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      Periodontal Ehlers–Danlos syndrome is associated with leukoencephalopathy

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          Abstract

          Here, we report brain white matter alterations in individuals clinically and genetically diagnosed with periodontal Ehlers–Danlos syndrome, a rare disease characterized by premature loss of teeth and connective tissue abnormalities. Eight individuals of two families clinically diagnosed with periodontal Ehlers–Danlos syndrome were included in the present study and underwent general physical, dental, and neurological examination. Whole exome sequencing was performed, and all patients included in the study underwent MRI of the brain. Whole exome sequencing revealed heterozygous C1R mutations c.926G>T (p.Cys309Phe, Family A) and c.149_150TC>AT (p.Val50Asp, Family B). All adult individuals ( n = 7; age range 31 to 68 years) investigated by MRI had brain white matter abnormalities. The MRI of one investigated child aged 8 years was normal. The MRI pattern was suggestive of an underlying small vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the neurologic features. Medical history revealed recurrent headaches or depression in some cases. Neurological examination was unremarkable in all individuals but one had mild cognitive decline and ataxia and experienced a seizure. The observation that periodontal Ehlers–Danlos syndrome caused by missense mutations in C1R is consistently associated with a leukoencephalopathy opens a new pathogenic link between the classical complement pathway, connective tissue, brain small vessels, and brain white matter abnormalities.

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          The 2017 international classification of the Ehlers-Danlos syndromes.

          The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.
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            Subcortical ischaemic vascular dementia.

            Vascular dementia is the second most common type of dementia. The subcortical ischaemic form (SIVD) frequently causes cognitive impairment and dementia in elderly people. SIVD results from small-vessel disease, which produces either arteriolar occlusion and lacunes or widespread incomplete infarction of white matter due to critical stenosis of medullary arterioles and hypoperfusion (Binswanger's disease). Symptoms include motor and cognitive dysexecutive slowing, forgetfulness, dysarthria, mood changes, urinary symptoms, and short-stepped gait. These manifestations probably result from ischaemic interruption of parallel circuits from the prefrontal cortex to the basal ganglia and corresponding thalamocortical connections. Brain imaging (computed tomography and magnetic resonance imaging) is essential for correct diagnosis. The main risk factors are advanced age, hypertension, diabetes, smoking, hyperhomocysteinaemia, hyperfibrinogenaemia, and other conditions that can cause brain hypoperfusion such as obstructive sleep apnoea, congestive heart failure, cardiac arrhythmias, and orthostatic hypotension. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)and some forms of cerebral amyloid angiopathy have a genetic basis. Treatment is symptomatic and prevention requires control of treatable risk factors.
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              Defining and categorizing leukoencephalopathies of unknown origin: MR imaging approach.

              To categorize leukoencephalopathies of unknown origin into a few major groups by using magnetic resonance (MR) imaging criteria to facilitate further studies, and to assess the possibility of defining "new" (i.e., until now unknown) disease entities within these major groups.
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                Author and article information

                Contributors
                +43-512-9003-70500 , johannes.zschocke@i-med.ac.at
                +31 20 4444856 , ms.vanderknaap@vumc.nl
                Journal
                Neurogenetics
                Neurogenetics
                Neurogenetics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1364-6745
                1364-6753
                8 December 2018
                8 December 2018
                2019
                : 20
                : 1
                : 1-8
                Affiliations
                [1 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Operative and Restorative Dentistry, , Medical University of Innsbruck, ; Anichstr. 35, 6020 Innsbruck, Austria
                [2 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Clinical Genetics, , VU University Medical Center, ; De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                [3 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Neurology, , Medical University of Innsbruck, ; Anichstr. 35, 6020 Innsbruck, Austria
                [4 ]ISNI 0000000404654431, GRID grid.5650.6, Department of Clinical Genetics, Academic Medical Center, ; de Boelelaan 1118, 1081 HV Amsterdam, The Netherlands
                [5 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Department of Neuroradiology, , Medical University Innsbruck, ; Anichstr. 35, 6020 Innsbruck, Austria
                [6 ]ISNI 0000 0000 8853 2677, GRID grid.5361.1, Division of Human Genetics, , Medical University of Innsbruck, ; Peter-Mayr Str. 1, 6020 Innsbruck, Austria
                [7 ]ISNI 0000 0004 0435 165X, GRID grid.16872.3a, Department of Child Neurology and Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, , VU University Medical Center, ; De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
                Author information
                http://orcid.org/0000-0001-6169-6812
                Article
                560
                10.1007/s10048-018-0560-x
                6411670
                30535813
                0690c9b0-5a93-4239-a49e-d1249ca1c35d
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 5 October 2018
                : 29 November 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: I 2909-B30
                Award Recipient :
                Funded by: Dutch ZonMw TOP
                Award ID: 91211005
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2019

                Genetics
                ehlers–danlos,leukoencephalopathy,small vessel disease,periodontitis,complement 1
                Genetics
                ehlers–danlos, leukoencephalopathy, small vessel disease, periodontitis, complement 1

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