Novel KRIT1/CCM1 and MGC4607/CCM2 Gene Variants in Chinese Families With Cerebral Cavernous Malformations.

Kang Wang,Dengchang Wu,Guohua Zhao,Baorong Zhang

doi:10.3389/fneur.2018.01128

Abstract

Familial cerebral cavernous malformations (CCMs) are autosomal dominant disorders characterized by hemorrhagic strokes, recurrent headache, epilepsy, and focal neurological deficits. Genetic variants in KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3 genes contribute to CCMs. The clinical information of two Chinese families with CCMs was collected. MRI and video-electroencephalography were performed. Genetic variants of CCM1, CCM2, and CCM3 genes were investigated by exome sequencing. The patients were presented with recurrent epilepsy or headache. Susceptibility-weighted images of brains showed many dark dots, while video-electroencephalography revealed many spikes from multiple brain regions of patients. Exome sequencing revealed a novel CCM1 genetic variant (c.1599_1601TGAdel, p.Asp533del) and a novel CCM2 genetic variant (c.773delA, p.K258fsX34) in Family one and Family two, respectively; cosegregation existed in these two families. The two family members presented typical CCMs symptoms. These two novel genetic variants in CCM1 and CCM2 genes were the causation of CCM in the two Chinese families, and our data enriched the genetic variant spectrum of CCM genes.

Highlights

Cerebral cavernous malformations (CCMs) are vascular anomalies characterized by densely packed tortuous microvessels outlined with deficient interstitial brain parenchyma
We described the clinical and neuroradiological findings in two Chinese families with cerebral cavernous malformations (CCMs) and identified two novel genetic variants in CCM1 and CCM2 genes, respectively
susceptibility-weighted images (SWI) of brain MRI taken on July 3, 2017 showed hundreds of dark dots and patches in different sizes distributed across the cerebral hemispheres, cerebellum, and brainstem, which indicates multiple cavernous malformations (Figure 2, upper row)

Summary

Introduction

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 affect the skin and liver, with increased propensity to leak and rupture, causing hemorrhagic strokes, recurrent headache, epilepsy, and focal neurological deficits (1). The prevalence of genetic variants in the three genes is unknown, there are several cases reported in different populations like Italian (5, 6), French (7), Spanish (8), Germany (9, 10), and Japanese (11).

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