Project description:Antibodies against IgLON5, a neuronal adhesion protein of unknown function, are markers of a novel neurological disorder termed anti-IgLON5 syndrome. The disorder shows a remarkable association with the HLA-DQB1*0501 and HLA-DRB1*1001 alleles, and postmortem studies demonstrate a novel neuronal tauopathy predominantly involving the hypothalamus and tegmentum of the brainstem. The role of IgLON5 antibodies in the pathogenesis of the disease is currently unknown. Here, we have determined the target epitopes of IgLON5 antibodies, the effects of the IgLON5 antibodies in rat hippocampal neurons, and the IgG subclass responsible for these effects.HEK293 cells expressing several deletion constructs of IgLON5 were used to determine the epitopes recognized by the serum of 15 patients with anti-IgLON5 syndrome. The role of glycosylation in immunogenicity was tested with PNGase F treatment of transfected cells. Dissociated hippocampal neuronal cultures were used to test by immunocytochemistry the effects of total IgG, IgG1, and IgG4 subclasses of IgLON5 antibodies.Patients' antibodies reacted with the immunoglobulin-like domain 2 of IgLON5. Glycosylation was not required for immunoreactivity. The predominant subclass of IgLON5 antibodies was IgG4 but all patients also had IgG1. The mean percentage of specific IgLON5 IgG4 and IgG1 of the samples analyzed by flow cytometry was 64 and 33 %, respectively. In cultures of hippocampal neurons, patients' antibodies caused a decrease of cell surface IgLON5 clusters that was not reversed after IgLON5 antibodies were removed from the media. The decrease of surface IgLON5 clusters correlated with the rate of antibody internalization. These effects were observed with purified IgG1 but not with the IgG4 antibodies.IgLON5 antibodies recognize the immunoglobulin-like domain 2 of the antigen, and the reactivity is not dependent on glycosylation. The effects observed on hippocampal neuronal cultures indicate an irreversible antibody-mediated internalization of surface IgLON5. These effects were mediated by specific IgLON5 IgG1 antibodies and suggest a pathogenic role of these antibodies in the disease.
Project description:RationaleAnti-IgLON5 disease is a complex neurological illness which is characterized by progressive sleep and movement disorders and defined by specific autoantibodies to IgLON5. We here describe the first case of a patient with coexisting anti-IgLON5 as well as anti-?-aminobutyric acid B (GABAB)-receptor antibodies and predominant clinical features of anti-IgLON5 disease.Patient concernsThe patient initially presented with subacute symptoms of severe sleep disorder, gait stability, dysarthria, cognitive impairment, depressive episode and hallucinations.DiagnosesThe patient was diagnosed with autoimmune encephalitis, based on clinical features and positive anti-IgLON5 antibodies in serum as well as in cerebrospinal fluid and anti-GABAB-receptor antibodies in serum only.InterventionsInitially, the patient was treated with high dosages of methylprednisolone and subsequently with plasmapheresis. Due to the lack of clinical improvement immunosuppressive treatment with intravenous cyclophosphamide was initiated.OutcomesFollowing the first year of cyclophosphamide treatment, neurological examination revealed an improvement in gait instability, visual and acoustic hallucinations and sleep disorder.LessonsThe case report demonstrates that anti-IgLON5 and anti-GABAB-receptor antibodies can coexist in the same patient whereas clinical leading symptoms are determined by those antibodies that were tested positive in cerebrospinal fluid.
Project description:Anti-IgLON5 disease is a progressive neurological disorder associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue, the neurodegeneration and accumulation of hyperphosphorylated tau (p-tau) are found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response causing inflammation and antibody formation remains to be elucidated. We investigated the effects of anti-IgLON5 antibodies on human neurons. Human neural stem cells were differentiated for 14-48 days and exposed from Days 9 to 14 (short-term) or Days 13 to 48 (long-term) to either (i) IgG from a patient with confirmed anti-IgLON5 antibodies or (ii) IgG from healthy controls. The electrical activity of neurons was quantified using multielectrode array assays. Cultures were immunostained for β-tubulin III and p-tau and counterstained with 4',6-Diamidine-2'-phenylindole dihydrochloride (DAPI). To study the impact on synapses, cultures were also immunostained for the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin. A lactate dehydrogenase release assay and nuclei morphology analysis were used to assess cell viability. Cultures exposed to anti-IgLON5 antibodies showed reduced neuronal spike rate and synaptic protein content, and the proportion of neurons with degenerative appearance including p-tau (T205)-positive neurons was higher when compared to cultures exposed to control IgG. In addition, cell death was increased in cultures exposed to anti-IgLON5 IgG for 21 days. In conclusion, pathological anti-IgLON5 antibodies induce neurodegenerative changes and cell death in human neurons. This supports the hypothesis that autoantibodies may induce the neurodegenerative changes found in patients with anti-IgLON5-mediated disease. Furthermore, this study highlights the potential use of stem cell-based in vitro models for investigations of antibody-mediated diseases. As anti-IgLON5 disease is heterogeneous, more studies with different IgLON5 antibody samples tested on human neurons are needed.
Project description:Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
Project description:We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define "definite", "probable" and "possible" diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A "definite" diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a "probable" diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A "possible" diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.
Project description:ObjectiveAnti-IgLON5 disease forms an interface between neuroinflammation and neurodegeneration and includes clinical phenotypes that are often similar to those of neurodegenerative diseases. An early diagnosis of patients with anti-IgLON5 disease and differentiation from neurodegenerative diseases is necessary and may have therapeutic implications.MethodsIn our small sample size study we investigated oculomotor function as a differentiating factor between anti-IgLON5 disease and neurodegenerative disorders. We examined ocular motor and vestibular function in four patients suffering from anti-IgLON5 disease using video-oculography (VOG) and a computer-controlled rotational chair system (sampling rate 60 Hz) and compared the data with those from ten age-matched patients suffering from progressive supranuclear palsy (PSP) and healthy controls (CON).ResultsPatients suffering from anti-IgLON5 disease differed from PSP most strikingly in terms of saccade velocity and accuracy, the presence of square wave jerks (SWJ) (anti-IgLON5 0/4 vs. PSP 9/10) and the clinical finding of supranuclear gaze palsy (anti-IgLON5 1/4). The presence of nystagmus, analysis of smooth pursuit eye movements, VOR and VOR suppression was reliable to differentiate between the two disease entities. Clear differences in all parameters, although not always significant, were found between all patients and CON.DiscussionWe conclude that the use of VOG as a tool for clinical neurophysiological assessment can be helpful in differentiating between patients with PSP and patients with anti-IgLON5 disease. VOG could have particular value in patients with suspected PSP and lack of typical Parkinson's characteristics. future trials are indispensable to assess the potential of oculomotor function as a biomarker in anti-IgLON5 disease.
Project description:Stiff limb syndrome (SLS) is a focal variant of the spectrum of stiff person syndrome. Its presentation with stiffness, limb posturing, and freezing-of-gait (FOG)-like episodes, together with the relative rareness of the disorder, make it conceivable that SLS might be misdiagnosed as atypical parkinsonism, in particular, corticobasal syndrome (CBS). To illustrate this, we present two cases of established SLS resembling CBS and discuss the distinguishing features that may alert the clinician to the correct diagnosis, with its obvious therapeutic and prognostic implications.
Project description:Corticobasal syndrome (CBS) is characterized by asymmetric involuntary movements including rigidity, tremor, dystonia, and myoclonus, and often associated with apraxia, cortical sensory deficits, and alien limb phenomena. Additionally, there are various nonmotor (cognitive and language) deficits. CBS is associated with several distinct histopathologies, including corticobasal degeneration, other forms of tau-related frontotemporal lobar degeneration such as progressive supranuclear palsy, and Alzheimer disease. Accurate antemortem diagnosis of underlying pathology in CBS is challenging, though certain clinical and imaging findings may be helpful. Five recent advances in the understanding of CBS are reviewed, including clinical and pathologic features, imaging and CSF biomarkers, the role of specific genes, and the concept of a spectrum of tauopathies.