hypo-intensities on SWI; those findings suggested chronic bleeding (Figure
The proband II:1 (Figure
CCM lesions detected by SWI-MRI. The proband's SWIs (II:1) revealed dot and patchy low intensity lesions on temporal lobe, cerebellum, and thalamus (upper row). SWIs of the proband's father (I:1) demonstrated more widely-distributed multiple CCMs throughout the cerebrum, cerebellum, and pons (lower row).
The proband's father I:1 was 60-years-old and began to develop episodic fears followed by confusion and motionlessness about 20 years ago; these episodes lasted 2 to 4 min each time and occurred 3 to 5 times per year, but it progressed to 5 to 10 times per month during the past 5 years. Although he took multiple medications, the compliance was poor. Sudden falls accompanied by extreme convulsion and tongue-bites occurred occasionally. He was a heavy alcohol consumer. Neurological examination and routine blood examinations were normal. SWI sequence of brain MRI revealed eight visible CCMs on the left temporal lobe, bilateral frontal lobe, pons, and cerebellum (Figure
In Family One, a novel
Alignment of the sequences of CCM1 protein in different mammalians.
Familial CCMs exhibit more aggressive manifestations and an earlier age of onset when compared with sporadic cases, but familial CCMs are rare, accounting for ~6% of all CCMs. The disease is commonly presented with seizure, headache, and cerebral hemorrhage, but 11–44% patients might be asymptomatic for a long time, sometimes even lifelong (
Familial CCMs follow the autosomal dominant inheritance, and genetic variants of
Currently, over 200 distinct germline genetic variants have been identified as causative genetic variants in the
In Family One, the
In Family Two, the
In conclusion, two novel genetic variants in
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.
Written informed consent to publish the report was obtained from each member of the family.
KW, DW, BZ, and GZ have actively participated in the data acquisition and interpretation, and they all commented and approved the final version of the manuscript. KW analyzed the data and drafted the manuscript. GZ designed the study and revised the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We are grateful to the patients and their family for their contributions to the study.