Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features

Abstract

<jats:sec><jats:title>Objective</jats:title><jats:p>Antibodies against contactin-associated protein-like 2 (CASPR2-Abs) have been described in acquired neuromyotonia, limbic encephalitis (LE) and Morvan syndrome (MoS). However, it is unknown whether these constitute one sole spectrum of diseases with the same immunopathogenesis or three distinct entities with different mechanisms.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A cluster analysis of neurological symptoms was performed in a retrospective cohort of 56 CASPR2-Abs patients. In parallel, immunological features and human leucocyte antigen (HLA) were studied.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Cluster analysis distinguished patients with predominant limbic symptoms (n=29/56) from those with peripheral nerve hyperexcitability (PNH; n=27/56). In the limbic-prominent group, limbic features were either isolated (LE/−; 18/56, 32.1%), or combined with extralimbic symptoms (LE/+; 11/56, 19.6%). Those with PNH were separated in one group with severe PNH and extralimbic involvement (PNH/+; 16/56, 28.6%), resembling historical MoS descriptions; and one group with milder and usually isolated PNH (PNH/−; 11/56, 19.6%). LE/− and LE/+ patients shared immunogenetic characteristics demonstrating a homogeneous entity. HLA-DRB1*11:01 was carried more frequently than in healthy controls only by patients with LE (94.1% vs 18.3%; p=1.3×10<jats:sup>−10</jats:sup>). Patients with LE also had serum titres (median 1:40 960) and rates of cerebrospinal fluid positivity (93.1%) higher than the other groups (p&lt;0.05). Conversely, DRB1*11:01 association was absent in PNH/+ patients, but only they had malignant thymoma (87.5%), serum antibodies against leucine-rich glioma-inactivated 1 protein (66.7%) and against netrin-1 receptor deleted in colorectal carcinoma (53.8%), and myasthenia gravis (50.0%).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Symptoms’ distribution supports specific clinical phenotypes without overlap between LE and MoS. The distinct immunogenetic characteristics shared by all patients with LE and the particular oncological and autoimmune associations of MoS suggest two very different aetiopathogenesis.</jats:p></jats:sec>

Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context

“…In addition, another study, besides replicating the above-mentioned HLA association with LGI1-mediated encephalitis, described an additional association between the HLA-DRB1*11:01∼DQA1*05:01∼DQB1*03:01 haplotype and anti-contactin-associated protein-2 (CASPR2) encephalitis ( Binks et al, 2018 ). Further, it has been recently suggested that the genetics of the HLA cluster may help to stratify anti-CASPR2-related clinical subtypes ( Muñiz-Castrillo et al, 2020 , Binks and Irani, 2020 ). Whether and how the HLA system is involved in the autoimmune encephalitis/psychosis remains an open question and will be an important avenue for future research, especially given the heightened levels of autoantibodies against the NMDA-R in 20% of patients diagnosed with schizophrenia (Jezequel et al, 2017).…”

Fundamental Mechanisms of Autoantibody-Induced Impairments on Ion Channels and Synapses in Immune-Mediated Cerebellar Ataxias

“…This heterogeneous nature in anti-Caspr2 Ab-associated syndrome was subsequently confirmed by Muñiz-Castrillo and colleagues [ 121 ]. In 2020, using cluster analysis on 56 patients, the authors clarified that the anti-Casp2 Ab-associated syndrome was separated into two groups without overlapping, a limbic-predominant group and peripheral nerve hyperexcitability-predominant (PNH) group [ 121 ]. The former group (52%) developed limbic symptoms alone (LE/-) or with extra-limbic symptoms (LE/+).…”

Combining clinical and molecular heterogeneity within CASPR2-antibody mediated diseases: towards the underlying disease biology

“…In the paper by Muñiz-Castrillo, the authors explain the complexity underlying the CASPR2-antibody diseases using a data-driven approach to phenotyping, in parallel with immunological and genetic markers integral to disease pathogenesis. 5 …”

“…In the paper by Muñiz-Castrillo, the authors explain the complexity underlying the CASPR2antibody diseases using a data-driven approach to phenotyping, in parallel with immunological and genetic markers integral to disease pathogenesis. 5 By cluster analysis, 56 patients with CASPR2-antibodies were divided into four groups: (i) a relatively isolated limbic encephalitis (LE) ('LE/-'; n=18), (ii) LE 'plus' non-limbic symptoms, including cerebellar ataxia, movement disorders, dysautonomia and weight loss ('LE/+'; n=11), (iii) a group with severe peripheral nerve hyperexcitability (PNH), plus dysautonomia, dyssomnia and malignant thymoma, but without limbic featuresclosely resembling contemporary descriptions of Morvan's syndrome ('PNH/+'; n=16) 2 and (iv) a less severe form of PNH with only few associated central nervous system (CNS) features ('PNH/-'; n=11). These phenotypes explained some of the variance observed across paraclinical findings, such as inflammation on MRI/cerebrospinal fluid (CSF).…”