Figure 1 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Binding of patient IgG to the Purkinje cell (PC) dendrites (PCD) in the molecular layer (ML), to the PC somata in the PC layer (PCL), and to the PC axons (PCA) in the white matter (WM) on murine cerebellum tissue sections. The observed staining pattern (A) is similar to that observed with anti-Ca/ARHGAP26 (see reference 30 ). Note that PC nuclei, interneurons, and granular cells are spared. Also note that the PCD (B and C) and the PCA (D and E) staining patterns can differ significantly depending on sectional planes. Axonal staining may not be detectable on all sections. GL, Granular cell layer.
Source publication
We report on a serum autoantibody associated with cerebellar ataxia. Immunohistochemical studies of sera from four patients referred for autoantibody testing revealed binding of high-titer (up to 1:5,000) IgG antibodies, mainly IgG1, to the molecular layer, Purkinje cell layer, and white matter on mouse, rat, porcine, and monkey cerebellum sections...
Citations
... Hu [5], Yo [6], Ri [7], CV2/CRPM5 [8], Amphiphysin [9], Ma2 [10]) are more relevant in paraneoplastic cases, various novel antibodies have been identified to explain hitherto unexplained, sporadic ataxia cases (e. g. ITPR1 [11,12], neurochondrin [13], Homer-3 [14,15]). The relevance of AAs in ataxias is strengthened by the recently proposed concept of Latent Autoimmune Cerebellar Ataxia (LACA) highlighting that AAs can occur not only in classical autoimmune ataxia syndromes with (sub-)acute onset, but also in slowly progressive ataxia resembling degenerative cerebellar ataxia (DCA) [16]. ...
... Patients with SCA29 present with infant-onset slowly progressive ataxia, delayed motor development, and Life 2023, 13, 1350 9 of 23 mild cognitive impairment [110]. Furthermore, patients with autoantibodies against IP 3 R1 also develop cerebellar ataxia [111]. The underlying mechanism of SCA15 and SCA29 pathology is likely due to suppressed cytosolic calcium signaling, which results from the loss-of-function of IP 3 R1. ...
In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar ataxias, a heterogeneous group of currently untreatable conditions, have not been identified to have a shared physiology that is a target of therapy. In this review, we propose that perturbations in cerebellar Purkinje neuron intrinsic membrane excitability, a result of ion channel dysregulation, is a common pathophysiologic mechanism that drives motor impairment and vulnerability to degeneration in cerebellar ataxias of widely differing genetic etiologies. We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson’s disease.
... The main limitations of this study are as follows: (i) the number of ISA patients was small, (ii) not all previously reported autoantibodies related to immune-mediated cerebellar ataxia, including anti-kelch-like protein 11 and antiglycine receptor autoantibodies, were investigated in the ISA patient serum samples [33][34][35][36][37][38], (iii) patients with gluten ataxia may not be completely excluded from the cohort, (iv) only serum samples were used. ...
Idiopathic sporadic ataxia (ISA) is the clinical term for nonfamilial ataxia with adult-onset and a slowly progressive course. However, immune-mediated cerebellar ataxia cannot be completely excluded from ISA. The current study investigated the neuropil antibodies against cell-surface antigens and clarified the clinical features and neuroimaging findings of patients with these antibodies. Using tissue-based immunofluorescence assays (TBAs), we examined antibodies against the cerebellum in serum samples from 67 patients who met the ISA diagnostic criteria, including 30 patients with multiple system atrophy with predominant cerebellar features (MSA-C) and 20 patients with hereditary ataxia (HA), and 18 healthy control subjects. According to the TBA results, we divided subjects into three groups: subjects positive for neuropil antibodies, subjects positive for intracellular antibodies only, and subjects negative for antibodies. We compared clinical features and neuroimaging findings in ISA patients among these three groups. The prevalence of neuropil antibodies in ISA (17.9%) was significantly higher than that in MSA-C (3.3%), HA (0%), or healthy subjects (0%). The neuropil antibody–positive ISA patients showed pure cerebellar ataxia more frequently than the other ISA patients. Two neuropil antibody–positive patients showed significant improvement of cerebellar ataxia after immunotherapy. We detected neuropil antibodies in 17.9% of ISA patients. Characteristic clinical features of neuropil antibody–positive ISA patients were pure cerebellar ataxia. Some cases of neuropil antibody–positive ISA responded to immunotherapy.
... In 2014, we described in this journal novel immunoglobulin G (IgG) autoantibodies against the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1; also termed IP3R1 or InsP3R1) in patients with autoimmune cerebellar ataxia [1]. The target antigen was identified by us in 2010 and the antibody initially termed anti-Sj after the index sample code. ...
... Immunohistochemistry (IHC) was performed as previously described [1]. Briefly, 4-μm cryosections of primate cerebellum (Euroimmun, Lübeck, Germany) were incubated for 1 h with diluted patient and control serum or cerebrospinal fluid (CSF) samples, respectively. ...
... In 2014, we reported on ITPR1-IgG/anti-Sj in a woman with a 10-year history of progressive ataxia of the upper limbs, dysarthria, and gaze disturbances. MRI revealed pontocerebellar atrophy [1]. A followup report on this patient was published in 2017 by Berzero et al. [26]. ...
Background
In 2014, we first described novel autoantibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1-IgG/anti-Sj) in patients with autoimmune cerebellar ataxia (ACA) in this journal. Here, we provide a review of the available literature on ITPR1-IgG/anti-Sj, covering clinical and paraclinical presentation, tumour association, serological findings, and immunopathogenesis.
Methods
Review of the peer-reviewed and PubMed-listed English language literature on ITPR1-IgG/anti-Sj. In addition, we provide an illustrative report on a new patient with ITPR1-IgG-associated encephalitis with cognitive decline and psychosis.
Results
So far, at least 31 patients with serum ITPR1-IgG/anti-Sj have been identified (clinical information available for 21). The most common manifestations were ACA, encephalopathy with seizures, myelopathy, and (radiculo)neuropathy, including autonomic neuropathy. In 45% of cases, an underlying tumour was present, making the condition a facultative paraneoplastic neurological disorder. The neurological syndrome preceded tumour diagnosis in all but one case. In most cases, immunotherapy had only moderate or no effect. The association of ITPR1-IgG/anti-Sj with manifestations other than ACA is corroborated by the case of a 48-year-old woman with high-titre ITPR1-IgG/anti-Sj antibodies and rapid cognitive decline, affecting memory, attention and executive function, and psychotic manifestations, including hallucinations, investigated here in detail. FDG-PET revealed right-temporal glucose hypermetabolism compatible with limbic encephalitis. Interestingly, ITPR1-IgG/anti-Sj mainly belonged to the IgG2 subclass in both serum and cerebrospinal fluid (CSF) in this and further patients, while it was predominantly IgG1 in other patients, including those with more severe outcome, and remained detectable over the entire course of disease. Immunotherapy with intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulins, was repeatedly followed by partial or complete recovery. Long-term treatment with cyclophosphamide was paralleled by relative stabilization, although the patient noted clinical worsening at the end of each treatment cycle.
Conclusions
The spectrum of neurological manifestations associated with ITPR1 autoimmunity is broader than initially thought. Immunotherapy may be effective in some cases. Studies evaluating the frequency of ITPR1-IgG/anti-Sj in patients with cognitive decline and/or psychosis of unknown aetiology are warranted. Tumour screening is essential in patients presenting with ITPR1-IgG/anti-Sj.
... The spectrum of onconeural antibodies representing markers for paraneoplastic cerebellar degeneration has been continuously expanded in the past 20 years [1][2][3][4]. A small number of relevant autoantibodies have been identified in patients with non-paraneoplastic cerebellar degeneration: glutamic acid decarboxylase [5], metabotropic glutamate receptor type 1 (mGluR1) [6,7], contactin-associated protein 2 (CASPR2) [8], Rho GTPase activating protein 26/ARHGAP26 [9], inositol-1,4,5-trisphosphate receptor type 1/ITPR1 [10] and, most recently, Homer-3 [11][12][13][14]. The Homer-3 protein can be detected almost exclusively perisynaptically in the cerebellum. ...
Introduction
Subacute cerebellar ataxia combined with cerebrospinal fluid (CSF) pleocytosis is the result of an immune response that can occur due to viral infections, paraneoplastic diseases or autoimmune-mediated mechanisms. In the following we present the first description of a patient with anti-Homer-3 antibodies in serum and CSF who has been diagnosed with paraneoplastic subacute cerebellar degeneration due to a papillary adenocarcinoma of the breast.
Case presentation
A 58-year-old female was admitted to our clinical department because of increasing gait and visual disturbances starting nine months ago. The neurological examination revealed a downbeat nystagmus, oscillopsia, a severe standing and gait ataxia and a slight dysarthria. Cranial MRI showed no pathological findings. Examination of CSF showed a lymphocytic pleocytosis of 11 cells/µl and an intrathecal IgG synthesis of 26%. Initially, standard serological testing in serum and CSF did not indicate any autoimmune or paraneoplastic aetiology. However, an antigen-specific indirect immunofluorescence test (IIFT) revealed the presence of anti-Homer-3 antibodies (IgG) with a serum titer of 1: 32,000 and a titer of 1: 100 in CSF. Subsequent histological examination of a right axillary lymph node mass showed papillary adenocarcinoma cells. Breast MRI detected multiple bilateral lesions as a diffuse tumour manifestation indicative of adenocarcinoma of the breast. Treatment with high-dose methylprednisolone followed by five plasmaphereses and treatment with 4-aminopyridine resulted in a moderate decrease of the downbeat nystagmus and she was able to move independently with a wheeled walker after 3 weeks. The patient was subsequently treated with chemotherapy (epirubicin, cyclophosphamide) and two series of immunoglobulins (5 × 30 g each). This resulted in a moderate improvement of the cerebellar symptoms with a decrease of ataxia and disappearance of the downbeat nystagmus.
Conclusion
The presented case of anti-Homer-3 antibody-associated cerebellar degeneration is the first that is clearly associated with the detection of a tumour. Interestingly, the Homer-3 protein interaction partner metabotropic glutamate receptor subtype 1A (mGluR1A) is predominantly expressed in Purkinje cells where its function is essential for motor coordination and motor learning. Based on our findings, in subacute cerebellar degeneration, we recommend considering serological testing for anti-Homer-3 antibodies in serum and cerebrospinal fluid together with tumor screening.
... The most prevalent symptoms for SCA 15 are gait ataxia, dysarthria, nystagmus and limb ataxia [14]. Anti-ITPR1 antibodies were originally described in patients with autoimmune cerebellar ataxia [10,11]. A more recent publication suggested a broader disease spectrum (see Table 2), including motor, sensory and autonomic symptoms [8,9]. ...
Background:
Recently, antibodies against the alpha isoform of the glial-fibrillary-acidic-protein (GFAPα) were identified in a small series of patients with encephalomyelitis. Coexisting autoantibodies (NMDA receptor, GAD65 antibodies) have been described in a few of these patients. We describe a patient with rapidly progressive encephalomyeloradiculitis and a combination of anti-ITPR1, anti-GFAP and anti-MOG antibodies.
Case presentation and literature review:
A 44-year old caucasian woman with a flu-like prodrome presented with meningism, progressive cerebellar signs and autonomic symptoms, areflexia, quadriplegia and respiratory insufficiency. MRI showed diffuse bilateral T2w-hyperintense brain lesions in the cortex, white matter, the corpus callosum as well as a longitudinal lesion of the medulla oblongata and the entire spinal cord. Anti-ITPR1, anti-GFAP and anti-MOG antibodies were detected in cerebrospinal fluid along with lymphocytic pleocytosis. Borderline tumor of the ovary was diagnosed. Thus, the disease of the patient was deemed to be paraneoplastic. The patient was treated by surgical removal of tumor, steroids, immunoglobulins, plasma exchange and rituximab. Four months after presentation, the patient was still tetraplegic, reacted with mimic expressions to pain or touch and could phonate solitary vowels. An extensive literature research was performed.
Conclusion:
Our case and the literature review illustrate that multiple glial and neuronal autoantibodies can co-occur, that points to a paraneoplastic etiology, above all ovarian teratoma or thymoma. Clinical manifestation can be a mixture of typically associated syndromes, e.g. ataxia associated with anti-ITPR1 antibodies, encephalomyelitis with anti-GFAPα antibodies and longitudinal extensive myelitis with anti-MOG antibodies.
... First, the antibody mainly responded to Purkinje cells, which are known to be a cell type expressed exclusively in the cerebellum, and the patient presented cerebellar ataxia manifestations. Second, the antibody belonged to the IgG1 subclass, a strong complement activator, suggesting that it may act on Purkinje cells via a complement-dependent mechanism, which is well-established feature in other autoantibodyassociated disorders (Jarius et al., 2014, Sven Jarius et al., 2010. Third, CSF analysis displayed inflammatory features and immunosuppressive therapy was followed by clinical stabilization and ataxia improvement. ...
... It is believed that nuclear or cytoplasmic antigens are not accessible to immune attack in situ. Given that antibodies targeting intracellular antigens (e.g., Hu, Yo Ri, Ta) are not pathogenic, it is therefore possible that Rab6A/Rab6B antibody has no such impact (Jarius et al., 2014). ...
In the current study we report a novel autoantibody against Purkinje cells in a patient with primary autoimmune cerebellar ataxia (PACA) associated with Sjogren's syndrome (SS). Tissue-based indirect immunofluorescence assay (TBA) of the patient's serum and cerebrospinal fluid (CSF) revealed IgG antibody to Purkinje cells and the granular layer of the rat cerebellum. Rab6A was identified as autoantigen by mass spectrometry (MS) and Western blotting, and the interactions between Rab6A or its homologous Rab6B and autoantibody in patient serum were verified by recombinant cell-based assay (CBA) and neutralization experiments. This autoantibody may represent a novel biomarker in the diagnosis of PACA.
... Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is an intracellular ligand-gated calcium channel mainly expressed in membranes surrounding the endoplasmic reticulum. It was first identified as an antibody associated with autoimmune cerebellar ataxia in 2014 by Jarius and colleagues after immunohistochemical testing showed binding of IgG1 antibodies in molecular and Purkinje cell layers on animal cerebellum sections in a pattern similar to, but not matching that of, anti-Ca/anti-RhoGTPase-activating protein 26 (ARHGAP26) antibodies (21,37). ...
Movement disorders are a common feature of many antibody-associated neurological disorders. In fact, cerebellar ataxia is one of the most common manifestations of autoimmune neurological diseases. Some of the first autoantibodies identified against antigen targets include anti-neuronal nuclear antibody type 1 (ANNA-1 or anti-Hu) and Purkinje cell cytoplasmic antibody (PCA-1) also known as anti-Yo have been identified in paraneoplastic cerebellar degeneration. Historically these antibodies have been associated with an underlying malignancy; however, recently discovered antibodies can occur in the absence of cancer as well, resulting in the clinical syndrome of autoimmune cerebellar ataxia. The pace of discovery of new antibodies associated with autoimmune or paraneoplastic cerebellar ataxia has increased rapidly over the last few years, and pathogenesis and potential treatment options remains to be explored. Here we will review the literature on recently discovered antibodies associated with autoimmune and paraneoplastic cerebellar ataxia including adaptor protein-3B2 (AP3B2); inositol 1,4,5-trisphophate receptor type 1 (ITPR1); tripartite motif-containing (TRIM) proteins 9, 67, and 46; neurochondrin; neuronal intermediate filament light chain (NIF); septin 5; metabotropic glutamate receptor 2 (mGluR2); seizure-related 6 homolog like 2 (SEZ6L2) and homer-3 antibodies. We will review their clinical characteristics, imaging and CSF findings and treatment response. In addition, we will discuss two clinical case examples of autoimmune cerebellar ataxia.
... Anti-PC antibodies mainly react with antigens in the cytoplasm and dendrites of PCs, so they have certain similarities in the morphology of IHC and are often discussed together. The properties of some anti-PCs antibodies reported are shown in Table 2 (23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). In addition, we also recognize that there are some unknown antibodies associated with ACA. ...
Autoimmune cerebellar ataxia (ACA) is an important cause of sporadic cerebellar ataxia. Technological innovation promotes the rapid development of cerebellar autoimmunity researches in recent years. More and more new antibodies have been proposed to be associated with ACA. Several autoantibodies against Purkinje cells (PCs) have been identified, which constitute the main components. These autoantigens are mainly located in the cytoplasm and dendrites of PCs, and exhibit a specific morphology in immunohistochemistry (IHC). Although the clinical features are relatively homogeneous, there were still some differences among different antibodies. Due to the lack of understanding of the disease and the limited detection technology, it is really difficult to diagnose and manage at present. However, unlike the most of hereditary ataxias, ACA is treatable, and even the neurological dysfunction of some patients may be reversible. Therefore, promptly identification, diagnosis and treatment may benefit some patients. Thus, this article elaborates on the clinical manifestations and laboratory characteristics of anti-PCs-antibody-associated ACA in order to help neurologists to understand ACA more comprehensively. At the same time, combining our previous exploratory work as well as the technology available, we try to propose a diagnostic strategy for ACA the text and the relevant differential diagnosis was illustrated in detail.
... ITPR1 is a ligand-gated calcium channel that has a role in intracellular calcium signalling and coincidence detection; it is particularly expressed on cerebellar PCs. 24 Interestingly, heterogenous deletions or missense mutations in ITPR1 have previously been implicated in spinocerebellar ataxia in humans and dogs. 21,25 It was been suggested that the accumulation of toxic metabolites (3-hydroxy-3-methyglutarate) can activate energy-demanding glutamatergic signalling pathways, resulting in an overexcitation of impaired postsynaptic neurons. ...
Case summary
A rescue charity-owned 6-month-old neutered female domestic shorthair cat was presented with progressive tetraparesis, increased extensor muscle tone and signs of spinocerebellar ataxia, including hypermetria. The cat’s male sibling, with similar progressive neurological signs, had been euthanased 2 months previously. An inherited metabolic disorder was suspected. Urine for determination of organic acid concentration was obtained and the cat was prescribed carnitine and taurine supplementation. The cat was euthanased 3 months later following progressive neurological signs, including ataxia, tetraparesis, tendency to fall, bilateral absent menace response and intention tremor. A selective post-mortem examination was obtained, taking samples from the brain, cervical spinal cord, tibial branch of the sciatic nerve, muscle, liver and kidneys. Organic acid analysis results received after euthanasia revealed a marked elevation of 3-hydroxy-3-methylglutaric acid (45 mmol/mol creatine [normal range 0–2]) and isovalerylglycine (27 mmol/mol creatinine [normal range 0–2]). 3-Hydroxy-3-methylglutaric acid was deemed clinically relevant as it is a metabolite of 3-hydroxy-3-methylglutaryl-CoA lyase, the enzyme involved in the final step of leucine degradation. Post-mortem examination revealed diffuse, chronic-active, severe olivoponto-(spino)-cerebellar degeneration.
Relevance and novel information
This is the first report of 3-hydroxy-3-methylglutaric aciduria in the veterinary literature and the first description of the neuropathology of this disorder in any species. 3-Hydroxy-3-methylglutaric aciduria in humans occurs rarely and is due to a deficiency in 3-hydroxy-3-methylglutaryl-coenzyme A lyase.
