A novel CCM2 variant in a family with non‐progressive cognitive complaints and cerebral microbleeds

Abstract

Lobar cerebral microbleeds are most often sporadic and associated with Alzheimer's disease. The aim of our study was to identify the underlying genetic defect in a family with cognitive complaints and multiple lobar microbleeds and a positive family history for early onset Alzheimer's disease. We performed exome sequencing followed by Sanger sequencing for validation purposes on genomic DNA of three siblings with cognitive complaints, reduced amyloid‐beta‐42 in CSF and multiple cerebral lobar microbleeds. We checked for the occurrence of the variant in a cohort of 363 patients with early onset dementia and/or microbleeds. A novel frameshift variant (c.236_237delAC) generating a premature stop codon in the CCM2 gene shared by all three siblings was identified. Pathogenicity of the variant was supported by the presence of cerebral cavernous malformations in two of the siblings and by the absence of the variant exome variant databases. Two siblings were homozygous for APOE‐ϵ4; one heterozygous. The cognitive complaints, reduced amyloid‐beta‐42 in CSF and microbleeds suggest preclinical Alzheimer's disease, but the stability of the cognitive complaints does not. We hypothesize that the phenotype in this family may be due to a combination of the CCM2 variant and the APOE status. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

“…Treatment for patients suffering from CCM's ranges from antiepileptic drugs for seizures to surgical excision for those suffering from seizures or hemorrhage (Günel et al., 1996). It has been shown that in addition to cerebral hemorrhagic strokes and seizures, CCM2 variants have been linked to cerebral microbleeds and suggest a link to preclinical Alzheimer's disease as a result of the CCM2 variant in patients (Cohn-Hokke et al., 2017).…”

Genetic Variants behind Cardiovascular Diseases and Dementia

“…The CMB counts per CMB volume increased as the disease deteriorated, and the CMB counts increased more rapidly in the thalamus, temporal, and frontal lobes [ 67 ]. One study found a frame shift variant (c.236_237delAC) in the CCM2 gene from three siblings with cognition decline, multiple CMBs, and a family history of early onset AD [ 68 ]. Moreover, the homozygous ε4 genotype of APOE was found in two siblings and was heterozygous in a third sibling.…”

“…Moreover, the homozygous ε4 genotype of APOE was found in two siblings and was heterozygous in a third sibling. This study showed that CMBs and dementia may be attributed to the interaction between the CCM2 variant and the APOE genotype [ 68 ]. Polymorphic variants of Aldehyde dehydrogenase 2 ( ALDH2 ) were found to be associated with alcoholic cardiomyopathy and stroke [ 69 ], and hypertensive male carriers of rs671 in the ALDH2 *1/*1 genotype were more likely to have CMBs than ALDH2 *2 allele carriers ( Table 4 ) [ 70 ].…”

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

“…Treatment for patients suffering from CCM's ranges from antiepileptic drugs for seizures to surgical excision for those suffering from seizures or hemorrhage 6 . It has been shown that in addition to cerebral hemorrhagic strokes and seizures, CCM2 variants have been linked to cerebral microbleeds and suggest a link to preclinical Alzheimer's disease as a result of the CCM2 variant in patients 8 .…”