Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Giau, Vo Van; Bagyinszky, Eva; Youn, Young Chul; An, Seong Soo A.; Kim, SangYun

doi:10.3390/ijms20174298

Cited by 31 publications

(26 citation statements)

References 165 publications

(287 reference statements)

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“…Moreover, only three genes were analyzed. It is possible that de novo mutations in other genes are also involved in the genetic determination of sporadic forms [16,18,86,87,88,89,90]. The limited number of resolved pedigrees and large number of genetically unexplained EOAD patients indicate that additional causal genes remain to be discovered.…”

Section: Discussionmentioning

confidence: 99%

“…In conclusion, among the distinct mutations in the Asian patients and isolated cases in the Asian population, definite pathogenicity accounted for less than 16%, leaving a large group of autosomal dominant pedigrees genetically unexplained. In addition, our findings suggest that continuing the investigation of families harboring known mutations and the elucidation of the missing genetic etiology in unexplained EOAD patients has a vast potential to improve our understanding about the complexity of AD [1,10,15,90,91]. We also suggest that the use of high-throughput sequencing technologies for patients with EOAD and data integration from other -omics analyses (epigenomics, proteomics, transcriptomics, and metabolomics) might help in better understanding the underlying molecular mechanisms of AD.…”

Section: Discussionmentioning

confidence: 99%

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APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Giau

Bagyinszky

Youn

et al. 2019

IJMS

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The number of patients with Alzheimer’s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with EOAD; only three variants were found in Korean patients with EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for EOAD patients can potentially improve our understanding of the molecular mechanisms of AD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Giau

Bagyinszky

Youn

et al. 2019

IJMS

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“…Common genetic variants in monogenic diseases may contribute to pathological progress in several CSVD subtypes, revealing distinct genetic mechanisms in different subtypes of CSVD. 59 A genome-wide association study found that epidermal growth factor containing fibulin extracellular matrix protein 1 (EFEMP1), tripartite motif 65 (TRIM65), neuralized E3 ubiquitin protein ligase 1 (NEURL1), and programmed cell death 11 (PDCD11) gene polymorphisms were related to the severity of WMH in CSVD. 60 However, there have been few direct genetic studies on the association between VBD and CSVD.…”

Section: Genetic Factorsmentioning

confidence: 99%

“…Genetic studies of sporadic CSVD have demonstrated a high degree of heritability, particularly among patients with young-onset stroke. Common genetic variants in monogenic diseases may contribute to pathological progress in several CSVD subtypes, revealing distinct genetic mechanisms in different subtypes of CSVD [ 59 ]. A genome-wide association study found that epidermal growth factor containing fibulin extracellular matrix protein 1 ( EFEMP1 ), tripartite motif 65 ( TRIM65 ), neuralized E3 ubiquitin protein ligase 1 ( NEURL1 ), and programmed cell death 11 ( PDCD11 ) gene polymorphisms were related to the severity of WMH in CSVD [ 60 ].…”

Section: Mechanisms Underlying the Association Between Iade And Csvdmentioning

confidence: 99%

Association between Intracranial Arterial Dolichoectasia and Cerebral Small Vessel Disease and Its Underlying Mechanisms

et al. 2020

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Intracranial arterial dolichoectasia (IADE), also known as dilatative arteriopathy of the brain vessels, refers to an increase in the length and diameter of at least one intracranial artery, and accounts for approximately 12% of all patients with stroke. However, the association of IADE with stroke is usually unclear. Cerebral small vessel disease (CSVD) is characterized by pathological changes in the small vessels. Clinically, patients with CSVD can be asymptomatic or present with stroke or cognitive decline. In the past 20 years, a series of studies have strongly promoted an understanding of the association between IADE and CSVD from clinical and pathological perspectives. It has been proposed that IADE and CSVD may be attributed to abnormal vascular remodeling driven by an abnormal matrix metalloproteinase/tissue inhibitor of metalloproteinase pathway. Also, IADErelated hemodynamic changes may result in initiation or progression of CSVD. Additionally, genetic factors are implicated in the pathogenesis of IADE and CSVD. Patients with Fabry’s disease and late-onset Pompe’s disease are prone to developing concomitant IADE and CSVD, and patients with collagen IV alpha 1 or 2 gene (<i>COL4A1/COL4A2</i>) and forkhead box C1 (<i>FOXC1</i>) variants present with IADE and CSVD. Race, strain, familial status, and vascular risk factors may be involved in the pathogenesis of IADE and CSVD. As well, experiments in mice have pointed to genetic strain as a predisposing factor for IADE and CSVD. However, there have been few direct genetic studies aimed towards determining the association between IADE and CSVD. In the future, more clinical and basic research studies are needed to elucidate the causal relationship between IADE and CSVD and the related molecular and genetic mechanisms.

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“…The topography of the cranial lesions (such as the incidence, severity, and location) differ depending on the disease origin. For example, in the most common inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), WMH tend to be located in the capsula externa and temporal pole (3). Contrarily, with age-related WMH, the lesions tend to involve the frontal lobes.…”

Section: Introductionmentioning

confidence: 99%

GJA1 Gene Polymorphisms and Topographic Distribution of Cranial MRI Lesions in Cerebral Small Vessel Disease

et al. 2020

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Vascular endothelial cell (EC) and blood–brain barrier (BBB) dysfunction is the core pathogenesis of cerebral small vessel disease (CSVD). Moreover, animal experiments have shown the importance of connexin (Cx)-43 in EC and BBB function. In this study, we recruited 200 patients diagnosed with sporadic CSVD. Initially, we examined imaging scores of white matter hyperintensities (WMH), lacunar infarction (LI), and cerebral microbleeds (CMB). Additionally, we performed next-generation sequencing of the GJA1 gene (Cx43 coding gene) to examine correlation between these single-nucleotide polymorphisms and the burden and distribution of CSVD. Fourteen target loci were chosen. Of these, 13 loci (92.9%) contributed toward risk for cerebellar LI, one locus (7.1%) was shown to be a protective factor for lobar CMB after FDR adjustment. In conclusion, single-nucleotide polymorphisms in the GJA1 gene appear to affect the distribution but not severity of CSVD.

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Genetic Factors of Cerebral Small Vessel Disease and Their Potential Clinical Outcome

Cited by 31 publications

References 165 publications

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

Association between Intracranial Arterial Dolichoectasia and Cerebral Small Vessel Disease and Its Underlying Mechanisms

GJA1 Gene Polymorphisms and Topographic Distribution of Cranial MRI Lesions in Cerebral Small Vessel Disease

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