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 collagenencoding 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.
In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for Ehlers-Danlos syndrome (EDS), the best-known and probably the most common of the disorders featuring joint hypermobility, identifies more than 20 different types of EDS, and highlights the need for a single set of criteria to substitute the previous ones for the overlapping EDS hypermobility type and joint hypermobility syndrome. Joint hypermobility is a feature commonly encountered in many other disorders, both genetic and acquired, and this finding is attracting the attention of an increasing number of medical and non-medical disciplines. In this paper, the terminology of joint hypermobility and related disorders is summarized. Different types of joint hypermobility, its secondary musculoskeletal manifestations and a simplified categorization of genetic syndromes featuring joint hypermobility are presented. The concept of a spectrum of pathogenetically related manifestations of joint hypermobility intersecting the categories of pleiotropic syndromes with joint hypermobility is introduced. A group of hypermobility spectrum disorders is proposed as diagnostic labels for patients with symptomatic joint hypermobility but not corresponding to any other syndromes with joint hypermobility.
The hypermobile type of Ehlers-Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue. It has been described largely in those with musculoskeletal complaints including joint hypermobility, joint subluxations/dislocations, as well as skin and soft tissue manifestations. Many patients report activity-related pain and some go on to have daily pain. Two undifferentiated syndromes have been used to describe these manifestations-joint hypermobility syndrome and hEDS. Both are clinical diagnoses in the absence of other causation. Current medical literature further complicates differentiation and describes multiple associated symptoms and disorders. The current EDS nosology combines these two entities into the hypermobile type of EDS. Herein, we review and summarize the literature as a better clinical description of this type of connective tissue disorder.
To test whether the hypothesis that the Alzheimer's A beta peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a striking reactive gliosis. Over 50% of the transgenic mice die by 12 months of age, half the normal life span of control mice. These data show that A beta is neurotoxic in vivo and suggest that apoptosis may be responsible for the accompanying neuronal loss, the principal underlying cellular feature of Alzheimer's disease.
Background
We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.
Methods
Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.
Results
Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.
Conclusions
In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.
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