HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Neuronal antibodies in nonparaneoplastic autoimmune cerebellar ataxias.

PURPOSE OF REVIEW: To describe relevant advances in nonparaneoplastic autoimmune cerebellar ataxias (ACA) with neuronal antibodies. RECENT FINDINGS: Apart from metabotropic glutamate receptor 1(mGluR1) antibodies, in recent years, the number of neuronal antibodies against surface antigens in ACA has increased with the description of glutamate kainate receptor subunit 2 (GluK2) antibodies in young patients with cerebellitis. Around 20% of patients with contactin-associated protein-like 2 (CASPR2) encephalitis also present prominent cerebellar ataxia. However, isolate cerebellar ataxia is unusual (<4%). Outcome in patients with neuronal antibodies against surface antigens remains suboptimal despite the cerebellar ataxia probably is antibody-mediated.Concerning neuronal antibodies against intracellular antigens, up to 25% of patients with glutamic acid decarboxylase (GAD) antibodies present transient episodes of vertigo or diplopia that antedate the development of the ACA. There is in-vitro evidence that septin-5 is partially exposed to the membrane and the antibodies may interfere with septin-5 function. The clinical significance of the remaining antibodies against intracellular antigens remains unclear. SUMMARY: The number of antibodies against surface antigens is increasing in ACA, but the response to the immunotherapy remains suboptimal. More studies are needed to clarify the role of most of the antibodies against intracellular antigens described in these patients.

Clinical approach to diagnosis of paraneoplastic neurologic syndromes.

The correct diagnosis of a paraneoplastic neurologic syndrome (PNS) first requires the identification of the syndrome as one of those defined as high-risk (previously called classical) or intermediate-risk for cancer in the 2021 PNS diagnostic criteria. Testing for neuronal antibodies should be restricted to these syndromes as indiscriminate request decreases the diagnostic value of the antibodies. Identifying onconeural (high-risk for cancer) or intermediate-risk for cancer antibodies supports the paraneoplastic diagnosis and mandates the search for an underlying cancer. Tumor screening must follow the published guidelines. Repeated screening is indicated in neurologic syndromes with onconeural antibodies and patients with high-risk for cancer neurologic syndromes unless they present neuronal antibodies which are not associated with cancer. Neuronal antibodies should be screened by immunohistochemistry and confirmed by immunoblot (intracellular antigens) or cell-based assay (CBA) (surface antigens). Positive results only by immunoblot or CBA should be taken with caution. Although the 2021 diagnostic criteria for PNS do not capture all PNS, as they do not allow to diagnose definite PNS neurologic syndromes without neuronal antibodies, the updated criteria represent a step forward to differentiate true PNS from neurologic syndromes that coincide in time with cancer diagnosis without having a pathogenic link.

Development of a Composite Score for the Clinical Assessment of Anti-IgLON5 Disease.

BACKGROUND AND OBJECTIVES: To develop a composite score to assess the severity of the multiple symptoms present in anti-IgLON5 disease. METHODS: The anti-IgLON5 disease composite score (ICS) was designed to evaluate 17 symptoms divided into 5 clinical domains (bulbar, sleep, movement disorders, cognition, and others). Each symptom was scored from 0 (absent/normal) to 3 or 6 (severe) depending on the contribution of the symptom to neurologic disability with a maximum ICS of 69. The ICS was tested in patients from 2 cohorts (Barcelona, Spain, and GENERATE, Germany) that included cases personally seen by the authors (internal) and patients whose ICS was obtained from information of questionnaires completed by the referring neurologists (external). Test-retest and interrater reliabilities of the ICS were assessed by the intraclass coefficient (ICC) and the correlation between the ICS and modified Rankin scale (mRS) with the nonparametric Spearman rank coefficient. The Wilcoxon signed rank test was used to compare the ICS at diagnosis of anti-IgLON5 disease and follow-up in a subset of patients with available clinical information. RESULTS: A total of 86 patients (46 from Barcelona cohort; 40 from GENERATE cohort) were included. The median ICS was 15 (range 2-31). The ICS was higher in the Barcelona cohort than in the German cohort (18 vs 12, p < 0.001), due to higher partial scores in sleep and movement disorder domains. There were no significant differences in the ICS between internal and external patients (15 vs 14, p = 0.96). The ICS correlated with the mRS score (r = 0.429, p < 0.001). Test-retest and interrater reliabilities were excellent with an ICC of 0.997 (95% CI 0.992-0.999) and 0.973 (95% CI 0.925-0.990), respectively. ICS was retested during follow-up in 27 patients, and it was similar to that at diagnosis in 10 clinically stable patients (median ICS at diagnosis 11.5 vs 11.5 at follow-up; p = 1), higher in 8 patients who worsened (12.5 vs 18; p = 0.012), and lower in 9 patients who improved after immunotherapy (14 vs 10; p = 0.007). DISCUSSION: The ICS is a valid method to assess the extension and severity of the different clinical manifestations of anti-IgLON5 disease.

IgLON5 deficiency produces behavioral alterations in a knockout mouse model.

Background: Anti-IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule of unknown function that is highly expressed in the brain. Our aim was to investigate the impact of IgLON5 loss-of-function in evaluating brain morphology, social behavior, and the development of symptoms observed in an IgLON5 knockout (IgLON5-KO) mouse model. Methods: The IgLON5-KO mice were generated using CRISPR-Cas9 technology. Immunohistochemistry on fixed sagittal brain sections and Western blotting brain lysates were used to confirm IgLON5 silencing and to evaluate the presence of other cell surface proteins. Two- month-old IgLON5-KO and wild-type (WT) mice underwent a comprehensive battery of behavioral tests to assess 1) locomotion, 2) memory, 3) anxiety, 4) social interaction, and 5) depressive-like behavior. Brain sections were examined for the presence of anatomical abnormalities and deposits of hyperphosphorylated tau in young adult (2-month-old) and aged (22-month-old) mice. Results: Mice did not develop neurological symptoms reminiscent of those seen in patients with anti-IgLON5 disease. Behavioral testing revealed that 2-month-old IgLON5-KO mice showed subtle alterations in motor coordination and balance. IgLON5-KO females exhibited hyperactivity during night and day. Males were observed to have depressive-like behavior and excessive nest-building behavior. Neuropathological studies did not reveal brain morphological alterations or hyperphosphorylated tau deposits. Conclusion: IgLON5-KO mice showed subtle alterations in behavior and deficits in fine motor coordination but did not develop the clinical phenotype of anti-IgLON5 disease.

Antibodies Against ZSCAN1 in Pediatric and Adult Patients With Non-Paraneoplastic ROHHAD Syndrome.

OBJECTIVES: To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS: Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS: Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION: Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.