Several hereditary ischemic small-vessel diseases of the brain have been reported during the last decade. Some of them have ophthalmological, mainly retinal, manifestations. Herein, we report on a family affected by vascular leukoencephalopathy and variable abnormalities of the anterior chamber of the eye.
After the occurrence of a small, deep infarct associated with white matter lesions in a patient with a medical history of congenital cataract and amblyopia, we conducted clinical and neuroradiological investigations in 10 of her relatives.
Diffuse leukoencephalopathy associated with ocular malformations of the Axenfeld-Rieger type was observed in five individuals. Familial genetic analyses led to the identification of a novel missense mutation in the COL4A1 gene, p.G720D, which cosegregates with the disease.
Our data corroborate previous observations demonstrating the role of COL4A1 in cerebral microangiopathy and expand the phenotypic spectrum associated with mutations in this gene. We delineate a novel association between the Axenfeld-Rieger anomaly and leukoencephalopathy and stroke. Ann Neurol 2007.
"E-mail: firstname.lastname@example.org Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2014 DOI 10.1002/ajmg.a.36907 Ó 2015 Wiley Periodicals, Inc. et al., 2006; Sibon et al., 2007; Vahedi et al., 2007; Alamowitch et al., 2009; Bilguvar et al., 2009; De Vries et al., 2009, Shah et al., 2010; Livingston et al., 2011; Meuwissen et al., 2011; Tonduti et al., 2012; Lemmens et al., 2013] "
"For example, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited cause of vascular dementia , is caused by mutations in NOTCH3 , a gene preferentially expressed in vascular smooth muscle , . Furthermore, mutations in COL4A1, a gene encoding the main component of smooth muscle basement membranes, also causes SVD in families with inherited leukoencephalopathy , , . Pathways by which mutant NOTCH3 and COL4A1 lead to smooth muscle dysfunction and SVD are under active investigation. "
[Show abstract][Hide abstract] ABSTRACT: Von Willebrand factor (vWF), a hemostatic protein normally synthesized and stored by endothelial cells and platelets, has been localized beyond the endothelium in vascular disease states. Previous studies have implicated potential non-hemostatic functions of vWF, but signaling mechanisms underlying its effects are currently undefined. We present evidence that vWF breaches the endothelium and is expressed in a transmural distribution pattern in cerebral small vessel disease (SVD). To determine the potential molecular consequences of vWF permeation into the vessel wall, we also tested whether vWF impairs Notch regulation of key smooth muscle marker genes. In a co-culture system using Notch ligand expressing cells to stimulate Notch in A7R5 cells, vWF strongly inhibited both the Notch pathway and the activation of mature smooth muscle gene promoters. Similar repressive effects were observed in primary human cerebral vascular smooth muscle cells. Expression of the intracellular domain of NOTCH3 allowed cells to bypass the inhibitory effects of vWF. Moreover, vWF forms molecular complexes with all four mammalian Notch ectodomains, suggesting a novel function of vWF as an extracellular inhibitor of Notch signaling. In sum, these studies demonstrate vWF in the vessel wall as a common feature of cerebral SVD; furthermore, we provide a plausible mechanism by which non-hemostatic vWF may play a novel role in the promotion of vascular disease.
PLoS ONE 09/2013; 8(9):e75808. DOI:10.1371/journal.pone.0075808 · 3.23 Impact Factor
"Therefore, it comes of no surprise that disturbances of collagen expression is related to severe disorders, such as HANAC (Hereditary Angiopathy, Nephropathy, Aneurysms, and Cramps) syndrome, a COL4A1-related disorder that presents with retinal tortuosity and muscle cramps and with variable combinations of small vessel brain disease , or the “COL4A1 stroke syndrome” . Furthermore, COL4A1 malfunction has been associated with cerebral microangiopathy, the Axenfeld-Rieger anomaly, and leukoencephalopathy and stroke . Collagen XV is pivotal to peripheral nerve maturation. "
[Show abstract][Hide abstract] ABSTRACT: Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.
Electronic supplementary material
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European Archives of Psychiatry and Clinical Neuroscience 03/2012; 262(7):565-77. DOI:10.1007/s00406-012-0306-y · 3.53 Impact Factor
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