Inositol 1,4,5-trisphosphate receptor type 1 autoantibody (ITPR1-IgG/anti-Sj)-associated autoimmune cerebellar ataxia, encephalitis and peripheral neuropathy: review of the literature

Abstract

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.

Neuronal antibodies in nonparaneoplastic autoimmune cerebellar ataxias

“…Despite they target the similar pathway, the clinical profiles are different. Whereas homer-3 antibodies are associated with a mostly isolated cerebellar ataxia [44], 50% of patients with ITPR1 antibodies present other neurological syndromes and 45% associate with cancer, usually breast or lung adenocarcinomas (Table 2) [45].…”

In Cerebellar Atrophy of 12-Month-Old ATM-Null Mice, Transcriptome Upregulations Concern Most Neurotransmission and Neuropeptide Pathways, While Downregulations Affect Prominently Itpr1, Usp2 and Non-Coding RNA

“…What other pathways were impacted in several components across the cerebellar transcriptome profile of ATM-null mice, given that the hypothesis-free global transcriptomics approach might give novel clues to understanding A-T pathogenesis better? Second messengers downstream from neuropeptide receptors appeared altered, in view of the G-protein signalling factors Rgs4, Rasgrf2 and Gpr165 upregulations [131,161,162], and the dysregulation of calcium modulators Necab1 (up) [163] versus Itpr1 (down, its lossof-function being the cause of autosomal dominant Spinocerebellar Ataxia types 15 and 29, as well as autoimmune cerebellar ataxia) [57,[164][165][166]. The decreased mRNA levels of inositol-trisphosphate receptor Itpr1, and of Cadps2 (the Ca 2+ -dependent release activator for neurotransmitters, neuropeptides and neurotrophins), might be underlying contributors to this generalised pathology, given that loss-of-function of both downregulated factors results in cerebellar ataxia [154,164,[167][168][169].…”

“…Second messengers downstream from neuropeptide receptors appeared altered, in view of the G-protein signalling factors Rgs4, Rasgrf2 and Gpr165 upregulations [131,161,162], and the dysregulation of calcium modulators Necab1 (up) [163] versus Itpr1 (down, its lossof-function being the cause of autosomal dominant Spinocerebellar Ataxia types 15 and 29, as well as autoimmune cerebellar ataxia) [57,[164][165][166]. The decreased mRNA levels of inositol-trisphosphate receptor Itpr1, and of Cadps2 (the Ca 2+ -dependent release activator for neurotransmitters, neuropeptides and neurotrophins), might be underlying contributors to this generalised pathology, given that loss-of-function of both downregulated factors results in cerebellar ataxia [154,164,[167][168][169]. As further coordinators of pathology that are potentially upstream, the deficits of inositol-triphosphate-associated Astn2, Sorl1, and Mpp4 levels could lead to inappropriate localisation of membrane proteins away from the tip of neural processes [170,171].…”