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A growing spectrum of neurological manifestations are being recognized in association with IgLON5 autoimmunity, including recent reports of motor-neuron-disease-like phenotype. Here we describe four cases of IgLON5 autoimmunity with motor neuron involvement and evaluate an additional 109 probable or definite amyotrophic lateral sclerosis cases seen in our neuromuscular clinic for IgLON5-IgG seropositivity. The presence of parasomnias, vocal cord dysfunction or hyperkinetic movements in a patient with motor-neuron-disease-like phenotype should prompt evaluation for IgLON5-IgG autoantibodies. Recognition and treatment of this autoimmune disease with immunosuppressive agents may bring about significant neurological improvement in a minority of cases.

Immune-mediated rippling muscle disease (iRMD) is a rare myopathy characterized by wavelike muscle contractions (rippling) and percussion- or stretch-induced muscle mounding. A serological biomarker of this disease is lacking.To describe a novel autoantibody biomarker of iRMD and report associated clinicopathological characteristics.This retrospective cohort study evaluated archived sera from 10 adult patients at tertiary care centers at the Mayo Clinic, Rochester, Minnesota, and BrighamWomen's Hospital, Boston, Massachusetts, who were diagnosed with iRMD by neuromuscular specialists in 2000 and 2021, based on the presence of electrically silent percussion- or stretch-induced muscle rippling and percussion-induced rapid muscle contraction with or without muscle mounding and an autoimmune basis. Sera were evaluated for a common biomarker using phage immunoprecipitation sequencing. Myopathology consistent with iRMD was documented in most patients. The median (range) follow-up was 18 (1-30) months.Diagnosis of iRMD.Detection of a common autoantibody in serum of patients sharing similar clinical and myopathological features.Seven male individuals and 3 female individuals with iRMD were identified (median [range] age at onset, 60 [18-76] years). An IgG autoantibody specific for caveolae-associated protein 4 (cavin-4) was identified in serum of patients with iRMD using human proteome phage immunoprecipitation sequencing. Immunoassays using recombinant cavin-4 confirmed cavin-4 IgG seropositivity in 8 of 10 patients with iRMD. Results for healthy and disease-control individuals (n = 241, including myasthenia gravis and immune-mediated myopathies) were cavin-4 IgG seronegative. Six of the 8 individuals with cavin-4 IgG were male, and the median (range) age was 60 (18-76) years. Initial symptoms included rippling of lower limb muscles in 5 of 8 individuals or all limb muscles in 2 of 8 sparing bulbar muscles, fatigue in 9 of 10, mild proximal weakness in 3 of 8, and isolated myalgia in 1 of 8, followed by development of diffuse rippling. All patients had percussion-induced muscle rippling and half had percussion- or stretch-induced muscle mounding. Four of the 10 patients had proximal weakness. Plasma creatine kinase was elevated in all but 1 patient. Six of the 10 patients underwent malignancy screening; cancer was detected prospectively in only 1. Muscle biopsy was performed in 7 of the 8 patients with cavin-4 IgG; 6 of 6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 patients whose results were seropositive and who received immunotherapy had complete resolution of symptoms, 1 had mild improvement, and 2 had no change.The findings indicate that cavin-4 IgG may be the first specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in muscle biopsies of patients with iRMD suggests the potential role of this autoantigen in disease pathogenesis.

Background and ObjectivesDiagnostic criteria emphasize the use of sensitive and disease-specific tests to distinguish patients with rapidly progressive dementia (RPD) due to Creutzfeldt-Jakob disease (CJD) vs other causes (mimics). These tests are often performed in specialized centers, with results taking days to return. There is a need to leverage clinical features and rapidly reporting tests to distinguish patients with RPD due to CJD from those due to other causes (mimics) early in the symptomatic course.MethodsIn this case-control series, clinical features and the results of diagnostic tests were compared between mimics (n = 11) and patients with definite (pathologically proven, n = 33) or probable CJD (with positive real-time quaking-induced conversion [RT-QuIC], n = 60). Patients were assessed at Mayo Clinic Enterprise or Washington University from January 2014 to February 2021. Mimics were enrolled in prospective studies of RPD; mimics met the diagnostic criteria for probable CJD but did not have CJD.ResultsMimics were ultimately diagnosed with autoimmune encephalitis (n = 6), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, dural arteriovenous fistula, cerebral amyloid angiopathy with related inflammation, and systemic lupus erythematous with polypharmacy. Age at symptom onset, sex, presenting features, and MRI and EEG findings were similar in CJD cases and mimics. Focal motor abnormalities (49/93, 11/11), CSF leukocytosis (4/92, 5/11), and protein >45 mg/dL (39/92, 10/11) were more common in mimics (p< 0.01). Positive RT-QuIC (77/80, 0/9) and total tau >1149 pg/mL (74/82, 2/10) were more common in CJD cases (allp< 0.01). Protein 14-3-3 was elevated in 64/89 CJD cases and 4/10 mimics (p= 0.067). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (5/9) and CSF (5/10) of mimics; nonspecific antibodies were detected within the serum of 9/71 CJD cases.DiscussionImmune-mediated, vascular, granulomatous, and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies. The detection of atypical features—particularly elevations in CSF leukocytes and protein—should prompt evaluation for mimics and consideration of empiric treatment while waiting for the results of more specific tests.

ObjectiveTo describe a novel autoantibody biomarker of Immune mediated rippling muscle disease (iRMD).BackgroundiRMD is a rare immunotherapy-responsive myopathy characterized by wave-like muscle contractions (rippling) and percussion/stretch-induced muscle mounding. However, serological biomarker of this disease is lacking.Design/MethodsA Retrospective review was done to identify iRMD patients with stored sera in Mayo Neuroimmunology laboratory. Archived sera from IRMD patients were evaluated for a common biomarker of IRMD using phage immunoprecipitation sequencing (PhIP-Seq).ResultsArchival sera from 10 patients with clinical diagnosis of iRMD were retrieved. Whole human proteome PhIP-Seq identified peptides corresponding to different regions of the cavin-4 in sera of iRMD patients. Eight of the ten iRMD cases were positive for cavin-4 IgG by immunofluorescent cell-based-assay (CBA) using cavin-4-transfected COS7 cells. The cavin-4-reactive IgG in all 8 positive sera was of IgG1 subclass. None of the disease control sera (98 immune-mediated myopathy/neuromuscular junction disorders, 20 autoimmune CNS diseases and 123 healthy subjects) contained cavin-4-reactive IgG. Furthermore, none of the iRMD patients' sera were positive for caveolin-3 IgG. The majority of seropositive cases were males (6/8, 75%) with median age of 51 years (range 18-76). Three seropositive patients had co-existing myasthenia gravis (38%). Creatine Kinase was elevated in 6/7 tested patients (median 771 U/L, range: 132-2625 U/L). Muscle biopsy was performed in 7 of the 8 cavin-4 IgG seropositive patients; 6/6 specimens analyzed immunohistochemically revealed a mosaic pattern of sarcolemmal cavin-4 immunoreactivity. Three of 6 seropositive patients who received immunotherapy had complete resolution of symptoms; one had mild improvement and two had no change.ConclusionsCavin-4 IgG is a novel and specific serological autoantibody biomarker identified in iRMD. Depletion of cavin-4 expression in iRMD patient muscle biopsies suggests the potential role of this autoantigen in disease pathogenesis.